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• W2087577664 endingPage "1966" @default.
• W2087577664 startingPage "1955" @default.
• W2087577664 abstract "Bile acids are physiological detergents that generate bile flow and facilitate intestinal absorption and transport of lipids, nutrients, and vitamins. Bile acids also are signaling molecules and inflammatory agents that rapidly activate nuclear receptors and cell signaling pathways that regulate lipid, glucose, and energy metabolism. The enterohepatic circulation of bile acids exerts important physiological functions not only in feedback inhibition of bile acid synthesis but also in control of whole-body lipid homeostasis. In the liver, bile acids activate a nuclear receptor, farnesoid X receptor (FXR), that induces an atypical nuclear receptor small heterodimer partner, which subsequently inhibits nuclear receptors, liver-related homolog-1, and hepatocyte nuclear factor 4α and results in inhibiting transcription of the critical regulatory gene in bile acid synthesis, cholesterol 7α-hydroxylase (CYP7A1). In the intestine, FXR induces an intestinal hormone, fibroblast growth factor 15 (FGF15; or FGF19 in human), which activates hepatic FGF receptor 4 (FGFR4) signaling to inhibit bile acid synthesis. However, the mechanism by which FXR/FGF19/FGFR4 signaling inhibits CYP7A1 remains unknown. Bile acids are able to induce FGF19 in human hepatocytes, and the FGF19 autocrine pathway may exist in the human livers. Bile acids and bile acid receptors are therapeutic targets for development of drugs for treatment of cholestatic liver diseases, fatty liver diseases, diabetes, obesity, and metabolic syndrome. Bile acids are physiological detergents that generate bile flow and facilitate intestinal absorption and transport of lipids, nutrients, and vitamins. Bile acids also are signaling molecules and inflammatory agents that rapidly activate nuclear receptors and cell signaling pathways that regulate lipid, glucose, and energy metabolism. The enterohepatic circulation of bile acids exerts important physiological functions not only in feedback inhibition of bile acid synthesis but also in control of whole-body lipid homeostasis. In the liver, bile acids activate a nuclear receptor, farnesoid X receptor (FXR), that induces an atypical nuclear receptor small heterodimer partner, which subsequently inhibits nuclear receptors, liver-related homolog-1, and hepatocyte nuclear factor 4α and results in inhibiting transcription of the critical regulatory gene in bile acid synthesis, cholesterol 7α-hydroxylase (CYP7A1). In the intestine, FXR induces an intestinal hormone, fibroblast growth factor 15 (FGF15; or FGF19 in human), which activates hepatic FGF receptor 4 (FGFR4) signaling to inhibit bile acid synthesis. However, the mechanism by which FXR/FGF19/FGFR4 signaling inhibits CYP7A1 remains unknown. Bile acids are able to induce FGF19 in human hepatocytes, and the FGF19 autocrine pathway may exist in the human livers. Bile acids and bile acid receptors are therapeutic targets for development of drugs for treatment of cholestatic liver diseases, fatty liver diseases, diabetes, obesity, and metabolic syndrome. Since the last special review of cholesterol 7α-hydroxylase (CYP7A1) published in the Journal of Lipid Research in 1977 (1Myant N.B. Mitropoulos K.A. Cholesterol 7α-hydroxylase.J. Lipid Res. 1977; 18: 135-153Abstract Full Text PDF PubMed Google Scholar), there has been remarkable progress on the molecular mechanisms of regulation of bile acid synthesis. The cloning of the key regulatory gene CYP7A1 about 20 years ago (2Noshiro M. Nishimoto M. Morohashi K. Okuda K. Molecular cloning of cDNA for cholesterol 7α-hydroxylase from rat liver microsomes. Nucleotide sequence and expression.FEBS Lett. 1989; 257: 97-100Crossref PubMed Scopus (0) Google Scholar, 3Li Y.C. Wang D.P. Chiang J.Y. Regulation of cholesterol 7α-hydroxylase in the liver. Cloning, sequencing, and regulation of cholesterol 7α-hydroxylase mRNA.J. Biol. Chem. 1990; 265: 12012-12019Abstract Full Text PDF PubMed Google Scholar, 4Jelinek D.F. Andersson S. Slaughter C.A. Russell D.W. Cloning and regulation of cholesterol 7α-hydroxylase, the rate-limiting enzyme in bile acid biosynthesis.J. Biol. Chem. 1990; 265: 8190-8197Abstract Full Text PDF PubMed Google Scholar), followed by the identification of the bile acid-activated receptor farnesoid X receptor (FXR, NR1H4) 10 years later (5Makishima M. Okamoto A.Y. Repa J.J. Tu H. Learned R.M. Luk A. Hull M.V. Lustig K.D. Mangelsdorf D.J. Shan B. Identification of a nuclear receptor for bile acids.Science. 1999; 284: 1362-1365Crossref PubMed Scopus (1886) Google Scholar, 6Wang H. Chen J. Hollister K. Sowers L.C. Forman B.M. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR.Mol. Cell. 1999; 3: 543-553Abstract Full Text Full Text PDF PubMed Scopus (1116) Google Scholar, 7