This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chiang, J. Y. L. Search for Related Content PubMed PubMed Citation Articles by Chiang, J. Y. L.

Bile Acid Regulation of Gene Expression: Roles of Nuclear Hormone Receptors

Department of Biochemistry and Molecular Pathology, Northeastern Ohio Universities College of Medicine, Rootstown, Ohio 44272

Correspondence: Address all correspondence and requests for reprints to: John Y. L. Chiang, Ph.D., Department of Biochemistry and Molecular Pathology, Northeastern Ohio Universities College of Medicine, 4209 SR 44, P.O. Box 95, Rootstown, Ohio 44272. E-mail: jchiang{at}neoucom.edu

	Abstract

Top Abstract I. Introduction II. Bile Acid Synthesis... III. Nuclear Hormone Receptor... IV. Molecular Mechanisms of... V. Drug Therapies Targeted... VI. Conclusion and Future... Note Added in Proof References

 
Bile acids derived from cholesterol and oxysterols derived from cholesterol and bile acid synthesis pathways are signaling molecules that regulate cholesterol homeostasis in mammals. Many nuclear receptors play pivotal roles in the regulation of bile acid and cholesterol metabolism. Bile acids activate the farnesoid X receptor (FXR) to inhibit transcription of the gene for cholesterol 7-hydroxylase, and stimulate excretion and transport of bile acids. Therefore, FXR is a bile acid sensor that protects liver from accumulation of toxic bile acids and xenobiotics. Oxysterols activate the liver orphan receptors (LXR) to induce cholesterol 7-hydroxylase and ATP-binding cassette family of transporters and thus promote reverse cholesterol transport from the peripheral tissues to the liver for degradation to bile acids. LXR also induces the sterol response element binding protein-1c that regulates lipogenesis. Therefore, FXR and LXR play critical roles in coordinate control of bile acid, cholesterol, and triglyceride metabolism to maintain lipid homeostasis. Nuclear receptors and bile acid/oxysterol-regulated genes are potential targets for developing drug therapies for lowering serum cholesterol and triglycerides and treating cardiovascular and liver diseases.

I. Introduction

II. Bile Acid Synthesis and Regulation

A. Bile acid biosynthetic pathways

B. Regulation of bile acid synthesis and cholesterol homeostasis

C. Bile acid synthesis deficiency

III. Nuclear Hormone Receptor Regulation of Bile Acid Synthesis

A. Structure and function of nuclear hormone receptors

B. Nuclear receptors involved in regulation of genes in bile acid synthesis

C. Nuclear receptor regulation of cholesterol homeostasis

IV. Molecular Mechanisms of Regulation of Bile Acid Metabolism

A. Nuclear receptor-mediated mechanism

B. Cell-signaling mechanism

V. Drug Therapies Targeted to Nuclear Receptors and Genes in Bile Acid Metabolism

A. Bile acid synthesis

B. Bile acid transport

C. Reverse cholesterol transport

D. Cholesterol absorption

VI. Conclusion and Future Perspectives

	I. Introduction

Top Abstract I. Introduction II. Bile Acid Synthesis... III. Nuclear Hormone Receptor... IV. Molecular Mechanisms of... V. Drug Therapies Targeted... VI. Conclusion and Future... Note Added in Proof References

 
CONVERSION OF CHOLESTEROL to bile acids in the liver and biliary excretion of cholesterol for eventual disposal in stool are two major routes for removing excess cholesterol from the body. Recent studies have shown that bile acids not only serve as the physiological detergents that facilitate the absorption, transport, and distribution of lipid-soluble vitamins and dietary fats, but also are the signaling molecules that activate nuclear receptors and regulate bile acid and cholesterol metabolism. In addition, bile acids induce the cytochrome P450 3A (CYP3A) family of cytochrome P450 enzymes that detoxify bile acids, drugs, and xenobiotics in the liver and intestine, and also induce hepatocyte apoptosis. Bile acids are synthesized in the liver, excreted into the bile, reabsorbed in the ileum, and transported back to the liver via portal circulation to inhibit bile acid synthesis by suppressing the gene encoding the rate-limiting enzyme, cholesterol 7-hydroxylase (CYP7A1) (1). The mechanisms of bile acid feedback regulation have been studied in animal and tissue culture models for more than three decades. Recent studies suggest that bile acids are able to activate a bile acid receptor, farnesoid X receptor (FXR), which regulates the target genes in bile acid synthesis, transport, and cholesterol metabolism (2, 3, 4, 5, 6). Oxysterols are derived from cholesterol and bile acid biosynthetic pathways and are potent ligands that activate oxysterol receptor, liver X receptor (LXR), which induces genes involved in reverse cholesterol transport (7, 8, 9). FXR and LXR may coordinately regulate bile acid synthesis and cholesterol homeostasis (10, 11, 12, 13). This review will focus on the molecular mechanisms of nuclear receptor regulation of bile acid and cholesterol homeostasis. Diseases caused by bile acid synthesis defects and the potential drug therapies targeted to nuclear receptors for lowering serum cholesterol levels will also be discussed.

	II. Bile Acid Synthesis and Regulation

Top Abstract I. Introduction II. Bile Acid Synthesis... III. Nuclear Hormone Receptor... IV. Molecular Mechanisms of... V. Drug Therapies Targeted... VI. Conclusion and Future... Note Added in Proof References

 
A. Bile acid biosynthetic pathways
The conversion of cholesterol to bile acids occurs exclusively in hepatocytes by a cascade of 12 reactions catalyzed by enzymes located in the endoplasmic reticulum, mitochondria, cytosol, and peroxisomes. Detailed descriptions of the reactions and enzymes involved in bile acid biosynthetic pathways can be found in recent reviews (1, 14, 15, 16, 17). Figure 1 shows several of the intermediates and important regulatory enzymes in two major bile acid biosynthetic pathways. The main bile acid biosynthetic (classic or neutral) pathway is initiated by CYP7A1, which is only expressed in the liver, whereas the alternative (or acidic) pathway is initiated by sterol 27-hydroxylase (CYP27A1), which is expressed in many tissues. In the classic pathway, modifications of the steroid nucleus, including hydroxylation at 7- and 12-positions, epimerization of the 3ß-hydroxyl group, and saturation of the steroid nucleus, precede the oxidative cleavage of a three-carbon side chain. In the alternative pathway, oxidative cleavage of the side chain precedes the modifications of the steroid nucleus. Cholic acid (CA) and chenodeoxycholic acid (CDCA) are two major primary bile acids found in human bile.

View larger version (28K): [in this window] [in a new window]   Figure 1. Bile acid biosynthetic pathways in the liver. Two major bile acid biosynthetic pathways are shown. Only major regulatory enzymes, CYP7A1, CYP8B1, CYP27A1, CYP7B1, and 3ß-HSD, and their substrates and products are shown.

2. The alternative or acidic pathway.
The alternative pathway was originally suggested by the identification of many acidic intermediates, which were not intermediates of the classic pathway (21, 22). The alternative pathway produces mainly CDCA (23, 24). In this pathway, CYP27A1 converts cholesterol to both 27-hydroxycholesterol and 3ß-hydroxy-5-cholestenoic acid (25). Oxysterol 7-hydroxylase (CYP7B1) then converts these two intermediates to 7,27-dihydroxycholesterol and 3ß,7-dihydroxy-5-cholestenoic acid, respectively. It is believed that the same enzymes of the classic pathway catalyze subsequent modifications of the sterol nucleus (26). Recent studies suggest that the acidic pathway also produces CA (27, 28, 29).

The relative contribution of the acidic pathway to overall bile acid synthesis is not certain. Metabolites of the acidic pathway are accumulated in patients with chronic liver diseases and are an indication of a larger contribution of this pathway to bile acid synthesis (21). The acidic pathway may contribute as much as 50% of total bile acid synthesis in primary cultures of rat and human hepatocytes (30). However, the alternative pathway contributes only less than 18% of total bile acid synthesis in humans (31). The neutral pathway is highly regulated and is stimulated by bile fistula or by feeding cholestyramine, a bile acid-binding resin, whereas the acidic pathway is not induced as much (32, 33, 34). In Cyp7a1-/- mice, bile acid synthesis is markedly reduced and the acidic pathway may be activated after weaning to provide 7-hydroxylated bile acids (35, 36). In contrast, bile acid synthesis, pool size, and composition are not altered in Cyp7b1-/- mice (37), and Cyp7a1 expression is increased to maintain bile acid homeostasis. These genetic knockout experiments support the suggestion that the neutral pathway involving CYP7A1 is the major regulated pathway, whereas the acidic pathway involving CYP7B1 is a constitutive pathway (37).

B. Regulation of bile acid synthesis and cholesterol homeostasis
The rate of bile acid synthesis parallels the activity of CYP7A1, which is the only rate-limiting enzyme of the bile acid biosynthetic pathway (19). Interruption of enterohepatic circulation of bile acids by biliary diversion or treatment with bile acid sequestrants increases the rate of bile acid synthesis and the activity of CYP7A1 by about 3- to 4-fold. Intraduodenal infusion of bile acids inhibits the rate of bile acid synthesis to the normal level (19). Enterohepatic circulation of bile acids is the most important physiological mechanism for controlling the overall rate of bile acid biosynthesis (38).

1. Bile acid feedback regulation of bile acid synthesis.
Bile acids excreted from the liver are reabsorbed in the intestine and transported back to the liver by a process called enterohepatic circulation of bile (39, 40). Conjugated bile acids synthesized in the liver are excreted into the bile canaliculi and stored in the gallbladder. After each meal, gallbladder contraction releases bile acids into the intestine for digestion of fats. Portions of CA and CDCA are converted to the secondary bile acids, deoxycholic acid (DCA) and lithocholic acid (LCA), respectively, by 7-dehydroxylase in the bacterial flora. These bile acids, with the exception of LCA, are efficiently reabsorbed in the ileum (41) and transported back to hepatocytes via portal venous circulation (42, 43, 44). Bile acids bind to hepatic bile acid-binding proteins and are transported to canalicular membrane for secretion into bile (45). This process is repeated several times after each meal and reabsorbs about 95% of bile acids in humans. The remaining 5% lost in feces is replenished by de novo bile acid synthesis. The details of bile acid transport systems in hepatocytes and intestine can be found in recent reviews (40, 46, 47, 48, 49).

2. Cholesterol homeostasis in the liver.
Figure 2 illustrates the central role that the liver plays in maintaining cholesterol homeostasis. Major pathways for input and output of cholesterol are shown. Four major cholesterol input mechanisms in the liver are 1) uptake serum cholesterol esters by a low-density lipoprotein (LDL) receptor-mediated endocytosis; 2) reverse cholesterol transport from peripheral tissues to the liver by the selective uptake of high-density lipoprotein (HDL) by the scavenger receptor subtype B1 (SR-B1) (50, 51); 3) absorption of dietary cholesterol in intestine and transport to the liver as chylomicrons (CM) by LDL receptors-mediated mechanism; and 4) de novo synthesis of cholesterol from acetyl-coenzyme A (CoA).

View larger version (84K): [in this window] [in a new window]   Figure 2. Bile acid synthesis and cholesterol homeostasis. Liver synthesizes cholesterol from acetyl-CoA, and HMG-CoA reductase is the rate-limiting enzyme of the pathway. The cholesterol pool in the liver is contributed by four input mechanisms. Serum cholesterol esters (CE) carried by LDL and IDL are taken up into the liver by LDL receptor (LDLR) or LDL receptor-related protein (LRP)-mediated endocytosis. Oxidized LDL is taken up into peripheral tissues by scavenger receptors SR-A1 and CD34. CEs are hydrolyzed to free cholesterol by cholesterol ester hydrolase (CEH) in peripheral tissues. Excess cholesterol is effluxed from peripheral tissues by ABCA1 transporter to form HDL. Lecithin-cholesterol acyltransferase (LCAT) converts cholesterol to CE, which is selectively taken up into the liver by HDL receptor, SR-B1. Dietary free cholesterol (FC) is absorbed into intestine and is reesterified to CEs by acyl-CoA-cholesterol acyltransferase 2 (ACAT2). CEs, ApoB48, and triglycerides are assembled to form chylomicron (CM). Triglycerides in CM are hydrolyzed by lipoprotein lipase (LPL) in the capillary of the adipose and muscle tissues to form free fatty acids, and CM is converted to chylomicron remnants (CMR). CEs in CMRs are taken up into liver by LDL receptor and LRP (apoE receptors). Two mechanisms are involved in output of cholesterol. Of the daily cholesterol catabolized, about 50% is converted to bile acids, which facilitate the excretion of 40% cholesterol into bile. The canalicular transport system is illustrated in detail in Fig. 4. Bile acids, cholesterol, and phospholipids form mixed micelles in the gallbladder (not shown), and are secreted into the intestine after each meal. About 95% of the bile acids are reabsorbed in the ileum, excreted into portal circulation, and up-taken into hepatocytes by sodium-dependent taurocholate cotransport peptide (NTCP). CEs, triglycerides, and ApoB100 are assembled to form VLDL in the liver. VLDL excreted in the serum is subsequently converted to IDL, LDL, and oxidized LDL. They are taken up by scavenger receptors, SR-A1 or SR-B1, into macrophages for disposal or into liver or adrenal for synthesis of bile acids or sex hormones.

Hydrophobic bile acids are toxic if accumulated in large quantities in hepatocytes. Therefore, bile acid synthesis and transport must be tightly regulated. Cholesterol is important for synthesis of bile acids, biological membranes, and steroid hormones, and its homeostasis needs to be maintained in tissues. The liver plays a central role in maintaining bile acid and cholesterol homeostasis. Interruption of the enterohepatic circulation of bile acids leads to an increase in bile acid synthesis and a reduction of plasma LDL cholesterol concentration (52, 53). Increased input of cholesterol and decreased output of bile acids may cause hypercholesterolemia, atherosclerosis, cholestasis, and cholelithiasis in humans (38, 46, 54).

3. Oxysterol regulation of cholesterol homeostasis.
Oxysterols are potent regulators of cholesterol synthesis and lipid metabolism (55). Oxysterols are derived from cholesterol, and the intermediates of the cholesterol and bile acid synthesis pathways by either enzymatic or nonenzymatic oxidations (7, 56). The most abundant oxysterols in human plasma are 27-hydroxycholesterol, 24(S)-hydroxycholesterol, and 7-hydroxycholesterol, which are generated predominately by CYP27A1 in the lung (57), sterol 24-hydroxylase in the brain (58, 59), and CYP7A1 in the liver, respectively. Another abundant oxysterol, 25-hydroxycholesterol, is synthesized by microsomal sterol 25-hydroxylase, a noncytochrome P450 enzyme (60). Oxysterols regulate cholesterol and fatty acid syntheses through a mechanism involving sterol response element-binding proteins (SREBPs) (61, 62, 63). When oxysterol levels are low in cells, SREBP is translocated from endoplasmic reticulum to the Golgi where the N-terminal 58-kDa fragment is cleaved by sterol-sensitive proteases, which are regulated by SREBP cleavage-activating protein. The matured SREBP enters the nucleus and binds to the sterol response elements of LDL receptor, 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, and other genes in cholesterol and fatty acid synthesis (63, 64, 65, 66, 67). In liver and peripheral tissues, CYP7B1 hydroxylates 27- or 25-hydroxycholesterol, whereas another 7-hydroxylase, CYP39A1, hydroxylates 24-hydroxycholesterol (68). It has been reported that the recombinant human CYP7A1 can function as an CYP7B1 of 20S-, 24-, 25-, or 27-hydroxycholesterol (69, 70). Conversion of monohydroxycholesterols to dihydroxycholesterols reduces the toxicity of monohydroxyl oxysterols. In atherosclerotic plaques, 27-hydroxycholesterol, 7-ketocholesterol, and 7ß-, and 7-hydroxycholesterol are the most abundant oxysterols, which cause foam cell formation from macrophages and lead to atherosclerosis in humans (56). Some oxysterols in peripheral tissues are excreted to circulation, transported to the liver, and converted to bile acids. This is a process analogous to reverse cholesterol transport and has been suggested as a defense against atherosclerosis in humans (71, 72).

C. Bile acid synthesis deficiency
1. Inborn errors of bile acid biosynthesis.
Several inborn errors of bile acid synthesis have been described in infants and children with various clinical presentations including advanced liver diseases, neonatal hepatitis, progressive cholestasis, and biliary atresia (73, 74, 75). Primary defects in bile acid synthesis may result in decreased bile formation, malabsorption of fat-soluble vitamins and fats, and accumulation of toxic, abnormal steroid intermediates in the liver, which may interfere with bile acid transport processes and lead to cholestasis and cirrhosis (76). The primary defects in bile acid biosynthesis are the defects in modifications of the sterol nucleus, including 3ß-HSD (77, 78, 79) and ⁴-3-oxosteroid-5ß-reductase deficiencies (80, 81), and the defects in side-chain oxidation due to CYP27A1 gene mutations (82). Defects in peroxisome biogenesis and enzymes in peroxisomal ß-oxidation may manifest as the secondary defect in bile acid synthesis, including Zellweger syndrome and related infantile Refsum disease and neonatal adrenoleukodystrophy (83). A defect in de novo cholesterol synthesis also causes the secondary defect in bile acid synthesis, the Smith-Lemli-Opitz syndrome due to a defect in 7-dehydrocholesterol ⁷-reductase (84, 85). Defects in bile acid transporters or 3ß-HSD cause progressive familial intrahepatic cholestasis (40, 46, 74, 77).

2. Deficiency of 7-hydroxylases.
Mice deficient in Cyp7a1 activity have been obtained by knockout of the Cyp7a1 gene (35). These mice display a complex phenotype including oily coats, hyperkeratosis, vision defects, and behavioral irregularities, which are consistent with malabsorption of vitamins E and D₃. Most Cyp7a1-/- mice died within 18 d; 40% of them died between d 1 and 4, and 45% died between d 11 and 18. Vitamin supplement to nursing mothers prevented deaths in the early period, and bile acid supplement prevented deaths in the later period. However, several 7-hydroxylated bile acids were detected in the bile and stool of adult Cyp7a1-/- mice. This was explained by the expression of hepatic CYP7B1 after weaning and accounted for the synthesis of abnormal 7-hydroxylated bile acids in these mice. The newborn Cyp7a1-/- mice developed neonatal cholestasis, which may be due to accumulation of monohydroxylated bile acids, 3-hydroxy-5-cholenoate and 3-hydroxy-5ß-cholanoate, and 27-hydroxycholesterol (86). An inherited deficiency of CYP7A1 has not been described in the literature (see Note Added in Proof, no. 1).

The CYP7A1 is a candidate gene for familial hypertriglyceridemia (87), gallstone disease (88, 89, 90), and hypercholesterolemia (52, 91). Several single-stranded conformation polymorphisms of the CYP7A1 have been identified (92). Polymorphisms in the 5'-flanking region and coding region were reported (93, 94). Genetic linkage analysis indicates a significant linkage between CYP7A1 and high plasma LDL-cholesterol concentrations (95). Two polymorphisms in the 5'-flanking region (-278CA and -554CT) may contribute to heritable variation in plasma LDL-cholesterol concentrations. The -278C alleles are associated with increased plasma LDL cholesterol concentration.

Setchell et al. (96) reported an inborn error of bile acid metabolism due to a defect of CYP7B1 in a child with severe neonatal cholestasis and cirrhosis. The absence of primary bile acid conjugates and accumulation of 3ß-hydroxy-⁵-cholenoic acids, the products of the acidic pathway, in serum and urine indicated a defect in 7-hydroxylation. In addition, the 27-hydroxycholesterol levels were 4500-fold higher than normal; however, there were no 7-hydroxylated bile acids. Neither CYP7A1 nor CYP7B1 activities were detectable. Analysis of the CYP7B1 identified a C-to-T mutation in exon 5, which converts Arg388 to a premature termination codon. The mechanism of liver injury in this patient is likely due to the accumulation of high levels of hepatotoxic monohydroxylated bile acids. These monohydroxylated bile acids may inhibit bile acid transport across canalicular membranes and reduce bile flow. There is no mutation in the coding exons of the CYP7A1 gene in this patient. It is possible that CYP7A1 may not be expressed in the neonatal human liver, and bile acid synthesis in early human development may proceed mainly via the acidic pathway (96).

3. Deficiency of CYP27A1.
Mutations of the CYP27A1 have been found in patients with cerebrotendinous xanthomatosis (CTX), a rare autosomal recessive defect of cholesterol metabolism manifested by tendon xanthomatosis, progressive neurological dysfunction, accumulation of cholesterol in the tissues, premature atherosclerosis, osteoporosis, and cholesterol gallstones (18, 82, 97). The defect leads to excessive accumulation of 7-hydroxycholesterol, 7-hydroxy-4-cholesten 3-one, 5ß-cholestane-3, 7, 12-triol, cholesterol, and cholestanol. The synthesis of bile acids, particularly CDCA, is reduced and leads to up-regulation of CYP7A1 and the accumulation of both 7-hydroxycholesterol and 7-hydroxy-4-cholesten-3-one. The precursor 7-hydroxy-4-cholesten-3-one is converted to cholestanol. Despite the normal circulating cholesterol levels in CTX patients, they develop xanthoma and premature atherosclerosis. This may be due to the reduced elimination of cholesterol from macrophages by CYP27A1. Mutations in the CYP27A1 of CTX patients have been identified (82, 98). CDCA therapy has been used to prevent or reverse neurological symptoms associated with this disease. Despite the link of CYP27A1 mutations to CTX, the etiology of this disease is still not known. Disruption of the Cyp27a1 gene in mice markedly reduced bile acid synthesis and fecal bile acid excretion by 80% (99). However, Cyp27a1-/- mice do not accumulate cholestanol and do not exhibit the progressive neurological defects observed in human CTX patients. The Cyp27a1-/- mice have enlarged livers and kidneys and have increased triglyceride levels, fatty acid synthesis, cholesterol absorption, and cholesterol synthesis (100). SREBP expression in livers of Cyp27a1-/- mice is elevated. Feeding CA reverses hepatomegaly and hypertriglyceridemia. It is concluded that CYP27A1 plays an important role in triglyceride metabolism.

	III. Nuclear Hormone Receptor Regulation of Bile Acid Synthesis

Top Abstract I. Introduction II. Bile Acid Synthesis... III. Nuclear Hormone Receptor... IV. Molecular Mechanisms of... V. Drug Therapies Targeted... VI. Conclusion and Future... Note Added in Proof References

 
Bile acid synthesis is highly regulated by many factors, including diets, nutrients, bile acids, and hormones, mainly by regulating CYP7A1 gene transcription (1). Many liver-specific transcription factors, mostly nuclear receptors, have been found to bind to and play important roles in regulating CYP7A1 transcription (1, 101, 102, 103, 104, 105, 106, 107, 108). Analysis of nucleotide sequences of two bile acid response elements (BAREs) identified in the rat CYP7A1, BARE-I (109) and BARE-II (110), revealed many AGGTCA-like repeating sequences. Chiang and co-workers (108) first reported that these hormone response elements in the BAREs bound retinoic acid receptor (RAR), chicken ovalbumin upstream promoter-transcription factor II (111, 112), hepatocyte nuclear factor 4 (HNF4) (108, 112), and peroxisome proliferator-activated receptor (PPAR) (113). They suggested that nuclear receptors might be involved in regulation of basal transcription as well as bile acid feedback regulation of the CYP7A1 gene (1, 109, 110). Subsequently, the rat CYP7A1 was identified as the first target gene of oxysterol receptor, LXR (9), and bile acid receptor, FXR (4, 5, 6). Further studies also identified pregnane X receptor (PXR), -fetoprotein transcription factor (FTF), and small heterodimer partner (SHP) as the bile acid-regulated nuclear receptors. Nuclear receptors involved in bile acid and cholesterol metabolism are described below.

A. Structure and function of nuclear hormone receptors
Nuclear receptors have a typical modular structure (Fig. 3), which contains a highly conserved DNA-binding domain in the N-terminal region and a moderately conserved ligand-binding domain in the C-terminal region. Ligand-independent activation function-1 and ligand-dependent activation function-2 are located in the N-terminal and C-terminal regions, respectively. Two cysteine-coordinated Zn²⁺ finger motifs located in the DNA-binding domain are directly involved in DNA binding and dimerization. The E region is also involved in dimerization and coregulator interaction. Nuclear receptors bind to the consensus hormone response elements located in genes. Upon ligand binding, nuclear receptors undergo conformational changes to release corepressors and recruit coactivators to bind to the activation function-2 helix (114, 115).

View larger version (31K): [in this window] [in a new window]   Figure 3. The general structures of nuclear hormone receptors. Upper figure shows the domain structure of a nuclear receptor. It contains activation function domain 1 (AF1), DNA binding domain (DBD), hinge region (D), ligand binding domain (LBD), and activation function domain 2 (AF2). With the exception of estrogen receptors (ERs), all classical steroid hormones receptors, i.e., glucocorticoid receptor (GR), mineralocorticoid receptor (MR), progesterone receptor (PR), androgen receptor (AR), bind to the palindromic repeating sequence, AGAACAN3TGTTCT. ERs bind to a direct repeat (DR) of the AGGTCA motif. Nonsteroid receptors bind to the DR, inverted repeat (IR), or everted repeat (ER) spacing by one to five nucleotides. LXRs, FXR, PPARs, retinoic acid receptors (RARs), and PXR form heterodimers with RXRs and bind to DR, ER or IR sequences as indicated. HNF4 binds to DNA as homodimers. NR5A2 monomeric receptors, -FTF, CPF, and LRH bind to an extended half-site preceded by a A/T-rich sequence.

B. Nuclear receptors involved in regulation of genes in bile acid synthesis
Nuclear receptors that have been identified to regulate genes in bile acid synthesis pathways and cholesterol metabolism are listed in Table 1 and described in detail below. These nuclear receptors are selectively expressed in the enterohepatic and peripheral tissues involved in bile acid synthesis, absorption, and transport, as well as cholesterol and lipoprotein transport (13). The NR1 family of nuclear receptors, including PXR, PPAR, LXR, and FXR, are activated by micromolar concentrations of bile acids, lipids, or steroids, which are 1000-fold higher than that for activation of the classic steroid hormone receptors, but are within the physiological or pathological concentrations.

RAR/RXR has been shown to bind to a DR5 motif and stimulates rat Cyp7a1 transcription (108, 120). Liver-specific disruption of Rxr in mice alters the expression of Cyp7a1, ApoaI, and ApocIII genes in liver (121). Cyp7a1 mRNA levels increase more than 8-fold in Rxr-/- compared with wild-type mice. This suggests that Cyp7a1 expression in the liver is under negative control mediated predominately by RXR and its partners FXR and PPAR. These two nuclear receptors negatively regulate CYP7A1 transcription. When fed a diet high in cholesterol, Cyp7a1 mRNA expression levels increase less than 2-fold in Rxr-/- mice, much less than the 4- to 5-fold increase in wild-type mice. This implies that the inhibitory effect, presumably by FXR and PPAR, must dominate over the stimulatory effect by LXR (122). This study reveals that RXR is involved in diverse physiological pathways regulating cholesterol, bile acids, and fatty acids, as well as steroid metabolism and homeostasis.

2. LXR (NR1H3).
NR1H3 subfamily receptors are activated by oxysterols (8, 123, 124). LXR has two isoforms, LXR (or RLD-1) (123, 125) and LXRß (UR, NER, RIP15, and OR-1) (126, 127, 128, 129). LXR is expressed in liver, spleen, adipose tissue, lung, and pituitary, whereas LXRß is expressed ubiquitously. Many oxysterols have been identified as the ligands of LXR (130). Among naturally occurring oxysterols, 22 (R)-hydroxycholesterol, 24 (S)-hydroxycholesterol, and 24 (S), 25-epoxycholesterol are the most potent LXR ligands. However, the physiological relevance of these oxysterols as the LXR ligands is not certain. The most abundant oxysterol in circulation, 27-hydroxycholesterol, has been shown to be a LXR ligand and may be the more relevant natural LXR ligand (131). In addition, 6-hydroxy bile acid analogs and cholestenoic acid have been identified as the selective ligands of LXR (132, 133).

LXR can act as either a positive or a negative regulator by binding different metabolites of the mevalonate pathway (134). LXR binds to a DR4 and stimulates rat CYP7A1 transcription (9). In Lxr-/- mice, the Cyp7a1 mRNA level is expressed normally in the liver, but is not stimulated by a high-cholesterol diet as in the wild-type mice (122), which leads to massive accumulation of cholesterol in the liver. Lxrß apparently is unable to compensate for Lxr deficiency in Lxr-/- mice. It was concluded that LXR might function as a cholesterol sensor, which stimulates Cyp7a1 expression to convert excess cholesterol to bile acids in response to high cholesterol (8, 9). However, LXR has much less effect on hamster and human CYP7A1, which lacks a DR4 motif (109). Therefore, the rat and mouse are unique in that they have the ability to efficiently convert excess cholesterol to bile acids by LXR-mediated stimulation of Cyp7a1 transcription. The role of LXR in regulation of CYP7A1 in humans remains elusive. In Lxr-/- mice, Srebp-1 and stearyl-CoA desaturase mRNA are reduced, suggesting that LXR plays a role in regulating triglyceride synthesis (122). This is confirmed by the identification of an LXR response element in SREBP-1c gene (135). Endogenous oxysterols derived from mevalonate pathway, most likely 24(S), 25 epoxycholesterol, activates LXR and induces SREBP-1c, which stimulates lipogenesis and leads to hypertriglyceridemia (136). This may explain why LXR-selective ligands induce SREBP-1c and hypertriglyceridemia in mice and hamsters (137). Disruption of Lxrß does not result in accumulation of cholesterol esters on a high-cholesterol diet as was observed in Lxr-/- mice (138).

Wild-type mice treated with a rexinoid, LG268, exhibit marked changes in cholesterol homeostasis including inhibition of intestinal cholesterol absorption and repression of bile acid synthesis (139). The observation that LG268 reduces Cyp7a1 mRNA levels is consistent with the report that CYP7A1 gene transcription is repressed by LG268 in transfection assays in HepG2 cells (140), and that the negative effect of RXR/FXR must dominate over the positive effect of RXR/LXR (121). Interestingly, the levels of mRNA hybridized with Abca1 cDNA probe in the intestine are increased. These authors suggest that rexinoids prevent the accumulation of cholesterol in liver and serum by both depleting bile acids, thus reducing intestinal reabsorption of cholesterol, and by Lxr induction of Abca1 transporter that efflux cholesterol from enterocytes. ATP-binding cassette transporter type A1 (ABCA1) functions as a cholesterol and phospholipid efflux regulator involved in HDL synthesis. Mutations of the ABCA1 gene have been identified in Tangier disease patients (141). However, the identity of ABCA1 transporter as a cholesterol efflux regulator in the intestine has not been firmly established. It has been reported that knockout of Abca1 gene in mice reduces intestinal cholesterol absorption (142). In complete contradiction, another laboratory reported increase of cholesterol absorption by ablation of the Abca1 gene (143). Recently, studies of sitosterolemia, an autosomal recessive disorder characterized by an increased intestinal absorption and decreased biliary excretion of dietary sterols, hypercholesterolemia, and premature coronary atherosclerosis, have identified mutations in the genes coding for ABCG5 and ABCG8 half-transporters. These transporters function as biliary sterol efflux regulators that limit intestinal absorption and promote biliary excretion of plant sterols (sitosterols) (144, 145). It is not known whether the same ABC transporters also regulate intestinal cholesterol absorption.

Several genes involved in reverse cholesterol transport are regulated by LXRs. Both Lxr and Lxrß regulate mouse Abca1 gene involved in cholesterol efflux in peripheral tissues (146, 147), human macrophage White protein (ABCG1), and the murine homolog Abc8 (148). LXR also controls lipid-induced expression of the apolipoprotein E (ApoE) gene in macrophages and adipocytes (149), the human cholesterol ester transfer protein (CETP) that mediates the exchange of cholesterol esters for triglycerides between HDL and triglyceride-rich lipoproteins (150), and the lipoprotein lipase (LPL) gene involved in hydrolysis of triglycerides carried by VLDL and CM (151). Interestingly, LXR regulates its own synthesis in macrophages, but not in adipocytes, hepatocytes, and other cell types (152).

3. FXR (NR1H4).
FXR (also named RIP14 and HRP1) was isolated by low-stringency screening of a liver cDNA library using oligonucleotides directed to the conserved DNA-binding domain of nuclear receptors (153) and by its ability to heterodimerize with RXR using yeast two-hybrid screening (128). FXR is closely related to the Drosophila ecdysone receptor and preferentially binds to an IR1 motif (128, 153). FXR and LXR are closely related and belong to the same NR1H subfamily of nuclear receptors. FXR is highly expressed in the liver, intestine, adrenal, and kidney (128, 153). Farnesol, juvenile hormone III, all-trans-retinoic acid, and TTNPB activate FXR at high concentrations (154). Recently, bile acids have been identified as the endogenous ligands for FXR (4, 5, 6). The hydrophobic bile acid, CDCA, is the most effective activator of FXR, with an EC₅₀ of about 10–20 µM, tested in kidney CV1 cells (6). The secondary bile acids, LCA and DCA, are less effective, and hydrophilic bile acids, ursodeoxycholic acid, and muricholic acids, are inactive.

When assayed in liver-derived cell lines, bile acid/FXR repressed CYP7A1 (4, 6, 140, 155), CYP27A1 (156), CYP8B1 (157), and NTCP gene transcription (158). In human embryonic kidney 293 cells, however, bile acids and cotransfection of FXR had no effect on CYP7A1 transcription. The FXR binding sequence IR1 is not present in the CYP7A1 gene and FXR does not bind to the BARE-II of CYP7A1 gene. Chiang et al. (140) suggested that FXR suppressed CYP7A1 transcription by an indirect mechanism involving other liver-specific factors (Section IV.A). It has been reported that FXR activates target genes by binding to the IR1 motifs in genes encoding ileum bile acid binding protein (IBABP) (6, 159), canalicular bile salt export pump (BSEP) (160), phospholipid transport protein (PLTP) (161), and ApoCII (162). These findings are consistent with elevated serum bile acids, cholesterol and triglycerides, reduced bile acid pool and fecal bile acid secretion, and lack of bile acid inhibition of Cyp7a1 expression in fxr-/- mice (163). These observations suggest that FXR plays a key role in lipid metabolism.

4. PPAR (NR1C1).
Three forms of PPAR, , , and (or ß), have been identified (164). PPAR is expressed in the liver, heart, and adipose tissues (164, 165), all of which have an active fatty acid ß-oxidation pathway. Fatty acids, eicosanoids, and hypolipidemic agents are ligands of PPARs (166, 167). PPAR is highly expressed in adipose tissues. PPAR (or ß) is expressed in most tissues. Fibrates are hypolipidemic drugs that affect many genes in lipid metabolism by activation of PPAR (164, 168).

Bile acid synthesis and pool sizes are reduced in gallstone and hypercholesterolemia patients treated with certain fibrates (169, 170). The PPAR ligand, Wy14,643, suppresses CYP7A1 mRNA levels and CYP7A1 luciferase reporter activity in HepG2 cells (113). A functional PPAR-responsive element has been mapped to the DR1 in BARE-II, which is also a HNF4 binding site. However, PPAR/RXR does not bind to this DR1 motif. It appears that PPAR interferes with HNF4 activation of the CYP7A1 by reducing the amount of HNF4 expressed (113, 171). Fibrate treatment changes bile acid composition by increasing CA and decreasing CDCA synthesis. This may be because PPAR stimulates CYP8B1 activity and increases CA synthesis in the rat (172). However, PPAR binds to the rat CYP8B1 gene rather weakly. In Ppar-/- mice, inhibitory effects of fibrates on bile acid synthesis and Cyp7a1 and Cyp27a1 expression were abolished (173).

PPAR appears to mediate fatty acid stimulation of LXR expression by binding to several PPAR response elements located in the 5'-upstream sequence of the LXR gene (174). PPAR has been shown to induce LXR, which then induces ABCA1 and ABCG1 expression in macrophages (149, 175). These findings suggest that the PPAR-LXR-ABC1 cascade is involved in cholesterol efflux in macrophages. Bile acids have been shown to antagonize PPAR activity; however, the physiological role of bile acids on PPAR regulation is not clear (176).

5. HNF4 (NR2A1).
HNF4 is the most abundant orphan nuclear receptor expressed in the liver. HNF4 homodimer binds to the DR1 motif and regulates the liver-specific expression of many genes involved in lipoprotein metabolism, including ApoAI, ApoB, and ApoCIII (177, 178), and glucose metabolism (179, 180). HNF4 has constitutive activity and is able to transactivate genes without ligand binding (181). Fatty acyl-CoA thioesters have been shown to activate HNF4; however, the physiological relevance of these ligands has been questioned (182). HNF4 binds to a DR1 sequence in the BARE-II and stimulates rat CYP7A1 promoter/reporter activity (108, 112). Mutation of the HNF4 binding site markedly reduced CYP7A1 promoter activity, indicating that HNF4 is crucial for basal level transcription (108, 112, 183). HNF4 binding sites have also been identified in the CYP8B1 (157, 184) and CYP27A1 genes. HNF4 has been shown to mediate bile acid repression of CYP8B1 transcription (157, 184). HNF4 activity is also regulated by posttranscriptional mechanisms, i.e., phosphorylation of the DNA-binding domain of HNF4 by protein kinase A reduced HNF4 transactivation activity (185). Bile acids or TNF has been shown to inhibit the transactivation potential of HNF4 via MAPK cascade (186).

Mutations of the HNF4 gene have been linked to maturity onset diabetes of the young (MODY1) (187, 188). HNF4 is an upstream regulator of HNF1 gene, the mutation of which has been linked to MODY3 (189, 190). Disruption of Hnf4 in mice is embryonic lethal, because HNF4 is critical for early liver development and differentiation. Liver-specific conditional disruption of the Hnf4 gene results in marked accumulation of lipids in the liver, reduction of serum cholesterol and triglycerides, and accumulation of bile acids in serum. These phenotypes may be explained by reduction of mRNA levels for Cyp7a1, Hnf4, ApoaII, ApocIII, Apob100, Ntcp (SLC10A1), Oatp1 (SLC21A1), and microsomal triglyceride transport protein (191). This is consistent with the important role that HNF4 plays in basal transcription of CYP7A1 and underscores the importance of this nuclear receptor in regulation of lipoprotein metabolism.

6. FTF (NR5A2).
The Fushi-tarazu factor-1 (Ftz-F1) family of monomeric nuclear receptors plays important roles in steroidogenesis, liver growth, endocrine development, and differentiation (192, 193). Two Ftz-F1 genes have been identified. Ftz-F1 (NR5A1) was first identified in Drosophila as a factor that activates the homeobox gene, fushi tarazu (194). A mouse homolog, steroidogenic factor 1 (SF-1), was first cloned from an adrenal gland cDNA library (195). The Ftz-F1ß (NR5A2) gene encodes -FTF and its homologs, rat FTF (196), human CPF (197), hepatitis B virus enhancer 1 factor (hB1F) (198), human FTF (hFTF) (199), mouse LRH (200), Xenopus laevis xFF1 (200), and the zebra fish (zFF1) (201). These NR5A2 variants differ in their N-terminal amino acid sequences and C-terminal truncation due to differential promoter usage and alternative mRNA splicing (201). All hFTFs lack a sequence corresponding to exon 2 of mouse FTF. hFTF is similar to CPF variant 1 and hB1F2 (541 amino acid residues) (202). CPF (495 amino acids) is identical with hB1F (198); they lack a sequence corresponding to both exons 2 and 3 of mouse FTF. CPF variant 2 is a truncated form (323 amino acid residues) lacking C-terminal 172 amino acid residues of ligand-binding domain and AF2 domains and is similar to hFTFs (199). FTF is the name recommended by the Genome Database Nomenclature Committee, and it is used here unless specified otherwise.

FTF is expressed in liver, intestine, and pancreas, and is most related to SF-1 expressed in steroidogenic tissues (203). FTF has intrinsic transcriptional activity and its ligand has not been identified. FTF binding sites have been identified in SF-1 (204), SHP (205), HBV (206), HNF3ß, HNF4, and HNF1 genes (202). The binding site for FTF in human CYP7A1 has been mapped to –₁₃₄TCAAGGCCA-₁₂₆ (197), which overlaps with the HNF4-binding site (-₁₄₄TGGACTtAGGTCA-₁₃₂) by three nucleotides (underlined). In rat CYP8B1, two FTF binding sites are identified (207). Embedded in the FTF site is a HNF4 binding site (184). In human CYP8B1, there is an overlapping HNF4 and FTF binding site (157). FTF is a weak transcription factor that, when transfected at high concentration, stimulates CYP7A1 reporter activity by about 2-fold in nonliver cells (197). It has been suggested that FTF functions as a competence factor for sterol regulation of mouse Cyp7a1 (2) and human CETP gene (208) by LXR. It is interesting that bile acids could induce FTF mRNA expression in rat livers and HepG2 cells (155, 184) and functioned as a repressor that inhibited human CYP7A1 and rat CYP8B1 transcription when assayed in HepG2 cells (155, 157, 184). Thus, FTF may directly inhibit rat CYP7A1 and human CYP8B1 in response to bile acids. The inhibitory effect of FTF is likely due to competition for HNF4 binding to the overlapping binding sites in the BAREs. Bile acids also induce FTF mRNA expression in the intestine (209). It is interesting that FTF induces the multidrug-resistant protein-3 (MRP3) gene involved in excretion of bile acids across basal lateral membrane into portal blood, and FXR does not regulate MRP3 gene (209). Thus, FTF may play a direct role not only in feedback inhibition of bile acid synthesis but also in stimulation of bile acid transport and absorption in the intestine. FTF gene transcription is regulated by GATA and basic helix-loop-helix transcription factors (202). FTF, in turn, regulates HNF4 and HNF1 gene transcription. Hence, FTF is an upstream regulator of the genes involved in early liver development. FTF may protect liver and intestine from cytotoxicity of bile acids during the development of the gastrointestinal tract.

7. SHP (NR0B2).
Using the mouse nuclear receptor, constitutive androgen receptor (CAR), as bait, two-hybrid screening identified SHP as an interacting factor (210). SHP is a unique orphan nuclear receptor that lacks a conserved DNA-binding domain but contains a receptor-interacting domain and a repressor domain (211). SHP is known to inhibit transactivation activity of RAR, CAR, HNF4, estrogen receptor and ß, PPAR, and thyroid hormone receptor (211, 212, 213, 214, 215). Thus, SHP is a promiscuous inhibitory heterodimer partner of nuclear receptors. SHP is closely related to DAX-1, a nuclear receptor expressed in steroidogenic tissues. DAX-1 was originally identified in X-linked adrenal hypoplasia congenita patients who have deletions or mutations of DAX-1 (216, 217, 218). Two mechanisms have been suggested for repression of nuclear receptor activity by SHP. First, SHP competes with other nuclear receptors for coactivators such as steroid receptor coactivator families of steroid receptor coactivators. Second, SHP represses nuclear receptors directly by its repressor function located at the C-terminal region (215). SHP transcription is stimulated by monomeric nuclear receptors bound to DNA, i.e., SF-1 and FTF (205). Because SHP interacts with FTF, SHP inhibits its own transcription by inhibiting FTF activity (155). Hence, FTF, FXR, and SHP tightly regulate the expression of SHP in the liver, similar to the regulation of CYP7A1 gene by these receptors. It would be interesting to disrupt the Shp gene or overexpress Shp in the mouse liver to verify the genes and pathways regulated by SHP (see Note Added in Proof, no. 2). SHP mRNA levels are relatively high in mouse livers but lower in rat livers. This may explain a much higher CYP7A1-specific activity in the rat than in mouse livers.

Recently, Goodwin et al. (3) reported that the FXR agonist, GW4064, repressed CYP7A1 mRNA but stimulated SHP mRNA expression in rats. They found an inverse relationship between CYP7A1 and SHP mRNA expression levels. FXR has been shown to bind mouse and human SHP promoter and stimulates SHP reporter activity (2, 3). In Fxr-/- (163) and in Cyp7a1-/- mice (2), SHP expression is reduced. Furthermore, SHP represses CYP7A1 in a dose-dependent manner by inhibiting the transactivating activity of FTF (LRH) (2, 3, 155). This is analogous to DAX-1 inhibition of SF-1 in steroidogenic tissues. Recently, Chen et al. (155) reported that feeding CDCA to rats had no effect on SHP mRNA expression in livers. However, overexpression of FXR in the presence of CDCA stimulated SHP mRNA expression levels in HepG2 cells. Species differences in SHP expression in response to bile acids may explain these descriptions. SHP mutations have been identified in obese Japanese with early onset of diabetes (219). It was suggested that SHP was a MODY gene that might regulate HNF4 activity and energy metabolism in the pancreas. A cascade mechanism of FXR regulation of CYP7A1 involving SHP will be described in Section IV.A.

8. PXR (NR1I2).
Mouse PXR or the human ortholog, steroid xenobiotic receptor, is a promiscuous xenobiotic receptor that is activated by structurally unrelated steroids, xenobiotics, and drugs, such as phenobarbital and antibiotics, and expressed predominantly in the liver and intestine (220, 221). PXR is most closely related to CAR, and shares common ligands and function. PXR ligands also induce the CYP3A family of cytochrome P450 enzymes. CYP3A4 is the most abundant cytochrome P450 isozyme expressed in human liver and intestine and metabolizes about 60% of clinical drugs in the liver and intestine (222). Dexamethasone, pregnenolone 16-carbonitrile (PCN), rifampicin, phenobarbital, and other drugs activate PXR, which forms a heterodimer with RXR and binds to the promiscuous response elements consisting of DR3, DR4, DR5, or ER6 in the CYP3A genes. Recently, LCA has been identified as a ligand of PXR (221, 223). It was suggested that PXR might function as a bile acid sensor that induced CYP3A4 to convert LCA to a hydrophilic bile acid, hyodeoxycholic acid (HDCA). PXR also induces the OATP2 (SLC21A6) in sinusoidal membrane. This was consistent with the observation that PCN did not affect bile acid secretion in Pxr-/- mice (224) and that Pxr null mice developed inflammatory response and liver damage upon LCA treatment. However, Pxr null mice were responsive to LCA induction of CYP3A (225). These results suggest that LCA induces OATP2, which transports LCA into hepatocytes to induce PXR to inhibit CYP7A1 transcription (225). Thus, PXR may play a protective role against hepatotoxicity and cholestasis induced by LCA (225). This is consistent with a previous report by Chiang et al. (226) that PCN and dexamethasone strongly inhibit CYP7A1 activity and protein expression in rat livers. Phenobarbital is known to stimulate CYP7A1 activity (226, 227). However, the mechanism by which PXR inhibits and phenobarbital induces CYP7A1 expression is not known at present. PXR also induces multidrug-resistant protein 1 (MDR1) and MRP2, which transport sulfate-conjugated tauco-CDCA and tauro-LCA to canaliculi (228).

C. Nuclear receptor regulation of cholesterol homeostasis
Figure 4 illustrates the central roles LXR and FXR play in coordinate regulation of bile acid synthesis, transport, and absorption in the liver and intestine, and cholesterol metabolism in the liver and peripheral tissues. When cholesterol levels increase in hepatocytes, oxysterols activate LXR, which stimulates the conversion of cholesterol to bile acids by inducing CYP7A1 transcription. LXR induces SREBP-1c to stimulate triglyceride synthesis by inducing genes involved in fatty acid synthesis. LDL receptor, HMG-CoA reductase, and other genes in cholesterol synthesis pathway may be also induced. LXR also induces genes involved in lipoprotein metabolism, including LPL, CETP, and PLTP.

View larger version (80K): [in this window] [in a new window]   Figure 4. LXR and FXR regulation of bile acid synthesis, transport, and absorption, as well as cholesterol homeostasis in the liver. In the liver, cholesterol is converted to bile acids (BA) and also oxidized to oxysterols by sterol hydroxylases. Oxysterols activate LXR, which induces transcription of genes for CYP7A1 and SREBP-1c. SREBP induces genes involved in fatty acid synthesis, LDL receptor, HMG-CoA reductase, and other genes in cholesterol synthesis. LXR also induces CETP and LPL involved in lipoprotein metabolism. Bile acids activate FXR and inhibit CYP7A1 and NTCP transcription. On the other hand, FXR induces the expression of bile salt export pump (BSEP), which excretes bile acids into bile. Cholesterol is excreted into bile by an unknown mechanism. Phosphatidylcholine (PC) is excreted by MDR2 to bile canaliculi. Cholesterol, PC, and bile acids form mixed micelles and are stored in the gallbladder. Bile acids secreted from the gallbladder are reabsorbed in the intestine by ASBT located in the brush border membrane. FXR induces ileum bile acid binding protein (IBABP), which binds and facilitates the efflux of bile acids by truncated ASBT (tASBT) located in the basolateral membrane into portal circulation to hepatocytes where bile acids are taken up by NTCP. LCA, a secondary bile acid formed in the intestine, induces OATP2 and transports LCA into hepatocytes for conversion to hyodeoxycholic acid by CYP3A, which is induced by PXR (not shown). Dietary cholesterol is absorbed into the intestine by an unknown mechanism. In the intestine, LXR induces ABCG5/G8 transporters and perhaps also ABCA1, which effluxes sitosterol (plant sterol) and cholesterol, respectively, from enterocytes. In peripheral tissues, oxidized LDL is taken up by SR-A1, and LXR induces ABCA1/G1, which effluxes cholesterol and phospholipids to form pre-HDL with ApoAI/ApoE. FXR induces PLTP, which transfers phospholipids from VLDL and LDL to pre-ßHDL and HDL3 to form HDL3 and HDL2, respectively. LXR induces CETP, which exchanges triglycerides for cholesterol between HDLs and other lipoproteins.

Increases in bile acid synthesis and pool size stimulate FXR, which inhibits CYP7A1 to decrease bile acid synthesis but stimulates BSEP expression to excrete bile acids into bile. Cholesterol is excreted into bile by an unknown mechanism, possibly involving ABCG5/G8, and MDR2 excretes phosphatidylcholine into bile to form mixed micelles with bile acids. In the intestine, bile acids are reabsorbed into enterocytes by sodium-dependent bile acid transporter (ASBT, SLC10A2) located in the brush border membrane and bind to IBABP, which may facilitate bile acid efflux by the truncated ASBT (tASBT), located in the basolateral membrane, to portal circulation (233). FXR inhibits the expression of NTCP in sinusoidal membrane to reduce reabsorption of bile salts into hepatocytes. Therefore, FXR may play major roles in bile acid metabolism, reverse cholesterol transport, and protect hepatocytes against cholestasis by 1) feedback inhibition of bile acid synthesis by CYP7A1; 2) stimulation of bile acid efflux from hepatocytes by BSEP; 3) inhibition of bile acid uptake into hepatocytes by NTCP; and 4) regulation of reverse cholesterol transport by inducing ApoCII and PLTP.

It should be emphasized that cholesterol metabolism in rats and mice is very different from humans and other species. Rats and mice have very little LDL and do not express CETP. Stimulation of CYP7A1 by a high-cholesterol diet is observed only in rats and some inbred strains of mice. The bile acid pools of rats and mice are more hydrophilic, containing mostly muricholic acids, and thus less effective in activation of FXR. Therefore, the positive effect of LXR may dominate over the negative effect of FXR to explain the high efficiency in conversion of cholesterol to bile acids in the rat and mouse. In contrast, a high-cholesterol diet does not stimulate, but represses CYP7A1 in the monkey, guinea pig, rabbit, and human. In the latter species the inhibitory effect of FXR may dominate over the stimulatory effect of LXR to explain the inhibition of CYP7A1 gene transcription by cholesterol. Therefore, cholesterol may indirectly activate FXR by stimulating the synthesis of bile acids. Thus, rats are resistant to diet-induced hypercholesterolemia, whereas rabbits, hamsters, and some humans develop hypercholesterolemia on a diet high in cholesterol.

	IV. Molecular Mechanisms of Regulation of Bile Acid Metabolism

Top Abstract I. Introduction II. Bile Acid Synthesis... III. Nuclear Hormone Receptor... IV. Molecular Mechanisms of... V. Drug Therapies Targeted... VI. Conclusion and Future... Note Added in Proof References

 
Bile acid feedback regulation of bile acid synthesis has been studied for more than three decades. Despite that, the molecular mechanism of bile acid feedback is poorly understood. During the last decade, cloning of the CYP7A1 cDNAs and the genes has contributed significantly to our understanding of the molecular mechanism of bile acid synthesis and regulation (1). Several mechanisms have since been proposed to explain bile acid feedback regulation of CYP7A1 transcription. The receptor-mediated mechanism originally proposed by Chiang and Stroup (109) is based on the finding that hormone response element-like repeats are present in the BAREs identified in the CYP7A1. Bile acids have been shown to activate protein kinase C (PKC) signaling pathway (234) and inflammatory cytokines (235, 236). A receptor-mediated mechanism might regulate bile acid synthesis under physiological conditions, whereas a cell-signaling mechanism possibly provides a rapid response to stress that is induced by bile acid overload (such as in cholestasis). These two mechanisms may converge to down-regulate the genes through the same transcription factors.

A. Nuclear receptor-mediated mechanism
Chiang and associates (1, 109) proposed that bile acids might bind to and activate a nuclear bile acid receptor, which interacts with a bile acid-responsive protein that transactivates CYP7A1 gene transcription. Interaction between bile acid receptor and bile acid-responsive protein might prevent a transactivating factor from binding to the BARE, thus inhibiting CYP7A1 transcription. It was further proposed that bile acid receptors and bile acid responsive proteins might be liver-enriched transcription factors or orphan nuclear receptors (1, 110). Identification of FXR as a bile acid receptor supports this mechanism. The comparison of nucleotide sequences of the BAREs identified in rat and human CYP7A1 (110, 155), rat and human CYP8B1 (157, 184), and human CYP27A1 show similar characteristics: they all contain overlapping binding sites for HNF4 and FTF. These two nuclear receptors may differentially regulate these genes by competing for binding to the BAREs. The relative expression levels of these two nuclear receptors in liver may also regulate these genes under different physiological conditions.

Figure 5 illustrates the receptor-mediated mechanisms of bile acid regulation of gene transcription based on the original mechanism proposed by Chiang and co-workers (1, 109, 110) and modified according to the FXR/SHP cascade mechanism proposed recently (2, 3, 155, 157). CDCA-activated FXR binds to the IR1 sequences and stimulates IBABP, BSEP, PLTP, and SHP transcription in the liver. SHP then interacts with FTF to repress CYP7A1, or with HNF4 to repress CYP8B1 and CYP27A1 transcription. It should be noted that bile acids also induce FTF, which directly inhibits genes in bile acid synthesis in the liver (155, 157, 184) but stimulates MRP3 gene in the intestine (209). Figure 5 also shows an SHP-independent mechanism by which the PXR activated by LCA represses CYP7A1 transcription by an unknown mechanism. On the other hand, PXR induces OATP2 to facilitate the transport of LCA to hepatocytes to induce CYP3A family enzymes that convert LCA to hyodeoxycholic acid. Vitamin D receptor has recently been identified as a LCA-activated receptor, which may also regulate bile acid synthesis (see Note Added in Proof, no. 3). Therefore, bile acids regulate bile acid synthesis, transport, absorption, and detoxification in the liver and intestine. It is intriguing that bile acids activate a very specific receptor, FXR, which induces a nonspecific, negative receptor, SHP. SHP then interacts with other nonspecific receptors (FTF and HNF4) and specifically inhibits the genes regulated by bile acids. The unique structures of BAREs in bile acid-repressed genes must be critical to provide specificity for bile acid inhibition. Tissue-specific expression of SHP, HNF4, and FTF may also provide specificity for this cascade mechanism of gene transcription. Further study by knocking out the shp gene in mice to study bile acid feedback regulation of genes transcription would provide more convincing evidence for the FXR/SHP-dependent mechanism (see Note Added in Proof, no. 2). In addition, bile acids may down-regulate a gene by SHP-independent mechanism, i.e., reducing HNF4 expression level and stimulation of FTF (184). When bile acid pool in the liver is reduced, increasing HNF4 expression and decreasing FTF expression would allow HNF4 to bind to the BARE and stimulate gene transcription. When bile acid pool increases, HNF4 expression is reduced and FTF is increased to allow FTF to bind to the BARE and down-regulate gene transcription.

View larger version (37K): [in this window] [in a new window]   Figure 5. Nuclear receptor-mediated mechanism. FXR and PXR are bile acid receptors. SHP, HNF4, and FTF are bile acid-responsive proteins that are regulated by bile acids. FXR/RXR binds to the IR1 sequence in IBABP, BSEP, PLTP, and SHP gene and activates their gene transcription. FXR indirectly represses gene transcription by induction of a negative receptor, SHP, which interacts with HNF4 or FTF and represses CYP7A1, CYP8B1, and CYP27A1 transcription. Bile acids also induce FTF, which interact with SHP or functions as a negative regulator that inhibits human CYP7A1, rat CYP8B1, and human CYP27A1 transcription. Bile acids also inhibit HNF4 gene transcription and contribute to the inhibition of HNF4-activated rat and human CYP8B1 and human CYP27A1. In SHP-independent mechanism, LCA activates PXR, which binds to an ER6 sequence in CYP3A and OATP2 genes. PXR inhibits CYP7A1 transcription by an unknown mechanism.

View larger version (41K): [in this window] [in a new window]   Figure 6. Cell signaling mechanism. Bile acids activate PKC, which initiates a MAPK signal transduction pathway to phosphate JNK1, 2. Bile acids also induce inflammatory cytokines, TNF and IL-1, which also activate MAPK cascade involving MEEK1 and SEK/MKK4, and phosphorylate JNK1/2. JNK1/2 phosphorylates c-Jun, which may interact with FTF (or other unknown factors) and repress CYP7A1. The phosphorylated c-Jun may induce SHP, which interacts with FTF and represses CYP7A1 transcription as in the nuclear receptor-mediated mechanism. JNK1/2 may phosphorylate HNF4 and inhibit its transactivation activity, leading to repression of CYP7A1 transcription. MEKK1, MAPK kinase kinase 1; SEK, stress-activated protein kinase kinase; MKK4, MAPK kinase kinase; JNK, c-Jun N-terminal kinase.

	V. Drug Therapies Targeted to Nuclear Receptors and Genes in Bile Acid Metabolism

Top Abstract I. Introduction II. Bile Acid Synthesis... III. Nuclear Hormone Receptor... IV. Molecular Mechanisms of... V. Drug Therapies Targeted... VI. Conclusion and Future... Note Added in Proof References

Therapies targeted to LXR and FXR would be ideal for drug development because nuclear receptors are activated by natural and synthetic ligands, which could be identified by high-throughput screening. FXR antagonists should dampen bile acid feedback inhibition and stimulate CYP7A1 transcription and result in increasing conversion of cholesterol to bile acids. However, it may be argued that an increase in bile acid synthesis and pool size would lead to stimulation of FXR, which subsequently reduces bile acid synthesis. This is compensated by FXR stimulation of BSEP for excretion of bile acid from hepatocytes. LXR agonists may stimulate CYP7A1 transcription in rats and mice (139) but may have much less effect on human CYP7A1. Therefore, FXR antagonists may be more effective than LXR agonists in stimulating bile acid synthesis and reducing serum cholesterol levels. Individual differences in response to a high-cholesterol diet may have different responses to FXR antagonists and LXR agonists. Rexinoids may stimulate FXR, LXR, PPAR, and other nuclear receptors heterodimerized with RXR (139). Because the effect of FXR may dominate over the effect of LXR in humans, rexinoids may inhibit bile acid synthesis (140).

B. Bile acid transport
FXR agonists should increase BSEP and reduce NTCP expression (3). However, stimulation of BSEP expression to excrete bile acids may not subsequently stimulate bile acid synthesis. FXR agonists also should stimulate IBABP expression in enterocytes, thus protecting intestine cells from the toxicity of bile acids. Bile acids and FXR agonists have been shown to reduce serum triglyceride level (162, 249). FXR agonists may be ideal drugs for treatment of cholesterol gallstone disease, hypertriglyceridemia, and cholestatic liver diseases. The effectiveness of bile acid sequestrants in interrupting bile acid reabsorption and stimulating bile acid synthesis suggests that the inhibitor of intestinal ASBT would be effective in reducing bile acid reabsorption. Several ileal bile acid transport inhibitors have been developed recently for cholesterol lowering (241, 250, 251). New bile acid sequestrants have been developed recently for improving efficacy and reducing gastrointestinal side effects (252, 253). The possible hypertriglyceridemic effects of these drugs need to be evaluated.

C. Reverse cholesterol transport
FXR agonists may increase HDL levels by inducing PLTP, which facilitates the synthesis of HDLs for reverse cholesterol transport, and by inducing ApocII (162), which activates LPL for hydrolysis of triglycerides in VLDL and CM. This may explain the hypotriglyceridemic effect of FXR agonists (162). LXR agonists may induce reverse cholesterol transport by inducing CETP, LPL, and ABCA1/G1 (12). Thus, LXR agonists may reduce serum cholesterol and intestinal cholesterol absorption by increasing cholesterol efflux from enterocytes. However, most of the cholesterol absorbed in the intestine is retained in the body, and cholesterol efflux from enterocytes does not contribute significantly to whole-body cholesterol homeostasis in humans. A potential problem for using LXR agonists is hypertriglyceridemia induced by induction of SREBP-1c, which stimulates fatty acid and triglyceride synthesis (135). A combination therapy of LXR and FXR agonists and compounds that activate both LXR and FXR, if obtained, may be used as an alternative therapy for treating hypercholesterolemia without causing hypertriglyceridemia.

D. Cholesterol absorption
About 50% of dietary cholesterol is absorbed in the intestine in humans by selective processes, most likely involving protein/receptor-mediated transport (229, 231, 254). In principal, inhibition of cholesterol absorption in the intestine would be an attractive strategy for reducing serum cholesterol. Several cholesterol absorption inhibitors have been developed (241, 255). Dietary supplement of margarine containing sitostanol esters (benetol) may inhibit cholesterol absorption and reduce serum cholesterol in a hypercholesterolemic population (256). Increasing cholesterol efflux in intestine also may reduce net intestinal cholesterol absorption. However, this process varies widely among different species and individuals. Rexinoids have been shown to stimulate cholesterol efflux from the intestine by inducing Abca1 transporter in mouse intestine (139). LXR agonists should have similar effects on cholesterol efflux.

	VI. Conclusion and Future Perspectives

Top Abstract I. Introduction II. Bile Acid Synthesis... III. Nuclear Hormone Receptor... IV. Molecular Mechanisms of... V. Drug Therapies Targeted... VI. Conclusion and Future... Note Added in Proof References

 
The cloning of the major regulatory genes in the bile acid biosynthetic pathways in the last 10 yr has contributed significantly to our understanding of the mechanism of regulation of bile acid synthesis and cholesterol homeostasis. These advances have led to the recent discovery of bile acids and oxysterols as signaling molecules and nuclear receptors LXR and FXR as oxysterol and bile acid receptors, respectively. It is predicted that many bile acid target genes that are involved in lipid metabolism will be identified. Further research on the complex mechanism of gene regulation by bile acids and oxysterols, and identification of endogenous ligands for nuclear receptors involved in regulation of lipid metabolism and homeostasis, will help elucidate the mechanism of pathogenesis of several metabolic diseases (see Note Added in Proof, no. 3). New drugs targeted to nuclear receptors and bile acid-regulated genes for treatment of hypercholesterolemia, hypertriglyceridemia, atherosclerosis, cholesterol gallstone disease, and cholestatic liver disease will be developed in the foreseeable future.

	Note Added in Proof

Top Abstract I. Introduction II. Bile Acid Synthesis... III. Nuclear Hormone Receptor... IV. Molecular Mechanisms of... V. Drug Therapies Targeted... VI. Conclusion and Future... Note Added in Proof References

 
Several papers, which are very important for this review, appeared after submission of this manuscript.

1. A family of CYP7A1 deficiency has recently been identified (259). Patients have hyperlipidemia, premature coronary and peripheral vascular disease, and premature gallstone disease. A double deletion (TT) in codon 413 results in a frame shift that converts a Leu to Arg, followed by a premature stop codon. The mutation is located in the putative sterol-binding sites of cytochrome P450 enzymes and results in a truncated protein of 413 amino acid residues devoid of the heme-binding domain. Patients are resistant to stain and have markedly reduced bile acid synthesis, and compensatory increase of CYP27A1 activity of the alternative pathway. However, the severe malnutrition phenotypes observed in Cyp7a1-null mice were not present in these patients.

2. Mice deficient of SHP have been obtained (260, 261). These mice appear normal except mild defects in bile acid and cholesterol homeostasis, and increase of bile acid synthesis, which is expected due to lacking SHP inhibition of CYP7A1. Surprisingly, these mice still responded to bile acid feedback inhibition when fed bile acids. Studies confirmed that SHP-independent mechanisms, such as bile acid activation of PXR and JNK pathways, were involved in bile acid feedback regulation of bile acid synthesis.

3. Vitamin D receptor (VDR) has recently been identified as the third bile acid receptor (262). VDR is activated by LCA at much lower concentrations (ED₅₀ = 8 µM) than PXR. This receptor may be an intestinal bile acid sensor that activates CYP3A4 in liver and intestine to detoxify LCA and protect against colon cancer.

	Acknowledgments

 
I gratefully acknowledge Lynn Anderson for creating the graphics for this study.

	Footnotes

 
This work was supported by NIH Grants GM-31584, DK-58379, and DK-44442 and by Aventis Pharma, Frankfurt, Germany.

This work is dedicated to the memory of Professor Z. Reno Vlahcevic, M.D., for his guidance, wisdom, and friendship.

Abbreviations: ABCA1, ATP-binding cassette protein A1; ACAT, acyl-CoA-cholesterol acyltransferase; apo, apolipoprotein; ASBT, apical sodium-dependent bile acid transporter; BARE, bile acid response element; BSEP, bile salt export pump; CA, cholic acid; CAR, constitutive androgen receptor; CDCA, chenodeoxycholic acid; CETP, cholesterol ester transfer protein; CM, chylomicron; CoA, coenzyme A; CPF, CYP7A1 promoter factor; CTX, cerebrotendinous xanthomatosis; CYP, cytochrome P450; CYP7A1, cholesterol 7- hydroxylase; CYP7B1, oxysterol 7-hydroxylase; CYP8B1, sterol 12-hydroxylase; CYP27A1, sterol 27-hydroxylase; DCA, deoxycholic acid; DR, direct repeat; FTF, -fetoprotein transcription factor; Ftz-F1, Fushi-tarazu factor 1; FXR, farnesoid X receptor; hB1F, hepatitis B virus enhancer 1 factor; HDL, high density lipoprotein; hFTF, human FTF; HMG-CoA, 3-hydroxy-3-methylglutaryl CoA; HNF4, hepatocyte nuclear factor 4; 3ß-HSD, 3ß-hydroxysteroid dehydrogenase; IBABP, ileum bile acid binding protein; IDL, intermediate-density lipoprotein; IR, inverted repeat; JNK, Jun N-terminal kinase; LCA, lithocholic acid; LDL, low density lipoprotein; LPL, lipoprotein lipase; LRH, mouse liver-related homolog; LXR, liver X receptor; MDR1, multidrug-resistant protein 1; NR1, nuclear receptor 1; MODY, maturity onset diabetes of the young; MRP3, multidrug-resistant protein-3; NTCP, sodium taurocholate cotransport peptide; OATP2, organic anion transport peptide 2; PCN, pregnenolone 16-carbonitrile; PLTP, phospholipid transfer protein; PPAR, peroxisome proliferator activated receptor; PXR, pregnane X receptor; RAR, retinoic acid receptor; RXR, retinoid X receptor; SF-1, steroidogenic factor 1; SHP, small heterodimer partner; SR-B1, scavenger receptor subclass B1; SREBP, sterol response element binding protein; tASBT, terminal apical sodium-dependent bile acid transporter; VLDL, very low density lipoprotein.

	References

Top Abstract I. Introduction II. Bile Acid Synthesis... III. Nuclear Hormone Receptor... IV. Molecular Mechanisms of... V. Drug Therapies Targeted... VI. Conclusion and Future... Note Added in Proof References

 

1. Chiang JYL 1998 Regulation of bile acid synthesis. Front Biosci 3:D176–D193
2. Lu TT, Makishima M, Repa JJ, Schoonjans K, Kerr TA, Auwerx J, Mangelsdorf DJ 2000 Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell 6:507–515[CrossRef][Medline]
3. Goodwin B, Jones SA, Price RR, Watson MA, McKee DD, Moore LB, Galardi C, Wilson JG, Lewis MC, Roth ME, Maloney PR, Willson TM, Kliewer SA 2000 A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 6:517–526[CrossRef][Medline]
4. Parks DJ, Blanchard SG, Bledsoe RK, Chandra G, Consler TG, Kliewer SA, Stimmel JB, Willson TM, Zavacki AM, Moore DD, Lehmann JM 1999 Bile acids: natural ligands for an orphan nuclear receptor. Science 284:1365–1368[Abstract/Free Full Text]
5. Wang H, Chen J, Hollister K, Sowers LC, Forman BM 1999 Endogenous bile acids are ligands for the nuclear receptor FXR/BAR. Mol Cell 3:543–553[Medline]
6. Makishima M, Okamoto AY, Repa JJ, Tu H, Learned RM, Luk A, Hull MV, Lustig KD, Mangelsdorf DJ, Shan B 1999 Identification of a nuclear receptor for bile acids. Science 284:1362–1365[Abstract/Free Full Text]
7. Schroepfer Jr GJ 2000 Oxysterols: modulators of cholesterol metabolism and other processes. Physiol Rev 80:361–554[Abstract/Free Full Text]
8. Peet DJ, Janowski BA, Mangelsdorf DJ 1998 The LXRs: a new class of oxysterol receptors. Curr Opin Genet Dev 8:571–575[CrossRef][Medline]
9. Lehmann JM, Kliewer SA, Moore LB, Smith-Oliver TA, Oliver BB, Su JL, Sundseth SS, Winegar DA, Blanchard DE, Spencer TA, Willson TM 1997 Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway. J Biol Chem 272:3137–3140[Abstract/Free Full Text]
10. Russell DW 1999 Nuclear orphan receptors control cholesterol catabolism. Cell 97:539–542[CrossRef][Medline]
11. Chawla A, Saez E, Evans RM 2000 Don’t know much bile-ology. Cell 103:1–4[CrossRef][Medline]
12. Repa JJ, Mangelsdorf DJ 1999 Nuclear receptor regulation of cholesterol and bile acid metabolism. Curr Opin Biotechnol 10:557–563[CrossRef][Medline]
13. Repa JJ, Mangelsdorf DJ 2000 The role of orphan nuclear receptors in the regulation of cholesterol homeostasis. Annu Rev Cell Dev Biol 16:459–481[CrossRef][Medline]
14. Russell DW, Setchell KDR 1992 Bile acid biosynthesis. Biochem 31:4737–4749[CrossRef][Medline]
15. Chiang JYL, Vlahcevic ZR 1996 The regulation of cholesterol conversion to bile acids. Greenwich, CT: JAI Press, Inc.; 269–316
16. Vlahcevic ZR, Pandak WM, Stravitz RT 1999 Regulation of bile acid biosynthesis. Gastroenterol Clin North Am 28:1–25[CrossRef][Medline]
17. Princen HMG, Post SM, Twisk J 1997 Regulation of bile acid biosynthesis. Curr Pharm Design 3:59–84
18. Bjorkhem I 1985 Mechanism of bile acid biosynthesis in mammalian liver. In: Danielsson H, Sjovall J, eds. Steroid and bile acid. The Netherlands: Elsevier Sci Pub; 231–277
19. Myant NB, Mitropoulos KA 1977 Cholesterol 7-hydroxylase. J Lipid Res 18:135–153[Medline]
20. Bjorkhem I 1992 Mechanism of degradation of the steroid side chain in the formation of bile acids. J Lipid Res 33:455–471[Medline]
21. Axelson M, Sjovall J 1990 Potential bile acid precursors in plasma-possible indicators of biosynthetic pathways to cholic and chenodeoxycholic acids in man. J Steroid Biochem 36:631–640[CrossRef][Medline]
22. Axelson M, Mork B, Sjovall J 1988 Occurrence of 3ß-hydroxy-5-cholestenoic acid, 3ß, 7-dihydroxy-5-cholestenoic acid and 7-hydroxy-3-oxo-4-cholestenoic acid as normal constitutes in human blood. J Lipid Res 29:629–641[Abstract]
23. Javitt NB, Pfeffer R, Kok E, Burstein S, Cohen BI, Budai K 1989 Bile acid synthesis in cell culture. J Biol Chem 264:10384–10387[Abstract/Free Full Text]
24. Javitt NB 1994 Bile acid synthesis from cholesterol: regulatory and auxiliary pathways. FASEB J 8:1308–1311[Abstract]
25. Pikuleva IA, Babiker A, Waterman MR, Bjorkhem I 1998 Activities of recombinant human cytochrome P450c27 (CYP27) which produce intermediates of alternative bile acid biosynthetic pathways. J Biol Chem 273:18153–18160[Abstract/Free Full Text]
26. Andersson S, Davis DL, Dahlback H, Jornvall H, Russell DW 1989 Cloning, structure, and expression of the mitochondrial cytochrome P450 sterol 27-hydroxylase, a bile acid biosynthetic enzyme. J Biol Chem 264:8222–8229[Abstract/Free Full Text]
27. Vlahcevic ZR, Eggertsen G, Bjorkhem I, Hylemon PB, Redford K, Pandak WM 2000 Regulation of sterol 12-hydroxylase and cholic acid biosynthesis in the rat. Gastroenterology 118:599–607[CrossRef][Medline]
28. Princen HMG, Meijer P, Wolthers BG, Vonk RJ, Kuipers F 1991 Cyclosporin A blocks bile acid synthesis in cultured hepatocytes by specific inhibition of chenodeoxycholic acid synthesis. Biochem J 275:501–505
29. Vlahcevic ZR, Stravitz RT, Heuman DM, Hylemon PB, Pandak WM 1997 Quantitative estimations of the contribution of different bile acid pathways to total bile acid synthesis in the rat. Gastroenterology 113:1949–1957[CrossRef][Medline]
30. Stravitz RT, Vlahcevic ZR, Russell TL, Heizer ML, Avadhani NG, Hylemon PB 1996 Regulation of sterol 27-hydroxylase and an alternative pathway of bile acid biosynthesis in primary cultures of rat hepatocytes. J Steroid Biochem Mol Biol 57:337–347[CrossRef][Medline]
31. Duane WC, Javitt NB 1999 27-Hydroxycholesterol. Production rates in normal human subjects. J Lipid Res 40:1194–1199[Abstract/Free Full Text]
32. Bertolotti M, Abate N, Loria P, Dilengite M, Carubbi F, Pinetti A, Digrisolo A, Carulli N 1991 Regulation of bile acid synthesis in humans: effect of treatment with bile acids, cholestyramine, or simvastatin on cholesterol 7-hydroxylation rates in vivo. Hepatology 14:830–837[CrossRef][Medline]
33. Einarsson K, Ericsson S, Ewerth S, Reihner E, Rudling M, Stahlberg D, Angelin B 1991 Bile acid sequestrants: mechanisms of action on bile acid and cholesterol metabolism. Eur J Clin Pharmacol 40:S53–S58
34. Einarsson K, Akerlund J-E, Reihner E, Bjorkhem I 1992 12-Hydroxylase activity in human liver and its relation to cholesterol 7-hydroxylase activity. J Lipid Res 33:1591–1595[Abstract]
35. Ishibashi S, Schwartz M, Frykman PK, Hertz J, Russell DW 1996 Disruption of cholesterol 7-hydroxylase gene in mice. I. Postnatal lethality reversed by bile acid and vitamin supplementation. J Biol Chem 271:18017–18023[Abstract/Free Full Text]
36. Schwarz M, Lund EG, Setchell KDR, Kayden HJ, Zerwekh JE, Bjorkhem I, Herz J, Russel DW 1996 Disruption of cholesterol 7-hydroxylase gene in mice. II. Bile acid deficiency is overcome by induction of oxysterol 7-hydroxylase. J Biol Chem 271:18024–18031[Abstract/Free Full Text]
37. Li-Hawkins J, Lund EG, Turley SD, Russell DW 2000 Disruption of the oxysterol 7-hydroxylase gene in mice. J Biol Chem 275:16536–16542[Abstract/Free Full Text]
38. Hofmann AF 1999 The continuing importance of bile acids in liver and intestinal disease. Arch Intern Med 159:2647–2658[Abstract/Free Full Text]
39. Carey MC, Duane WC 1994 Enterohepatic circulation. In: Arias IM, Boyer JL, Fausto N, Jakoby WB, Schachter D, Shafritz DA, eds. The liver: biology and pathology. 3^rd ed. New York: Raven Press; 719–768
40. Bahar RJ, Stolz A 1999 Bile acid transport. Gastroenterol Clin North Am 28:27–58[CrossRef][Medline]
41. Wong MH, Oelkers P, Craddock AL, Dawson PA 1994 Expression cloning and characterization of the hamster ileal sodium-dependent bile acid transporter. J Biol Chem 269:1340–1347[Abstract/Free Full Text]
42. Hagenbuch B, Meier PJ 1996 Sinusoidal (basolateral) bile salt uptake systems of hepatocytes. Semin Liver Dis 16:129–136[Medline]
43. Hagenbuch B, Stieger B, Foguet M, Lubbert H, Meier P 1991 Functional expression cloning and characterization of the hepatocyte Na+/bile acid cotransport system. Proc Natl Acad Sci USA 88:10629–10633[Abstract/Free Full Text]
44. Kullak-Ublick G-A, Hagenbuch B, Stieger B, Schteingart CD, Hofman AF, Wolkoff AW, Meier PJ 1995 Molecular and functional characterization of an organic anion transporting polypeptide cloned from human liver. Gastroenterology 109:1274–1282[CrossRef][Medline]
45. Stolz A, Takikawa H, Ookhtens M, Kaplowitz N 1989 The role of cytoplasmic proteins in hepatic bile acid transport. Annu Rev Physiol 51:161–176[CrossRef][Medline]
46. Jansen PL, Muller M, Sturm E 2001 Genes and cholestasis. Hepatology 34:1067–1074[CrossRef][Medline]
47. Muller M, Jansen PL 1998 The secretory function of the liver: new aspects of hepatobiliary transport. J Hepatol 28:344–354[CrossRef][Medline]
48. Dawson PA, Oelkers P 1995 Bile acid transporters. Curr Opin Lipidol 6:109–114[Medline]
49. Suchy FJ, Sippel CJ, Ananthanarayana M 1997 Bile acid transport across the hepatocyte canalicular membrane. FASEB J 11:199–205[Abstract]
50. Kozarsky KF, Donahee MH, Rigotti A, Iqbal SN, Edelman ER, Krieger M 1997 Overexpression of the HDL receptor SR-BI alters plasma HDL and bile cholesterol levels. Nature 387:414–417[CrossRef][Medline]
51. Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M 1996 Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 271:518–520[Abstract]
52. Cohen JC 1999 Contribution of cholesterol 7-hydroxylase to the regulation of lipoprotein metabolism. Curr Opin Lipidol 10:303–307[CrossRef][Medline]
53. Einarsson K, Angelin B 1991 The catabolism of cholesterol. Curr Opin Lipidol 2:190–196
54. Angelin B, Eriksson M, Rudling M 1999 Bile acids and lipoprotein metabolism: a renaissance for bile acids in the post-statin era? Curr Opin Lipidol 10:269–274[CrossRef][Medline]
55. Kandutsch AA, Chen HW 1974 Inhibition of sterol synthesis in cultured mouse cells by cholesterol derivatives oxygenated in the side chain. J Biol Chem 249:6057–6061[Abstract/Free Full Text]
56. Brown AJ, Jessup W 1999 Oxysterols and atherosclerosis. Atherosclerosis 142:1–28[CrossRef][Medline]
57. Babiker A, Andersson O, Lindblom D, van der Linden J, Wiklund B, Lutjohann D, Diczfalusy U, Bjorkhem I 1999 Elimination of cholesterol as cholestenoic acid in human lung by sterol 27-hydroxylase: evidence that most of this steroid in the circulation is of pulmonary origin. J Lipid Res 40:1417–1425[Abstract/Free Full Text]
58. Bjorkhem I, Lutjohann D, Diczfalusy U, Stahle L, Ahlborg G, Wahren J 1998 Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation. J Lipid Res 39:1594–1600[Abstract/Free Full Text]
59. Lund EG, Guileyardo JM, Russell DW 1999 cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain. Proc Natl Acad Sci USA 96:7238–7243[Abstract/Free Full Text]
60. Lund EG, Kerr TA, Sakai J, Li WP, Russell DW 1998 cDNA cloning of mouse and human cholesterol 25-hydroxylases, polytopic membrane proteins that synthesize a potent oxysterol regulator of lipid metabolism. J Biol Chem 273:34316–34327[Abstract/Free Full Text]
61. Brown MS, Goldstein JL 1997 The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89:331–340[CrossRef][Medline]
62. Edwards PA, Ericsson J 1999 Sterols and isoprenoids: signaling molecules derived from the cholesterol biosynthetic pathway. Annu Rev Biochem 68:157–185[CrossRef][Medline]
63. Bennett MK, Osborne TF 2000 Nutrient regulation of gene expression by the sterol regulatory element binding proteins: increased recruitment of gene-specific coregulatory factors and selective hyperacetylation of histone H3 in vivo. Proc Natl Acad Sci USA 97:6340–6344[Abstract/Free Full Text]
64. Bennett MK, Lopez JM, Sanchez HB, Osborne TF 1995 Sterol regulation of fatty acid synthase promoter: coordinate feedback regulation of two major pathways. J Biol Chem 270:25578–25583[Abstract/Free Full Text]
65. Chouinard Jr RA, Luo Y, Osborne TF, Walsh A, Tall AR 1998 Sterol regulatory element binding protein-1 activates the cholesteryl ester transfer protein gene in vivo but is not required for sterol up-regulation of gene expression. J Biol Chem 273:22409–22414[Abstract/Free Full Text]
66. Hua X, Yokoyama C, Wu J, Briggs MR, Brown MS, Goldstein JL, Wang X 1993 SREBP-2, a second basic-helix-loop-helix-leucine zipper protein that stimulates transcription by binding to a sterol regulatory element. Proc Natl Acad Sci USA 90:11603–11607[Abstract/Free Full Text]
67. Jackson SM, Ericksson J, Metherall JE, Edwards PA 1996 Role for sterol regulatory element binding protein in the regulation of farnesyl diphosphate synthase and in the control of cellular levels of cholesterol and triglyceride: evidence from sterol regulation-defective cells. J Lipid Res 37:1712–1721[Abstract]
68. Li-Hawkins J, Lund EG, Bronson AD, Russell DW 2000 Expression cloning of an oxysterol 7-hydroxylase selective for 24-hydroxycholesterol. J Biol Chem 275:16543–16549[Abstract/Free Full Text]
69. Norlin M, Andersson U, Bjorkhem I, Wikvall K 2000 Oxysterol 7-hydroxylase activity by cholesterol 7-hydroxylase (CYP7A). J Biol Chem 275:34046–34053[Abstract/Free Full Text]
70. Norlin M, Toll A, Bjorkhem I, Wikvall K 2000 24-Hydroxycholesterol is a substrate for hepatic cholesterol 7-hydroxylase (CYP7A). J Lipid Res 41:1629–1639[Abstract/Free Full Text]
71. Bjorkhem I, Andersson O, Diczfalusy U, Sevastik B, Xiu RJ, Duan C, Lund E 1994 Atherosclerosis and sterol 27-hydroxylase: evidence for a role of this enzyme in elimination of cholesterol from human macrophages. Proc Natl Acad Sci USA 91:8592–8596[Abstract/Free Full Text]
72. Bjorkhem I, Diczfalusy U, Lutjohann D 1999 Removal of cholesterol from extrahepatic sources by oxidative mechanisms. Curr Opin Lipidol 10:161–165[CrossRef][Medline]
73. Setchell KD, Street JM 1987 Inborn errors of bile acid synthesis. Semin Liver Dis 7:85–99[Medline]
74. Balistreri WF 1999 Inborn errors of bile acid biosynthesis and transport. Novel forms of metabolic liver disease. Gastroenterol Clin North Am 28:145–172[CrossRef][Medline]
75. Bove KE, Daugherty CC, Tyson W, Mierau G, Heubi JE, Balistreri WF, Setchell KD 2000 Bile acid synthetic defects and liver disease. Pediatr Dev Pathol 3:1–16[CrossRef][Medline]
76. Trauner M, Meier PJ, Boyer JL 1998 Molecular pathogenesis of cholestasis. N Engl J Med 339:1217–1227[Free Full Text]
77. Schwarz M, Wright AC, Davis DL, Nazer H, Bjorkhem I, Russell DW 2000 The bile acid synthetic gene 3ß-hydroxy-(5)-C(27)-steroid oxidoreductase is mutated in progressive intrahepatic cholestasis. J Clin Invest 106:1175–1184[Medline]
78. Clayton PT, Leonard JV, Lawson AM, Setchell KD, Andersson S, Egestad B, Sjovall J 1987 Familial giant cell hepatitis associated with synthesis of 3ß,7-dihydroxy- and 3ß,7, 12-trihydroxy-5-cholenoic acids. J Clin Invest 79:1031–1038
79. Buchmann MS, Kvittingen EA, Nazer H, Gunasekaran T, Clayton PT, Sjovall J, Bjorkhem I 1990 Lack of 3ß-hydroxy-5-C27-steroid dehydrogenase/isomerase in fibroblasts from a child with urinary excretion of 3ß-hydroxy-5-bile acids. A new inborn error of metabolism. J Clin Invest 86:2034–2037
80. Setchell KD, Suchy FJ, Welsh MB, Zimmer-Nechemias L, Heubi J, Balistreri WF 1988 4–3-Oxosteroid 5ß-reductase deficiency described in identical twins with neonatal hepatitis. A new inborn error in bile acid synthesis. J Clin Invest 82:2148–2157
81. Shneider BL, Setchell KD, Whitington PF, Neilson KA, Suchy FJ 1994 4–3-Oxosteroid 5ß-reductase deficiency causing neonatal liver failure and hemochromatosis. J Pediatr 124:234–238[Medline]
82. Bjorkhem I, Leitersdorf I 2000 Sterol 27-hydroxylase deficiency: a rare cause of xanthomas in normocholesterolemic humans. Trends Endocrinol Metab 11:180–183[CrossRef][Medline]
83. Clayton PT 1991 Inborn errors of bile acid metabolism. J Inherit Metab Dis 14:478–496[CrossRef][Medline]
84. Alley TL, Scherer SW, Huizenga JJ, Tsui LC, Wallace MR 1997 Physical mapping of the chromosome 7 breakpoint region in an SLOS patient with t(7;20) (q32.1;q13.2). Am J Med Genet 68:279–281[CrossRef][Medline]
85. Tint GS, Irons M, Elias ER, Batta AK, Frieden R, Chen TS, Salen G 1994 Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N Engl J Med 330:107–113[Abstract/Free Full Text]
86. Arnon R, Yoshimura T, Reiss A, Budai K, Lefkowitch JH, Javitt NB 1998 Cholesterol 7-hydroxylase knockout mouse: a model for monohydroxy bile acid-related neonatal cholestasis. Gastroenterology 115:1223–1228[CrossRef][Medline]
87. Angelin B, Einarsson K, Hellstrom K, Leijd B 1978 Bile acid kinetics in relation to endogenous triglyceride metabolism in various types of hyperlipoproteinemia. J Lipid Res 19:1004–1016[Abstract]
88. Paumgartner G, Sauerbruch T 1991 Gallstones: pathogenesis. Lancet 338:1117–1121[CrossRef][Medline]
89. Berr F, Pratschke E, Fisher S, Paumgartner G 1992 Disorders of bile acid metabolism in cholesterol gallstone disease. J Clin Invest 90:859–868
90. Khanuja B, Cheah Y-C, Hunt M, Nishina PM, Wang DQ, Chen HW, Billheimer JT, Carey MC, Paigen B 1995 Lith 1, a major gene affecting cholesterol gallstone formation among inbred strains of mice. Proc Natl Acad Sci USA 92:7729–7733[Abstract/Free Full Text]
91. Vega GL, von Bergmann K, Grundy SM, Beltz W, Jahn C, East C 1987 Increased catabolism of VLDL-apolipoprotein B and synthesis of bile acids in a case of hypobetalipoproteinemia. Metabolism 36:262–269[CrossRef][Medline]
92. Cohen JC, Cali JJ, Jelinek DF, Mehrabian M, Sparkes RS, Lusis AJ, Russell DW, Hobbs HH 1992 Cloning of the human cholesterol 7-hydroxylase gene (CYP7) and localization to chromosome 8q11–q12. Genomics 14:153–161[CrossRef][Medline]
93. Thompson JF, Lira ME, Lloyd DB, Hayes LS, Williams S, Elsenboss L 1993 Cholesterol 7-hydroxylase promoter separated from cyclophilin pseudogene by Alu sequence. Biochim Biophys Acta 1168:239–242[Medline]
94. Karam WG, Chiang JYL 1992 Polymorphisms of human cholesterol 7-hydroxylase. Biochem Biophys Res Commun 185:588–595[CrossRef][Medline]
95. Wang J, Freeman DJ, Grundy SM, Levine DM, Guerra R, Cohen JC 1998 Linkage between cholesterol 7-hydroxylase and high plasma low-density lipoprotein cholesterol concentration. J Clin Invest 101:1283–1291[Medline]
96. Setchell KDR, Schwarz M, O’Connell NC, Lund EG, Davis DL, Lathe R, Thompson HR, Weslie TR, Sokol RJ, Russell DW 1998 Identification of a new inborn error in bile acid synthesis: mutation of the oxysterol 7-hydroxylase gene causes severe neonatal liver disease. J Clin Invest 102:1690–1703[Medline]
97. Oftebro H, Bjorkhem I, Skrede S, Schreiner A, Pederson JI 1980 Cerebrotendinous xanthomatosis: a defect in mitochondrial 26-hydroxylation required for normal biosynthesis of cholic acid. J Clin Invest 65:1418–1430
98. Leitersdorf E, Safadi R, Meiner V, Reshef A, Bjorkhem I, Friedlander Y, Morkos S, Berginer VM 1994 Cerebrotendinous xanthomatosis in the Israeli Druze: molecular genetics and phenotypic characteristics. Am J Hum Genet 55:907–915[Medline]
99. Rosen H, Reshef A, Maeda N, Lippoldt A, Shpizen S, Triger L, Eggersen G, Bjorkhem I, Leitersdorf E 1998 Markedly reduced bile acid synthesis but maintained levels of cholesterol and vitamin D metabolites in mice with disrupted sterol 27-hydroxylase gene. J Biol Chem 273:14805–14812[Abstract/Free Full Text]
100. Repa JJ, Lund EG, Horton JD, Leitersdorf E, Russell DW, Dietschy JM, Turley SD 2000 Disruption of the sterol 27-hydroxylase gene in mice results in hepatomegaly and hypertriglycridemia: reversal by cholic acid feeding. J Biol Chem 275:39685–39692[Abstract/Free Full Text]
101. Li YC, Wang DP, Chiang JYL 1990 Regulation of cholesterol 7-hydroxylase in the liver: cDNA cloning, sequencing and regulation of cholesterol 7-hydroxylase mRNA. J Biol Chem 265:12012–12019[Abstract/Free Full Text]
102. Pandak WM, Li YC, Chiang JYL, Studer EJ, Gurley EC, Heuman DM, Vlahcevic ZR, Hylemon PB 1991 Regulation of cholesterol 7-hydroxylase mRNA and transcriptional activity by taurocholate and cholesterol in the chronic biliary diverted rat. J Biol Chem 266:3416–3421[Abstract/Free Full Text]
103. Hylemon PB, Gurley EC, Stravitz RT, Litz JS, Pandak WM, Chiang JY, Vlahcevic ZR 1992 Hormonal regulation of cholesterol 7-hydroxylase mRNA levels and transcriptional activity in primary rat hepatocyte cultures. J Biol Chem 267:16866–16871[Abstract/Free Full Text]
104. Crestani M, Galli G, Chiang JYL 1993 Genomic cloning, sequencing and analysis of hamster cholesterol 7-hydroxylase gene (CYP7). Arch Biochem Biophys 306:451–460[CrossRef][Medline]
105. Crestani M, Karam WG, Chiang JYL 1994 Effects of bile acids and steroid/thyroid hormones on the expression of cholesterol 7-hydroxylase mRNA and the CYP7 gene in HepG2 cells. Biochem Biophys Res Commun 198:546–553[CrossRef][Medline]
106. Crestani M, Sadeghpour A, Stroup D, Galli G, Chiang JYL 1996 The opposing effects of retinoic acid and phorbol esters converge to a common response element in the promoter of the rat cholesterol 7-hydroxylase gene (CYP7A). Biochem Biophys Res Commun 225:585–592[CrossRef][Medline]
107. Wang DP, Stroup D, Marrapodi M, Crestani M, Galli G, Chiang JYL 1996 Transcriptional regulation of the human cholesterol 7-hydroxylase gene (CYP7A) in HepG2 cells. J Lipid Res 37:1831–1841[Abstract]
108. Crestani M, Sadeghpour A, Stroup D, Gali G, Chiang JYL 1998 Transcriptional activation of the cholesterol 7-hydroxylase gene (CYP7A) by nuclear hormone receptors. J Lipid Res 39:2192–2200[Free Full Text]
109. Chiang JYL, Stroup D 1994 Identification and characterization of a putative bile acid responsive element in cholesterol 7-hydroxylase gene promoter. J Biol Chem 269:17502–17507[Abstract/Free Full Text]
110. Stroup D, Crestani M, Chiang JYL 1997 Identification of a bile acid response element in the cholesterol 7-hydroxylase gene (CYP7A). Am J Physiol 273:G508–G517
111. Stroup D, Crestani M, Chiang JYL 1997 Orphan receptors chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) and retinoid X receptor (RXR) activate and bind the rat cholesterol 7-hydroxylase gene (CYP7A). J Biol Chem 272:9833–9839[Abstract/Free Full Text]
112. Stroup D, Chiang JYL 2000 HNF4 and COUP-TFII interact to modulate transcription of the cholesterol 7-hydroxylase gene (CYP7A). J Lipid Res 41:1–11[Abstract/Free Full Text]
113. Marrapodi M, Chiang JYL 2000 Peroxisome proliferators down-regulate the expression of the human cholesterol 7-hydroxylase gene (CYP7A1). J Lipid Res 41:514–520[Abstract/Free Full Text]
114. Glass CK, Rose DW, Rosenfeld MG 1997 Nuclear receptor coactivators. Curr Opin Cell Biol 9:222–232[CrossRef][Medline]
115. Xu L, Glass CK, Rosenfeld MG 1999 Coactivator and corepressor complexes in nuclear receptor function. Curr Opin Genet Dev 9:140–147[CrossRef][Medline]
116. Mangelsdorf DJ, Evans RM 1995 The RXR heterodimers and orphan receptors. Cell 83:841–850[CrossRef][Medline]
117. Chambon P 1996 A decade of molecular biology of retinoic acid receptors. FASEB J 10:940–954[Abstract]
118. Kastner P, Mark M, Chambon P 1995 Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life? Cell 83:859–869[CrossRef][Medline]
119. Heyman RA, Mangelsdorf DJ, Dyck JA, Stein RB, Eichele G, Evans RM, Thaller C 1992 9-cis Retinoic acid is a high affinity ligand for the retinoid X receptor. Cell 68:397–406[CrossRef][Medline]
120. Crestani M, Stroup D, Chiang JYL 1995 Hormonal regulation of the cholesterol 7-hydroxylase gene (CYP7). J Lipid Res 36:2419–2432[Abstract]
121. Wan YJ, An D, Cai Y, Repa JJ, Hung-Po Chen T, Flores M, Postic C, Magnuson MA, Chen J, Chien KR, French S, Mangelsdorf DJ, Sucov HM 2000 Hepatocyte-specific mutation establishes retinoid X receptor as a heterodimeric integrator of multiple physiological processes in the liver. Mol Cell Biol 20:4436–4444[Abstract/Free Full Text]
122. Peet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro JM, Hammer RE, Mangelsdorf DJ 1998 Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR. Cell 93:693–704[CrossRef][Medline]
123. Willy P, Umesono K, Ong E, Evans R, Heyman R, Mangelsdorf D 1995 LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev 9:1033–1045[Abstract/Free Full Text]
124. Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ 1996 An oxysterol signalling pathway mediated by the nuclear receptor LXR. Nature 383:728–731[CrossRef][Medline]
125. Apfel R, Benbrook D, Lernhardt E, Ortiz MA, Salbert G, Pfahl M 1994 A novel orphan receptor specific for a subset of thyroid hormone-responsive elements and its interaction with the retinoid/thyroid hormone receptor subfamily. Mol Cell Biol 14:7025–7035[Abstract/Free Full Text]
126. Song C, Kokontis JM, Hipaka RA, Liao S 1994 Ubiquitous receptor: a receptor that modulates gene activation by retinoic acid and thyroid hormone receptors. Proc Natl Acad Sci USA 91:10809–10813[Abstract/Free Full Text]
127. Shinar DM, Endo N, Rutledge SJ, Vogel R, Rodan GA, Schmidt A 1994 NER, a new member of the gene family encoding the human steroid hormone nuclear receptor. Gene 147:273–276[CrossRef][Medline]
128. Seol W, Choi HS, Moore DD 1995 Isolation of proteins that interact specifically with the retinoid X receptor: two novel orphan receptors. Mol Endocrinol 9:72–85[Abstract/Free Full Text]
129. Teboul M, Enmark E, Li Q, Wikstrom AC, Pelto-Huikko M, Gustafsson J-A 1995 OR-1, a member of the nuclear receptor superfamily that interacts with the 9-cis-retinoic acid receptor. Proc Natl Acad Sci USA 92:2096–2100[Abstract/Free Full Text]
130. Janowski BA, Grogan MJ, Jones SA, Wisely GB, Kliewer SA, Corey EJ, Mangelsdorf DJ 1999 Structural requirements of ligands for the oxysterol liver X receptors LXR and LXRß. Proc Natl Acad Sci USA 96:266–271[Abstract/Free Full Text]
131. Fu X, Menke JG, Chen Y, Zhou G, MacNaul KL, Wright SD, Sparrow CP, Lund EG 2001 27-Hydroxycholesterol is an endogenous ligand for LXR in cholesterol-loaded cells. J Biol Chem 276:38378–38387[Abstract/Free Full Text]
132. Song C, Hiipakka RA, Liao S 2000 Selective activation of liver X receptor by 6-hydroxy bile acids and analogs. Steroids 65:423–427[CrossRef][Medline]
133. Song C, Liao S 2000 Cholestenoic acid is a naturally occurring ligand for liver X receptor . Endocrinology 141:4180–4184[Abstract/Free Full Text]
134. Forman BM, Ruan B, Chen J, Schroepfer GJ, Evans RM 1997 The orphan nuclear receptor LXR is positively and negatively regulated by distinct products of mevalonate metabolism. Proc Natl Acad Sci USA 94:10588–10593[Abstract/Free Full Text]
135. Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I, Shan B, Brown MS, Goldstein JL, Mangelsdorf DJ 2000 Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXR and LXRß. Genes Dev 14:2819–2830[Abstract/Free Full Text]
136. DeBose-Boyd RA, Ou J, Goldstein JL, Brown MS 2001 Expression of sterol regulatory element-binding protein 1c (SREBP-1c) mRNA in rat hepatoma cells requires endogenous LXR ligands. Proc Natl Acad Sci USA 98:1477–1482[Abstract/Free Full Text]
137. Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S, Wang S, Thoolen M, Mangelsdorf DJ, Lustig KD, Shan B 2000 Role of LXRs in control of lipogenesis. Genes Dev 14:2831–2838[Abstract/Free Full Text]
138. Alberti S, Schuster G, Parini P, Feltkamp D, Diczfalusy U, Rudling M, Angelin B, Bjorkhem I, Pettersson S, Gustafsson JA 2001 Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRß-deficient mice. J Clin Invest 107:565–573[Medline]
139. Repa JJ, Turley SD, Lobaccaro JA, Medina J, Li L, Lustig K, Shan B, Heyman RA, Dietschy JM, Mangelsdorf DJ 2000 Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science 289:1524–1529[Abstract/Free Full Text]
140. Chiang JYL, Kimmel R, Weinberger C, Stroup D 2000 FXR responds to bile acids and represses cholesterol 7-hydroxylase gene (CYP7A1) transcription. J Biol Chem 275:10918–10924[Abstract/Free Full Text]
141. Bodzioch M, Orso E, Klucken J, Langmann T, Bottcher A, Diederich W, Drobnik, W, Barlage S, Buchler C, Porsch-Ozcurumez M, Kaminski WE, Hahmann HW, Oette K, Rothe G, Aslanidis C, Lackner KJ, Schmitz G 1999 The gene encoding ATP-binding cassette transporter 1 is mutated in Tangier disease. Nat Genet 22:347–351[CrossRef][Medline]
142. Drobnik W, Lindenthal B, Lieser B, Ritter M, Christiansen Weber T, Liebisch G, Giesa U, Igel M, Borsukova H, Buchler C, Fung-Leung WP, Von Bergmann K, Schmitz G 2001 ATP-binding cassette transporter A1 (ABCA1) affects total body sterol metabolism. Gastroenterology 120:1203–1211[CrossRef][Medline]
143. McNeish J, Aiello RJ, Guyot D, Turi T, Gabel C, Aldinger C, Hoppe KL, Roach ML, Royer LJ, de Wet J, Broccardo C, Chimini G, Francone OL 2000 High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1. Proc Natl Acad Sci USA 97:4245–4250[Abstract/Free Full Text]
144. Berge KE, Tian H, Graf GA, Yu L, Grishin NV, Schultz J, Kwiterovich P, Shan B, Barnes R, Hobbs HH 2000 Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 290:1771–1775[Abstract/Free Full Text]
145. Lee MH, Lu K, Hazard S, Yu H, Shulenin S, Hidaka H, Kojima H, Allikmets R, Sakuma N, Pegoraro R, Srivastava AK, Salen G, Dean M, Patel SB 2001 Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat Genet 27:79–83[Medline]
146. Costet P, Luo Y, Wang N, Tall AR 2000 Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J Biol Chem 275:28240–28245[Abstract/Free Full Text]
147. Schwartz K, Lawn RM, Wade DP 2000 ABC1 gene expression and ApoA-I-mediated cholesterol efflux are regulated by LXR. Biochem Biophys Res Commun 274:794–802[CrossRef][Medline]
148. Venkateswaran A, Repa JJ, Lobaccaro JM, Bronson A, Mangelsdorf DJ, Edwards PA 2000 Human white/murine ABC8 mRNA levels are highly induced in lipid-loaded macrophages. A transcriptional role for specific oxysterols. J Biol Chem 275:14700–14707[Abstract/Free Full Text]
149. Laffitte BA, Repa JJ, Joseph SB, Wilpitz DC, Kast HR, Mangelsdorf DJ, Tontonoz P 2001 LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc Natl Acad Sci USA 98:507–512[Abstract/Free Full Text]
150. Luo Y, Tall AR 2000 Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element. J Clin Invest 105:513–520[Medline]
151. Zhang Y, Repa JJ, Gauthier K, Mangelsdorf DJ 2001 Regulation of lipoprotein lipase by the oxysterol receptors, LXR and LXRß. J Biol Chem 276:43018–43024[Abstract/Free Full Text]
152. Whitney KD, Watson MA, Goodwin B, Galardi CM, Maglich JM, Wilson JG, Willson TM, Collins JL, Kliewer SA 2001 Liver X receptor (LXR) regulation of the LXR gene in human macrophages. J Biol Chem 276:43509–43515[Abstract/Free Full Text]
153. Forman BM, Goode E, Chen J, Oro AE, Bradley DJ, Perlmann T, Noonan DJ, Burka LT, McMorris T, Lamph WW, Evans RW, Weinberger C 1995 Identification of a nuclear receptor that is activated by farnesol metabolites. Cell 81:687–693[CrossRef][Medline]
154. Zavacki AM, Lehmann JM, Seol W, Willson TM, Kliewer SA, Moore DD 1997 Activation of the orphan receptor RIP14 by retinoids. Proc Natl Acad Sci USA 94:7909–7914[Abstract/Free Full Text]
155. Chen W, Owsley E, Yang Y, Stroup D, Chiang JY 2001 Nuclear receptor-mediated repression of human cholesterol 7-hydroxylase gene transcription by bile acids. J Lipid Res 42:1402–1412[Abstract/Free Full Text]
156. Chiang JYL, Chen WC, Zhang M, Cowsley E, Yang YZ 2001 Nuclear receptor regulation of the human cholesterol 7-hydroxylase, sterol 27-hydroxylase and sterol 12-hydroxylase gene in bile acid synthesis. In: van Berge Henegouwen GP, Keppler D, Leuschner U, Paumgartner G, Stiehl A, eds. Biology of bile acids in health and disease. Lancaster, UK: Kluwer Academic Publishers;17–25
157. Zhang M, Chiang JY 2001 Transcriptional regulation of the human sterol 12-hydroxylase gene (CYP8B1): roles of hepatocyte nuclear factor 4 (HNF4) in mediating bile acid repression. J Biol Chem 276:41690–41699[Abstract/Free Full Text]
158. Denson LA, Sturm E, Echevarria W, Zimmerman TL, Makishima M, Mangelsdorf DJ, Karpen SJ 2001 The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp. Gastroenterology 121:140–147[CrossRef][Medline]
159. Grober J, Zaghini I, Fujii H, Jones SA, Kliewer SA, Willson TM, Ono T, Besnard P 1999 Identification of a bile acid-responsive element in the human ileal bile acid-binding protein gene. Involvement Of the farnesoid X receptor/9-cis-retinoic acid receptor heterodimer. J Biol Chem 274:29749–29754[Abstract/Free Full Text]
160. Ananthanarayanan M, Balasubramanian NV, Makishima M, Mangelsdorf DJ, Suchy FJ 2001 Human bile salt export pump (BSEP) promoter is transactivated by the farnesoid X receptor/bile acid receptor (FXR/BAR). J Biol Chem 276:28857–28865[Abstract/Free Full Text]
161. Urizar NL, Dowhan DH, Moore DD 2000 The farnesoid X-activated receptor mediates bile acid activation of phospholipid transfer protein gene expression. J Biol Chem 275:39313–39317[Abstract/Free Full Text]
162. Kast HR, Nguyen CM, Sinal CJ, Jones SA, Laffitte BA, Reve K, Gonzalez FJ, Willson TM, Edwards PA 2001 Farnesoid X-activated receptor induces apolipoprotein c-II transcription: a molecular mechanism linking plasma triglyceride levels to bile acids. Mol Endocrinol 15:1720–1728[Abstract/Free Full Text]
163. Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ 2000 Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102:731–744[CrossRef][Medline]
164. Desvergne B, Wahli W 1999 Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 20:649–688[Abstract/Free Full Text]
165. Kersten S, Desvergne B, Wahli W 2000 Roles of PPARs in health and disease. Nature 405:421–424[CrossRef][Medline]
166. Keller H, Dreyer C, Medin J, Mahfoudi A, Ozato K, Wahli W 1993 Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers. Proc Natl Acad Sci USA 90:2160–2164[Abstract/Free Full Text]
167. Devchand PR, Keller H, Peters JM, Vazquez M, Gonzalez FJ, Wahli W 1996 The PPAR-leukotriene B4 pathway to inflammation control. Nature 384:39–43[CrossRef][Medline]
168. Schoonjans K, Staels B, Auwerx J 1996 Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. J Lipid Res 37:907–925[Abstract]
169. Stahlberg D, Reihner E, Rudling M, Berglund L, Einarsson K, Angelin B 1994 Influence of bezafibrate on hepatic cholesterol metabolism in gallstone patients: reduced activity of cholesterol 7-hydroxylase. Hepatology 21:1025–1030[CrossRef]
170. Bertolotti M, Concari M, Loria P, Abate N, Pinetti A, Guicciardi ME, Carulli N 1995 Effects of different phenotypes of hyperlipoproteinemia and of treatment with fibric acid derivatives on the rates of cholesterol 7-hydroxylation in humans. Arterioscler Thromb Vasc Biol 15:1064–1069[Abstract/Free Full Text]
171. Patel DD, Knight BL, Soutar AK, Gibbons GF, Wade DP 2000 The effect of peroxisome-proliferator-activated receptor- on the activity of the cholesterol 7-hydroxylase gene. Biochem J 351:747–753
172. Hunt MC, Yang YZ, Eggertsen G, Carneheim CM, Gafvels M, Einarsson C, Alexson SE 2000 The peroxisome proliferator-activated receptor (PPAR) regulates bile acid biosynthesis. J Biol Chem 275:28947–28953[Abstract/Free Full Text]
173. Post SM, Duez H, Gervois PP, Staels B, Kuipers F, Princen HM 2001 Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-mediated downregulation of cholesterol 7-hydroxylase and sterol 27-hydroxylase expression. Arterioscler Thromb Vasc Biol 21:1840–1845[Abstract/Free Full Text]
174. Tobin KA, Steineger HH, Alberti S, Spydervold O, Auwerx J, Gustafsson JA, Nebb HI 2000 Cross-talk between fatty acid and cholesterol metabolism mediated by liver X receptor-. Mol Endocrinol 14:741–752[Abstract/Free Full Text]
175. Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, Liao D, Nagy L, Edwards PA, Curtiss LK, Evans RM, Tontonoz P 2001 A PPAR-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell 7:161–171[CrossRef][Medline]
176. Sinal CJ, Yoon M, Gonzalez FJ 2001 Antagonism of the actions of peroxisome proliferator-activated receptor by bile acids. J Biol Chem 276:47154–47162[Abstract/Free Full Text]
177. Harnish DC, Malik S, Kilbourne E, Costa R, Karathanasis SK 1996 Control of apolipoprotein AI gene expression through synergistic interactions between hepatocyte nuclear factors 3 and 4. J Biol Chem 271:13621–13628[Abstract/Free Full Text]
178. Vergnes L, Taniguchi T, Omori K, Zakin MM, Ocha A 1997 The apolipoprotein A-I/C-III/A-IV gene cluster: ApoC-III and ApoA-IV expression is regulated by two common enhancers. Biochim Biophys Acta 1348:299–310[Medline]
179. Jiang G, Nepomuceno L, Hopkins K, Sladek FM 1995 Exclusive homodimerization of the orphan receptor hepatocyte nuclear factor 4 defines a new subclass of nuclear receptors. Mol Cell Biol 15:5131–5143[Abstract]
180. Ginsburg GS, Ozer J, Karathanasis SK 1995 Intestinal apolipoprotein A1 gene transcription is regulated by multiple distinct DNA elements and is synergistically activated by the orphan nuclear receptor, hepatocyte nuclear factor 4. J Clin Invest 96:528–538
181. Sladek FM, Zhong W, Lai E, Darnell JE 1990 Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Gene Dev 4:2353–2365[Abstract/Free Full Text]
182. Hertz R, Seckbach M, Zakin MM, Bar-Tana J 1996 Transcriptional suppression of the transferrin gene by hypolipidemic peroxisome proliferators. J Biol Chem 271:218–224[Abstract/Free Full Text]
183. Cooper AD 1997 Bile salts biosynthesis: an alternate synthetic pathway joins the mainstream. Gastroenterology 113:2005–2008[Medline]
184. Yang Y, Zhang M, Eggertsen G, Chiang JYL 2002 On the mechanism of bile acid inhibition of rat sterol 12-hydroxylase (CYP8B1) transcription: roles of -fetoprotein transcription factor (FTF) and hepatocyte nuclear factor 4 (HNF4). Biochim Biophys Acta 1583:63–73[Medline]
185. Viollet B, Kahn A, Raymondjean M 1997 Protein kinase A-dependent phosphorylation modulates DNA-binding activity of hepatocyte nuclear factor 4. Mol Cell Biol 17:4208–4219[Abstract]
186. De Fabiani E, Mitro N, Anzulovich AC, Pinelli A, Galli G, Crestani M 2001 The negative effects of bile acids and tumor necrosis factor- on the transcription of cholesterol 7-hydroxylase gene (CYP7A1) converge to hepatic nuclear factor-4. A novel mechanism of feedback regulation of bile acid synthesis mediated by nuclear receptors. J Biol Chem 276:30708–30716[Abstract/Free Full Text]
187. Yamagata K, Furuta H, Oda N, Kaisaki PJ, Menzel S, Cox NJ, Fajans SS, Signorini S, Stoffel M, Bell GI 1996 Mutations in the hepatocyte nuclear factors-4 gene in maturity-onset diabetes of the young (MODY1). Nature 384:458–460[CrossRef][Medline]
188. Stoffel M, Duncan SA 1997 The maturity-onset diabetes of the young (MODY1) transcription factor HNF4 regulates expression of genes required for glucose transport and metabolism. Proc Natl Acad Sci USA 94:13209–13214[Abstract/Free Full Text]
189. Yamagata K, Oda N, Kaisaki PJ, Menzel S, Furuta H, Vaxillaire M, Southam L, Cox RD, Lathrop GM, Boriraj VV, Chen X, Cox NJ, Oda Y, Yano H, Le Beau MM, Yamada S, Nishigori H, Takeda J, Fajans SS, Hattersley AT, Iwasaki N, Hansen T, Pedersen O, Polonsky KS, Turner RC, Velho G, Chevre JC, Froguel P, Bell GI 1996 Mutations in the hepatocyte nuclear factor-1 gene in maturity-onset diabetes of the young (MODY3). Nature 384:455–458[CrossRef][Medline]
190. Iwasaki N, Oda N, Ogata M, Hara M, Hinokio Y, Oda Y, Yamagata K, Kanematsu S, Ohgawara H, Omori Y, Bell GI 1997 Mutations in the hepatocyte nuclear factor-1/MODY3 gene in Japanese subjects with early- and late-onset NIDDM. Diabetes 46:1504–1508[Abstract]
191. Hayhurst GP, Lee YH, Lambert G, Ward JM, Gonzalez FJ 2001 Hepatocyte nuclear factor 4 (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Mol Cell Biol 21:1393–1403[Abstract/Free Full Text]
192. Parker KL, Schimmer BP 1997 Steroidogenic factor 1: a key determinant of endocrine development and function. Endocr Rev 18:361–377[Abstract/Free Full Text]
193. Parker KL 1998 The roles of steroidogenic factor 1 in endocrine development and function. Mol Cell Endocrinol 140:59–63[CrossRef][Medline]
194. Lavorgna G, Ueda H, Clos J, Wu C 1991 FTZ-F1, a steroid hormone receptor-like protein implicated in the activation of fushi tarazu. Science 252:848–851[Abstract/Free Full Text]
195. Lala DS, Rice DA, Parker KL 1992 Steroidogenic factor I, a key regulator of steroidogenic enzyme expression, is the mouse homolog of fushi tarazu-factor I. Mol Endocrinol 6:1249–1258[Abstract/Free Full Text]
196. Galarneau L, Pare JF, Allard D, Hamel D, Levesque L, Tugwod JD, Green S, Belanger L 1996 The 1-fetoprotein locus is activated by a nuclear receptor of the Drosophila FTZ-F1 family. Mol Cell Biol 16:3853–3865[Abstract]
197. Nitta M, Ku S, Brown C, Okamoto AY, Shan B 1999 CPF: an orphan nuclear receptor that regulates liver-specific expression of the human cholesterol 7-hydroxylase gene. Proc Natl Acad Sci USA 96:6660–6665[Abstract/Free Full Text]
198. Li M, Xie YH, Kong YY, Wu X, Zhu L, Wang Y 1998 Cloning and characterization of a novel human hepatocyte transcription factor, hB1F, which binds and activates enhancer II of hepatitis B virus. J Biol Chem 273:29022–29031[Abstract/Free Full Text]
199. Galarneau L, Drouin R, Belanger L 1998 Assignment of the fetoprotein transcription factor gene (FTF) to human chromosome band 1q32.11 by in situ hybridization. Cytogenet Cell Genet 82:269–270[CrossRef][Medline]
200. Ellinger-Ziegelbauer H, Hihi AK, Laudet V, Keller H, Wahli W, Dreyer C 1994 FTZ-F1-related orphan receptors in Xenopus laevis: transcriptional regulators differentially expressed during early embryogenesis. Mol Cell Biol 14:2786–2797[Abstract/Free Full Text]
201. Lin W, Wang HW, Sum C, Liu D, Hew CL, Chung B 2000 Zebrafish ftz-f1 gene has two promoters, is alternatively spliced, and is expressed in digestive organs. Biochem J 348:439–446
202. Pare JF, Roy S, Galarneau L, Belanger L 2001 The mouse fetoprotein transcription factor (FTF) gene promoter is regulated by three GATA elements with tandem E-box and Nkx motifs, and FTF in turn activates the HNF3ß, HNF4 and HNF1 gene promoters. J Biol Chem 276:13136–13144[Abstract/Free Full Text]
203. Lala DS, Syka PM, Lazarchik SB, Mangelsdorf DJ, Parker KL 1997 Activation of the orphan nuclear receptor steroidogenic factor 1 by oxysterols. Proc Natl Acad Sci USA 94:4895–4900[Abstract/Free Full Text]
204. Oba K, Yanase T, Ichino I, Goto K, Takayanagi R, Nawata H 2000 Transcriptional regulation of the human FTZ-F1 gene encoding Ad4BP/SF-1. J Biochem (Tokyo) 128:517–528[Abstract/Free Full Text]
205. Lee YK, Parker KL, Choi HS, Moore DD 1999 Activation of the promoter of the orphan receptor SHP by orphan receptors that bind DNA as monomers. J Biol Chem 274:20869–20873[Abstract/Free Full Text]
206. Gilbert S, Galarneau L, Lamontagne A, Roy S, Belanger L 2000 The hepatitis B virus core promoter is strongly activated by the liver nuclear receptor fetoprotein transcription factor or by ectopically expressed steroidogenic factor 1. J Virol 74:5032–5039[Abstract/Free Full Text]
207. del Castillo-Olivares A, Gil G 2000 1-Fetoprotein transcription factor is required for the expression of sterol 12 -hydroxylase, the specific enzyme for cholic acid synthesis. Potential role in the bile acid-mediated regulation of gene transcription. J Biol Chem 275:17793–17799[Abstract/Free Full Text]
208. Luo Y, Liang Cp C, Tall AR 2001 The orphan nuclear receptor LRH-1 potentiates the sterol-mediated induction of the human CETP gene by LXR. J Biol Chem 276:24767–24773[Abstract/Free Full Text]
209. Inokuchi A, Hinoshita E, Iwamoto Y, Kohno K, Kuwano M, Uchiumi T 2001 Enhanced expression of the human multidrug resistance protein 3 by bile salt in human enterocytes: a transcriptional control of a plausible bile acid transporter. J Biol Chem 276:46822–46829[Abstract/Free Full Text]
210. Seol W, Choi HS, Moore DD 1996 An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors. Science 272:1336–1339[Abstract]
211. Seol W, Chung M, Moore DD 1997 Novel receptor interaction and repression domains in the orphan receptor SHP. Mol Cell Biol 17:7126–7131[Abstract]
212. Johansson L, Thomsen JS, Damdimopoulos AE, Spyrou G, Gustafsson JA, Treuter E 1999 The orphan nuclear receptor SHP inhibits agonist-dependent transcriptional activity of estrogen receptors ER and ERß. J Biol Chem 274:345–353[Abstract/Free Full Text]
213. Masuda N, Yasumo H, Tamura T, Hashiguchi N, Furusawa T, Tsukamoto T, Sadano H, Osumi T 1997 An orphan nuclear receptor lacking a zinc-finger DNA-binding domain: interaction with several nuclear receptors. Biochim Biophys Acta 1350:27–32[Medline]
214. Seol W, Hanstein B, Brown M, Moore DD 1998 Inhibition of estrogen receptor action by the orphan receptor SHP (short heterodimer partner). Mol Endocrinol 12:1551–1557[Abstract/Free Full Text]
215. Lee YK, Dell H, Dowhan DH, Hadzopoulou-Cladaras M, Moore DD 2000 The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: two mechanisms for repression. Mol Cell Biol 20:187–195[Abstract/Free Full Text]
216. Zanaria E, Muscatelli F, Bardoni B, Strom TM, Guioli S, Guo W, Lalli E, Moser C, Walker AP, McCabe ER, Meitinger T, Monaco AP, Sassone-Corsi P, Camerino G 1994 An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita. Nature 372:635–641[CrossRef][Medline]
217. Lalli E, Bardoni B, Zazopoulos E, Wurtz JM, Strom TM, Moras D, Sassone-Corsi P 1997 A transcriptional silencing domain in DAX-1 whose mutation causes adrenal hypoplasia congenita. Mol Endocrinol 11:1950–1960[Abstract/Free Full Text]
218. Ito M, Yu R, Jameson JL 1997 DAX-1 inhibits SF-1-mediated transactivation via a carboxy-terminal domain that is deleted in adrenal hypoplasia congenita. Mol Cell Biol 17:1476–1483[Abstract]
219. Nishigori H, Tomura H, Tonooka N, Kanamori M, Yamada S, Sho K, Inoue I, Kikuchi N, Onigata K, Kojima I, Koham T, Yamagata K, Yang Q, Matsuzawa Y, Miki T, Seino S, Kim MY, Choi HS, Lee YK, Moore DD, Takeda J 2001 Mutations in the small heterodimer partner gene are associated with mild obesity in Japanese subjects. Proc Natl Acad Sci USA 98:575–580[Abstract/Free Full Text]
220. Kliewer SA, Moore JT, Wade L, Staudinger JL, Watson MA, Jones SA, McKee DD, Oliver BB, Willson TM, Zetterstrom RH, Perlmann T, Lehmann JM 1998 An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway. Cell 92:73–82[CrossRef][Medline]
221. Blumberg B, Sabbagh Jr W, Juguilon H, Bolado Jr J, van Meter CM, Ong CS, Evans RM 1998 SXR, a novel steroid and xenobioticsensing nuclear receptor. Genes Dev 12:3195–3205[Abstract/Free Full Text]
222. Goodwin B, Redinbo MR, Kliewer SA 2002 Regulation of cyp3a gene transcription by the pregnane X receptor. Annu Rev Pharmacol Toxicol 42:1–23[CrossRef][Medline]
223. Staudinger JL, Goodwin B, Jones SA, Hawkins-Brown D, Mackenzie KI, LaTour A, Liu Y, Klaassen CD, Brown KK, Reinhard J, Willson TM, Koller BH, Kliewer SA 2001 The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc Natl Acad Sci USA 98:3369–3374[Abstract/Free Full Text]
224. Staudinger J, Liu Y, Madan A, Habeebu S, Klaassen CD 2001 Coordinate regulation of xenobiotic and bile acid homeostasis by pregnane X receptor. Drug Metab Dispos 29:1467–1472[Abstract/Free Full Text]
225. Xie W, Radominska-Pandya A, Shi Y, Simon CM, Nelson MC, Ong ES, Waxman DJ, Evans RM 2001 An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids. Proc Natl Acad Sci USA 98:3375–3380[Abstract/Free Full Text]
226. Chiang JYL, Miller WF, Lin GM 1990 Regulation of cholesterol 7-hydroxylase in the liver: purification of cholesterol 7-hydroxylase and the immunochemical evidence for the induction of cholesterol 7-hydroxylase by cholestyramine and circadian rhythm. J Biol Chem 265:3889–3897[Abstract/Free Full Text]
227. Sudjana-Sugiaman E, Eggertsen G, Bjorkhem I 1994 Stimulation of HMG-CoA reductase as a consequence of phenobarbital-induced primary stimmulation of cholesterol 7-hydroxylase in rat liver. J Lipid Res 35:319–327[Abstract]
228. Kast HR, Goodwin B, Tarr PT, Jones SA, Anisfeld AM, Stoltz CM, Tontonoz P, Kliewer S, Willson TM, Edwards PA 2002 Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid x-activated receptor, and constitutive androstane receptor. J Biol Chem 277:2908–2915[Abstract/Free Full Text]
229. Detmers PA, Patel S, Hernandez M, Montenegro J, Lisnock JM, Pikounis B, Steiner M, Kim D, Sparrow C, Chao YS, Wright SD 2000 A target for cholesterol absorption inhibitors in the enterocyte brush border membrane. Biochim Biophys Acta 1486:243–252[Medline]
230. Hernandez M, Montenegro J, Steiner M, Kim D, Sparrow C, Detmers PA, Wright SD, Chao YS 2000 Intestinal absorption of cholesterol is mediated by a saturable, inhibitable transporter. Biochim Biophys Acta 1486:232–242[Medline]
231. Kramer W, Glombik H, Petry S, Hever H, Schafer H, Wendler W, Corsiero D, Girbig F, Weyland C 2000 Identification of binding proteins for cholesterol absorption inhibitors as components of the intestinal cholesterol transporter. FEBS Lett 487:293–297[CrossRef][Medline]
232. Rust S, Rosier M, Funke H, Real J, Amoura Z, Piette JC, Deleuze JF, Brewer HB, Duverger N, Denefle P, Assmann G 1999 Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1. Nat Genet 22:352–355[CrossRef][Medline]
233. Lazaridis KN, Tietz P, Wu T, Kip S, Dawson PA, LaRusso NF 2000 Alternative splicing of the rat sodium/bile acid transporter changes its cellular localization and transport properties. Proc Natl Acad Sci USA 97:11092–11097[Abstract/Free Full Text]
234. Stravitz RT, Vlahcevic ZR, Gurley EC, Hylemons PB 1995 Repression of cholesterol 7-hydroxylase transcription by bile acids is mediated through protein kinase C in primary cultures of rat hepatocytes. J Lipid Res 36:1359–1368[Abstract]
235. Miyake JH, Wang SL, Davis RA 2000 Bile acid induction of cytokine expression by macrophages correlates with repression of hepatic cholesterol 7-hydroxylase. J Biol Chem 275:21805–21808[Abstract/Free Full Text]
236. Feingold KR, Spady DK, Pollock AS, Moser AH, Grunfeld C 1996 Endotoxin, TNF, and IL-1 decrease cholesterol 7-hydroxylase mRNA levels and activity. J Lipid Res 37:223–228[Abstract]
237. Stravitz RT, Rao YP, Vlahcevic ZR, Gurley EC, Jarvis WD, Hylemon PB 1996 Hepatocellular protein kinase C activation by bile acids: implications for regulation of cholesterol 7-hydroxylase. Am J Physiol 34:G293–G303
238. Stravitz RT, Vlahcevic ZR, Hylemon PB 1999 Signal transduction pathways regulating cholesterol 7-hydroxylase transcription by bile acids. In: Paumgaartner G, Stiel A, Gerok W, Keppler D, Leuschner U, eds. Dordrecht, Germany: Kluwer Academic Pubishers; 39–50
239. Gupta S, Stravitz RT, Dent P, Hylemon PB 2001 Down-regulation of cholesterol 7-hydroxylase (CYP7A1) gene expression by bile acids in primary rat hepatocytes is mediated by the c-Jun N-terminal kinase pathway. J Biol Chem 276:15816–15822[Abstract/Free Full Text]
240. Chang L, Karin M 2001 Mammalian MAP kinase signalling cascades. Nature 410:37–40[CrossRef][Medline]
241. Izzat NN, Deshazer ME, Loose-Mitchell DS 2000 New molecular targets for cholesterol-lowering therapy. J Pharmacol Exp Ther 293:315–320[Abstract/Free Full Text]
242. Spady DK, Cuthbert JA, Willard MN, Meidell RS 1998 Overexpression of cholesterol 7-hydroxylase (CYP7A) in mice lacking the low density lipoprotein (LDL) receptor gene. LDL transport and plasma LDL concentrations are reduced. J Biol Chem 273:126–132[Abstract/Free Full Text]
243. Moore GL, Drevon CA, Machleder D, Trawick JD, McClelland A, Roy S, Lyons R, Jambou R, Davis RA 1997 Expression of human cholesterol 7-hydroxylase in atherosclerosis-susceptible mice via adenovirus infection. Biochem J 324:863–869
244. Agellon LB 1997 Partial transfection of liver with a synthetic cholesterol 7-hydroxylase transgene is sufficient to stimulate the reduction of cholesterol in the plasma of hypercholesterolemic mice. Biochem Cell Biol 75:255–262[CrossRef][Medline]
245. Pandak WM, Schwarz C, Hylemon PB, Mallonee D, Valerie K, Heuman DM, Fisher RA, Redford K, Vlahcevic ZR 2001 Effects of CYP7A1 overexpression on cholesterol and bile acid homeostasis. Am J Physiol Gastrointest Liver Physiol 281:G878–G889
246. Miyake JH, Doung XD, Strauss W, Moore GL, Castellani LW, Curtiss LK, Taylor JM, Davis RA 2001 Increased production of Apo B100-containing lipoproteins in the absence of hyperlipidemia in transgenic mice expressing cholesterol 7-hydroxylase. J Biol Chem 276:23304–23311[Abstract/Free Full Text]
247. Miyake JH, Duong-Polk XT, Taylor JM, Du EZ, Castellani LW, Lusis AJ, Davis RA 2002 Transgenic expression of cholesterol 7-hydroxylase prevents atherosclerosis in C57BL/6J mice. Arterioscler Thromb Vasc Biol 22:121–126[Abstract/Free Full Text]
248. Hall E, Hylemon P, Vlahcevic Z, Mallonee D, Valerie K, Avadhani N, Pandak W 2001 Overexpression of CYP27 in hepatic and extrahepatic cells: role in the regulation of cholesterol homeostasis. Am J Physiol Gastrointest Liver Physiol 281:G293–G301
249. Maloney PR, Parks DJ, Haffner CD, Fivush AM, Chandra G, Plunket KD, Creech KL, Moore LB, Wilson JG, Jones SA, Willson TM 2000 Identification of a chemical tool for the orphan nuclear receptor FXR. J Med Chem 43:2971–2974[CrossRef][Medline]
250. Kramer W, Wess G 1996 Bile acid transport systems as pharmaceutical targets. Eur J Clin Invest 26:715–732[Medline]
251. Higaki J, Hara S, Takasu N, Tonda K, Miyata K, Shike T, Nagata K, Mizui T 1998 Inhibition of ileal Na+/bile acid cotransporter by S-8921 reduces serum cholesterol and prevents atherosclerosis in rabbits. Arterioscler Thromb Vasc Biol 18:1304–1311[Abstract/Free Full Text]
252. Benson GM, Alston DR, Hickey DM, Jaxa-Chamiec AA, Whittaker CM, Haynes C, Glen A, Blanchard S, Cresswell SR, Suckling KE 1997 SK&F 97426-A: a novel bile acid sequestrant with higher affinities and slower dissociation rates for bile acids in vitro than cholestyramine. J Pharm Sci 86:76–81[CrossRef][Medline]
253. Wilson TA, Nicolosi RJ, Rogers EJ, Sacchiero R, Goldberg DJ 1998 Studies of cholesterol and bile acid metabolism, and early atherogenesis in hamsters fed GT16–239, a novel bile acid sequestrant (BAS). Atherosclerosis 140:315–324[CrossRef][Medline]
254. Lu K, Lee MH, Patel SB 2001 Dietary cholesterol absorption; more than just bile. Trends Endocrinol Metab 12:314–320[CrossRef][Medline]
255. Harwood Jr HJ, Chandler CE, Pellarin LD, Bangerter RW, Wilkins RW, Long CA, Cosgrove PG, Malinow MR, Marzetta CA, Pettini JL, Savoy YE, Mayne JT 1993 Pharmacologic consequences of cholesterol absorption inhibition: alteration in cholesterol metabolism and reduction in plasma cholesterol concentration induced by the synthetic saponin ß-tigonenin cellobioside (CP-88818; tiqueside). J Lipid Res 34:377–395[Abstract]
256. Miettinen TA, Puska P, Gylling H, Vanhanen H, Vartiainen E 1995 Reduction of serum cholesterol with sitostanol-ester margarine in a mildly hypercholesterolemic population. N Engl J Med 333:1308–1312[Abstract/Free Full Text]
257. Laffitte BA, Joseph SB, Walczak R, Pei L, Wilpitz DC, Collins JL, Tontonoz P 2001 Autoregulation of the human liver X receptor promoter. Mol Cell Biol 21:7558–7568[Abstract/Free Full Text]
258. del Castillo-Olivares A, Gil G 2001 Suppression of sterol 12-hydroxylase transcription by the short heterodimer partner: insights into the repression mechanism. Nucleic Acids Res 29:4035–4042[Abstract/Free Full Text]
259. Pillinger CR, Eng C, Salen G, Shefer S, Batta AK, Erickson SK, Verhagen A, Rivera CR, Mulvihill SJ, Malloy MJ, Kane JP 2002 Human cholesterol 7-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype. J Clin Invest 110:109–117[CrossRef][Medline]
260. Wang L, Lee YK, Bundman D, Han Y, Thevananther S, Kim CS, Chua SS, Wei P, Heyman RA, Karin M, Moore DD 2002 Redundant pathways for negative feedback regulation of bile acid production. Dev Cell 6:721–731
261. Kerr TA, Saeki S, Schneider M, Schaefer K, Berdy S, Redder T, Shan B, Russell DW, Schwarz M 2002 Loss of nuclear receptor SHP impairs but does not eliminate negative feedback regulation of bile acid synthesis. Dev Cell 2:713–720[CrossRef][Medline]
262. Makishima M, Lu TT, Xie W, Whitfield GK, Domoto H, Evans RM, Haussler MR, Mangelsdorf DJ 2002 Vitamin D receptor as an intestinal bile acid sensor. Science 296:1313–1316[Abstract/Free Full Text]

This article has been cited by other articles:

				I. P. Y. Lam, L. T. O. Lee, H.-S. Choi, G. Alpini, and B. K. C. Chow Bile acids inhibit duodenal secretin expression via orphan nuclear receptor small heterodimer partner (SHP) Am J Physiol Gastrointest Liver Physiol, July 1, 2009; 297(1): G90 - G97. [Abstract] [Full Text] [PDF]

				Y. J. Cui, L. M. Aleksunes, Y. Tanaka, M. J. Goedken, and C. D. Klaassen Compensatory Induction of Liver Efflux Transporters in Response to ANIT-Induced Liver Injury Is Impaired in FXR-Null Mice Toxicol. Sci., July 1, 2009; 110(1): 47 - 60. [Abstract] [Full Text] [PDF]

				D.-J. Shin and T. F. Osborne FGF15/FGFR4 Integrates Growth Factor Signaling with Hepatic Bile Acid Metabolism and Insulin Action J. Biol. Chem., April 24, 2009; 284(17): 11110 - 11120. [Abstract] [Full Text] [PDF]

				T. H. van Dijk, A. Grefhorst, M. H. Oosterveer, V. W. Bloks, B. Staels, D.-J. Reijngoud, and F. Kuipers An Increased Flux through the Glucose 6-Phosphate Pool in Enterocytes Delays Glucose Absorption in Fxr-/- Mice J. Biol. Chem., April 17, 2009; 284(16): 10315 - 10323. [Abstract] [Full Text] [PDF]

				J. Miao, Z. Xiao, D. Kanamaluru, G. Min, P. M. Yau, T. D. Veenstra, E. Ellis, S. Strom, K. Suino-Powell, H. E. Xu, et al. Bile acid signaling pathways increase stability of Small Heterodimer Partner (SHP) by inhibiting ubiquitin-proteasomal degradation Genes & Dev., April 15, 2009; 23(8): 986 - 996. [Abstract] [Full Text] [PDF]

				S. Han and J. Y. L. Chiang Mechanism of Vitamin D Receptor Inhibition of Cholesterol 7{alpha}-Hydroxylase Gene Transcription in Human Hepatocytes Drug Metab. Dispos., March 1, 2009; 37(3): 469 - 478. [Abstract] [Full Text] [PDF]

				K. Ding and I. J. Kullo Evolutionary Genetics of Coronary Heart Disease Circulation, January 27, 2009; 119(3): 459 - 467. [Full Text] [PDF]

				M. J. Park, K. H. Kim, H. Y. Kim, K. Kim, and J. Cheong Bile acid induces expression of COX-2 through the homeodomain transcription factor CDX1 and orphan nuclear receptor SHP in human gastric cancer cells Carcinogenesis, December 1, 2008; 29(12): 2385 - 2393. [Abstract] [Full Text] [PDF]

				A. K. Deo and S. M. Bandiera Identification of Human Hepatic Cytochrome P450 Enzymes Involved in the Biotransformation of Cholic and Chenodeoxycholic Acid Drug Metab. Dispos., October 1, 2008; 36(10): 1983 - 1991. [Abstract] [Full Text] [PDF]

				D.-J. Shin and T. F. Osborne Peroxisome Proliferator-activated Receptor-{gamma} Coactivator-1{alpha} Activation of CYP7A1 during Food Restriction and Diabetes Is Still Inhibited by Small Heterodimer Partner J. Biol. Chem., May 30, 2008; 283(22): 15089 - 15096. [Abstract] [Full Text] [PDF]

				C. E. Oropeza, L. Li, and A. McLachlan Differential Inhibition of Nuclear Hormone Receptor-Dependent Hepatitis B Virus Replication by the Small Heterodimer Partner J. Virol., April 15, 2008; 82(8): 3814 - 3821. [Abstract] [Full Text] [PDF]

				Q. Zhang, F. He, R. Kuruba, X. Gao, A. Wilson, J. Li, T. R. Billiar, B. R. Pitt, W. Xie, and S. Li FXR-mediated regulation of angiotensin type 2 receptor expression in vascular smooth muscle cells Cardiovasc Res, February 1, 2008; 77(3): 560 - 569. [Abstract] [Full Text] [PDF]

				J. Li, A. Wilson, R. Kuruba, Q. Zhang, X. Gao, F. He, L.-M. Zhang, B. R. Pitt, W. Xie, and S. Li FXR-mediated regulation of eNOS expression in vascular endothelial cells Cardiovasc Res, January 1, 2008; 77(1): 169 - 177. [Abstract] [Full Text] [PDF]

				Q. Li, M.-J. Chu, and J. Xu Tissue- and Nuclear Receptor-Specific Function of the C-Terminal LXXLL Motif of Coactivator NCoA6/AIB3 in Mice Mol. Cell. Biol., December 1, 2007; 27(23): 8073 - 8086. [Abstract] [Full Text] [PDF]

				C. Mataki, B. C. Magnier, S. M. Houten, J.-S. Annicotte, C. Argmann, C. Thomas, H. Overmars, W. Kulik, D. Metzger, J. Auwerx, et al. Compromised Intestinal Lipid Absorption in Mice with a Liver-Specific Deficiency of Liver Receptor Homolog 1 Mol. Cell. Biol., December 1, 2007; 27(23): 8330 - 8339. [Abstract] [Full Text] [PDF]

				M. Noshiro, E. Usui, T. Kawamoto, H. Kubo, K. Fujimoto, M. Furukawa, S. Honma, M. Makishima, K.-i. Honma, and Y. Kato Multiple Mechanisms Regulate Circadian Expression of the Gene for Cholesterol 7{alpha}-Hydroxylase (Cyp7a), a Key Enzyme in Hepatic Bile Acid Biosynthesis J Biol Rhythms, August 1, 2007; 22(4): 299 - 311. [Abstract] [PDF]

				K. Sumi, T. Tanaka, A. Uchida, K. Magoori, Y. Urashima, R. Ohashi, H. Ohguchi, M. Okamura, H. Kudo, K. Daigo, et al. Cooperative Interaction between Hepatocyte Nuclear Factor 4{alpha} and GATA Transcription Factors Regulates ATP-Binding Cassette Sterol Transporters ABCG5 and ABCG8 Mol. Cell. Biol., June 15, 2007; 27(12): 4248 - 4260. [Abstract] [Full Text] [PDF]

				S. M. Houten, D. H. Volle, C. L. Cummins, D. J. Mangelsdorf, and J. Auwerx In Vivo Imaging of Farnesoid X Receptor Activity Reveals the Ileum as the Primary Bile Acid Signaling Tissue Mol. Endocrinol., June 1, 2007; 21(6): 1312 - 1323. [Abstract] [Full Text] [PDF]

				A. K. Bhattacharyya, D. S. Lin, and W. E. Connor Cholestanol metabolism in patients with cerebrotendinous xanthomatosis: absorption, turnover, and tissue deposition J. Lipid Res., January 1, 2007; 48(1): 185 - 192. [Abstract] [Full Text] [PDF]

				S. M. Post, M. Groenendijk, C. C. van der Hoogt, C. Fievet, G. Luc, M. Hoekstra, H. M.G. Princen, B. Staels, and P. C.N. Rensen Cholesterol 7{alpha}-Hydroxylase Deficiency in Mice on an APOE*3-Leiden Background Increases Hepatic ABCA1 mRNA Expression and HDL-Cholesterol Arterioscler. Thromb. Vasc. Biol., December 1, 2006; 26(12): 2724 - 2730. [Abstract] [Full Text] [PDF]

				T. Li, X. Kong, E. Owsley, E. Ellis, S. Strom, and J. Y. L. Chiang Insulin Regulation of Cholesterol 7{alpha}-Hydroxylase Expression in Human Hepatocytes: ROLES OF FORKHEAD BOX O1 AND STEROL REGULATORY ELEMENT-BINDING PROTEIN 1c J. Biol. Chem., September 29, 2006; 281(39): 28745 - 28754. [Abstract] [Full Text] [PDF]

				D.-J. Shin, M. Plateroti, J. Samarut, and T. F. Osborne Two uniquely arranged thyroid hormone response elements in the far upstream 5' flanking region confer direct thyroid hormone regulation to the murine cholesterol 7{alpha} hydroxylase gene Nucleic Acids Res., September 1, 2006; 34(14): 3853 - 3861. [Abstract] [Full Text] [PDF]

				H. Yamaguchi, M. Okada, S. Akitaya, H. Ohara, T. Mikkaichi, H. Ishikawa, M. Sato, M. Matsuura, T. Saga, M. Unno, et al. Transport of fluorescent chenodeoxycholic acid via the human organic anion transporters OATP1B1 and OATP1B3 J. Lipid Res., June 1, 2006; 47(6): 1196 - 1202. [Abstract] [Full Text] [PDF]

				C.-W. Chen and H.-H. Cheng A Rice Bran Oil Diet Increases LDL-Receptor and HMG-CoA Reductase mRNA Expressions and Insulin Sensitivity in Rats with Streptozotocin/Nicotinamide-Induced Type 2 Diabetes J. Nutr., June 1, 2006; 136(6): 1472 - 1476. [Abstract] [Full Text] [PDF]

				J. Miao, S. Fang, Y. Bae, and J. K. Kemper Functional Inhibitory Cross-talk between Constitutive Androstane Receptor and Hepatic Nuclear Factor-4 in Hepatic Lipid/Glucose Metabolism Is Mediated by Competition for Binding to the DR1 Motif and to the Common Coactivators, GRIP-1 and PGC-1{alpha} J. Biol. Chem., May 26, 2006; 281(21): 14537 - 14546. [Abstract] [Full Text] [PDF]

				K.-H. Song, T. Li, and J. Y. L. Chiang A Prospero-related Homeodomain Protein Is a Novel Co-regulator of Hepatocyte Nuclear Factor 4{alpha} That Regulates the Cholesterol 7{alpha}-Hydroxylase Gene J. Biol. Chem., April 14, 2006; 281(15): 10081 - 10088. [Abstract] [Full Text] [PDF]

				R. Deng, D. Yang, J. Yang, and B. Yan Oxysterol 22(R)-Hydroxycholesterol Induces the Expression of the Bile Salt Export Pump through Nuclear Receptor Farsenoid X Receptor but Not Liver X Receptor J. Pharmacol. Exp. Ther., April 1, 2006; 317(1): 317 - 325. [Abstract] [Full Text] [PDF]

				J. Koga, H. Kubota, S. Gomi, K. Umemura, M. Ohnishi, and T. Kono Cholic Acid, a Bile Acid Elicitor of Hypersensitive Cell Death, Pathogenesis-Related Protein Synthesis, and Phytoalexin Accumulation in Rice Plant Physiology, April 1, 2006; 140(4): 1475 - 1483. [Abstract] [Full Text] [PDF]

				Y.-K. Lee, Y.-H. Choi, S. Chua, Y. J. Park, and D. D. Moore Phosphorylation of the Hinge Domain of the Nuclear Hormone Receptor LRH-1 Stimulates Transactivation J. Biol. Chem., March 24, 2006; 281(12): 7850 - 7855. [Abstract] [Full Text] [PDF]

				F. He, J. Li, Y. Mu, R. Kuruba, Z. Ma, A. Wilson, S. Alber, Y. Jiang, T. Stevens, S. Watkins, et al. Downregulation of Endothelin-1 by Farnesoid X Receptor in Vascular Endothelial Cells Circ. Res., February 3, 2006; 98(2): 192 - 199. [Abstract] [Full Text] [PDF]

				G. Zollner, M. Wagner, P. Fickert, A. Geier, A. Fuchsbichler, D. Silbert, J. Gumhold, K. Zatloukal, A. Kaser, H. Tilg, et al. Role of nuclear receptors and hepatocyte-enriched transcription factors for Ntcp repression in biliary obstruction in mouse liver Am J Physiol Gastrointest Liver Physiol, November 1, 2005; 289(5): G798 - G805. [Abstract] [Full Text] [PDF]

				Y. Weng, C. C. DiRusso, A. A. Reilly, P. N. Black, and X. Ding Hepatic Gene Expression Changes in Mouse Models with Liver-specific Deletion or Global Suppression of the NADPH-Cytochrome P450 Reductase Gene: MECHANISTIC IMPLICATIONS FOR THE REGULATION OF MICROSOMAL CYTOCHROME P450 AND THE FATTY LIVER PHENOTYPE J. Biol. Chem., September 9, 2005; 280(36): 31686 - 31698. [Abstract] [Full Text] [PDF]

				C. Gnerre, G. U. Schuster, A. Roth, C. Handschin, L. Johansson, R. Looser, P. Parini, M. Podvinec, K. Robertsson, J.-A. Gustafsson, et al. LXR deficiency and cholesterol feeding affect the expression and phenobarbital-mediated induction of cytochromes P450 in mouse liver J. Lipid Res., August 1, 2005; 46(8): 1633 - 1642. [Abstract] [Full Text] [PDF]

				Y. Lu, J.-M. Heydel, X. Li, S. Bratton, T. Lindblom, and A. Radominska-Pandya LITHOCHOLIC ACID DECREASES EXPRESSION OF UGT2B7 IN CACO-2 CELLS: A POTENTIAL ROLE FOR A NEGATIVE FARNESOID X RECEPTOR RESPONSE ELEMENT Drug Metab. Dispos., July 1, 2005; 33(7): 937 - 946. [Abstract] [Full Text] [PDF]

				S W C van Mil, R H J Houwen, and L W J Klomp Genetics of familial intrahepatic cholestasis syndromes J. Med. Genet., June 1, 2005; 42(6): 449 - 463. [Abstract] [Full Text] [PDF]

				K. M. Robertson, G. U. Schuster, K. R. Steffensen, O. Hovatta, S. Meaney, K. Hultenby, L. C. Johansson, K. Svechnikov, O. Soder, and J.-A. Gustafsson The Liver X Receptor-{beta} Is Essential for Maintaining Cholesterol Homeostasis in the Testis Endocrinology, June 1, 2005; 146(6): 2519 - 2530. [Abstract] [Full Text] [PDF]

				S. Fiorucci, C. Clerici, E. Antonelli, S. Orlandi, B. Goodwin, B. M. Sadeghpour, G. Sabatino, G. Russo, D. Castellani, T. M. Willson, et al. Protective Effects of 6-Ethyl Chenodeoxycholic Acid, a Farnesoid X Receptor Ligand, in Estrogen-Induced Cholestasis J. Pharmacol. Exp. Ther., May 1, 2005; 313(2): 604 - 612. [Abstract] [Full Text] [PDF]

				B. Cariou, D. Duran-Sandoval, F. Kuipers, and B. Staels Farnesoid X Receptor: A New Player in Glucose Metabolism? Endocrinology, March 1, 2005; 146(3): 981 - 983. [Full Text] [PDF]

				C. A. M. Stedman, C. Liddle, S. A. Coulter, J. Sonoda, J. G. A. Alvarez, D. D. Moore, R. M. Evans, and M. Downes Nuclear receptors constitutive androstane receptor and pregnane X receptor ameliorate cholestatic liver injury PNAS, February 8, 2005; 102(6): 2063 - 2068. [Abstract] [Full Text] [PDF]

				S. Teng and M. Piquette-Miller The Involvement of the Pregnane X Receptor in Hepatic Gene Regulation during Inflammation in Mice J. Pharmacol. Exp. Ther., February 1, 2005; 312(2): 841 - 848. [Abstract] [Full Text] [PDF]

				N. Balasubramaniyan, M. Shahid, F. J. Suchy, and M. Ananthanarayanan Multiple mechanisms of ontogenic regulation of nuclear receptors during rat liver development Am J Physiol Gastrointest Liver Physiol, February 1, 2005; 288(2): G251 - G260. [Abstract] [Full Text] [PDF]

				T. Li and J. Y. L. Chiang Mechanism of rifampicin and pregnane X receptor inhibition of human cholesterol 7{alpha}-hydroxylase gene transcription Am J Physiol Gastrointest Liver Physiol, January 1, 2005; 288(1): G74 - G84. [Abstract] [Full Text] [PDF]

				J. Zhang, W. Huang, M. Qatanani, R. M. Evans, and D. D. Moore The Constitutive Androstane Receptor and Pregnane X Receptor Function Coordinately to Prevent Bile Acid-induced Hepatotoxicity J. Biol. Chem., November 19, 2004; 279(47): 49517 - 49522. [Abstract] [Full Text] [PDF]

				S. Bhalla, C. Ozalp, S. Fang, L. Xiang, and J. K. Kemper Ligand-activated Pregnane X Receptor Interferes with HNF-4 Signaling by Targeting a Common Coactivator PGC-1{alpha}: FUNCTIONAL IMPLICATIONS IN HEPATIC CHOLESTEROL AND GLUCOSE METABOLISM J. Biol. Chem., October 22, 2004; 279(43): 45139 - 45147. [Abstract] [Full Text] [PDF]

				T. Kino and G. P. Chrousos Combating Atherosclerosis With LXR{alpha} And PPAR{alpha} Agonists: Is Rational Multitargeted Polypharmacy the Future of Therapeutics in Complex Diseases? Mol. Interv., October 1, 2004; 4(5): 254 - 257. [Abstract] [Full Text] [PDF]

				L. Alvarez, P. Jara, E. Sanchez-Sabate, L. Hierro, J. Larrauri, M. C. Diaz, C. Camarena, A. De la Vega, E. Frauca, E. Lopez-Collazo, et al. Reduced hepatic expression of farnesoid X receptor in hereditary cholestasis associated to mutation in ATP8B1 Hum. Mol. Genet., October 1, 2004; 13(20): 2451 - 2460. [Abstract] [Full Text] [PDF]

				I. Pineda Torra, L. P. Freedman, and M. J. Garabedian Identification of DRIP205 as a Coactivator for the Farnesoid X Receptor J. Biol. Chem., August 27, 2004; 279(35): 36184 - 36191. [Abstract] [Full Text] [PDF]

				W. Khovidhunkit, M.-S. Kim, R. A. Memon, J. K. Shigenaga, A. H. Moser, K. R. Feingold, and C. Grunfeld Thematic review series: The Pathogenesis of Atherosclerosis. Effects of infection and inflammation on lipid and lipoprotein metabolism mechanisms and consequences to the host J. Lipid Res., July 1, 2004; 45(7): 1169 - 1196. [Abstract] [Full Text] [PDF]

				L. A. Freeman, A. Kennedy, J. Wu, S. Bark, A. T. Remaley, S. Santamarina-Fojo, and H. B. Brewer Jr. The orphan nuclear receptor LRH-1 activates the ABCG5/ABCG8 intergenic promoter J. Lipid Res., July 1, 2004; 45(7): 1197 - 1206. [Abstract] [Full Text] [PDF]

				D. S. Riddick, C. Lee, A. Bhathena, Y. E. Timsit, P.-Y. Cheng, E. T. Morgan, R. A. Prough, S. L. Ripp, K. K. M. Miller, A. Jahan, et al. TRANSCRIPTIONAL SUPPRESSION OF CYTOCHROME P450 GENES BY ENDOGENOUS AND EXOGENOUS CHEMICALS Drug Metab. Dispos., April 1, 2004; 32(4): 367 - 375. [Abstract] [Full Text] [PDF]

				J.-Y. Kim, K. Chu, H.-J. Kim, H.-A Seong, K.-C. Park, S. Sanyal, J. Takeda, H. Ha, M. Shong, M.-J. Tsai, et al. Orphan Nuclear Receptor Small Heterodimer Partner, a Novel Corepressor for a Basic Helix-Loop-Helix Transcription Factor BETA2/NeuroD Mol. Endocrinol., April 1, 2004; 18(4): 776 - 790. [Abstract] [Full Text] [PDF]

				S. M. Post, M. Groenendijk, K. Solaas, P. C. N. Rensen, and H. M. G. Princen Cholesterol 7{alpha}-Hydroxylase Deficiency in Mice on an APOE*3-Leiden Background Impairs Very-Low-Density Lipoprotein Production Arterioscler. Thromb. Vasc. Biol., April 1, 2004; 24(4): 768 - 774. [Abstract] [Full Text] [PDF]

				C. Stedman, G. Robertson, S. Coulter, and C. Liddle Feed-forward Regulation of Bile Acid Detoxification by CYP3A4: STUDIES IN HUMANIZED TRANSGENIC MICE J. Biol. Chem., March 19, 2004; 279(12): 11336 - 11343. [Abstract] [Full Text] [PDF]

				Y. Inoue, A.-M. Yu, J. Inoue, and F. J. Gonzalez Hepatocyte Nuclear Factor 4{alpha} Is a Central Regulator of Bile Acid Conjugation J. Biol. Chem., January 23, 2004; 279(4): 2480 - 2489. [Abstract] [Full Text] [PDF]

				D.-J. Shin, J. A. Campos, G. Gil, and T. F. Osborne PGC-1{alpha} Activates CYP7A1 and Bile Acid Biosynthesis J. Biol. Chem., December 12, 2003; 278(50): 50047 - 50052. [Abstract] [Full Text] [PDF]

				T. Kok, C. V. Hulzebos, H. Wolters, R. Havinga, L. B. Agellon, F. Stellaard, B. Shan, M. Schwarz, and F. Kuipers Enterohepatic Circulation of Bile Salts in Farnesoid X Receptor-deficient Mice: EFFICIENT INTESTINAL BILE SALT ABSORPTION IN THE ABSENCE OF ILEAL BILE ACID-BINDING PROTEIN J. Biol. Chem., October 24, 2003; 278(43): 41930 - 41937. [Abstract] [Full Text] [PDF]

				E. De Fabiani, N. Mitro, F. Gilardi, D. Caruso, G. Galli, and M. Crestani Coordinated Control of Cholesterol Catabolism to Bile Acids and of Gluconeogenesis via a Novel Mechanism of Transcription Regulation Linked to the Fasted-to-fed Cycle J. Biol. Chem., October 3, 2003; 278(40): 39124 - 39132. [Abstract] [Full Text] [PDF]

				A F Hofmann Inappropriate ileal conservation of bile acids in cholestatic liver disease: homeostasis gone awry Gut, September 1, 2003; 52(9): 1239 - 1241. [Full Text]

				S. Kang, N. J. Spann, T. Y. Hui, and R. A. Davis ARP-1/COUP-TF II Determines Hepatoma Phenotype by Acting as Both a Transcriptional Repressor of Microsomal Triglyceride Transfer Protein and an Inducer of CYP7A1 J. Biol. Chem., August 15, 2003; 278(33): 30478 - 30486. [Abstract] [Full Text] [PDF]

				M. Hoekstra, J. K. Kruijt, M. Van Eck, and T. J. C. van Berkel Specific Gene Expression of ATP-binding Cassette Transporters and Nuclear Hormone Receptors in Rat Liver Parenchymal, Endothelial, and Kupffer Cells J. Biol. Chem., July 3, 2003; 278(28): 25448 - 25453. [Abstract] [Full Text] [PDF]

				J. A. Holt, G. Luo, A. N. Billin, J. Bisi, Y. Y. McNeill, K. F. Kozarsky, M. Donahee, D. Y. Wang, T. A. Mansfield, S. A. Kliewer, et al. Definition of a novel growth factor-dependent signal cascade for the suppression of bile acid biosynthesis Genes & Dev., July 1, 2003; 17(13): 1581 - 1591. [Abstract] [Full Text] [PDF]

				S. K. Erickson, S. R. Lear, S. Deane, S. Dubrac, S. L. Huling, L. Nguyen, J. S. Bollineni, S. Shefer, H. Hyogo, D. E. Cohen, et al. Hypercholesterolemia and changes in lipid and bile acid metabolism in male and female cyp7A1-deficient mice J. Lipid Res., May 1, 2003; 44(5): 1001 - 1009. [Abstract] [Full Text] [PDF]

				M. Trauner and J. L. Boyer Bile Salt Transporters: Molecular Characterization, Function, and Regulation Physiol Rev, April 1, 2003; 83(2): 633 - 671. [Abstract] [Full Text] [PDF]

				J. Y. L. Chiang Bile Acid Regulation of Hepatic Physiology: III. Bile acids and nuclear receptors Am J Physiol Gastrointest Liver Physiol, March 1, 2003; 284(3): G349 - G356. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chiang, J. Y. L. Search for Related Content PubMed PubMed Citation Articles by Chiang, J. Y. L.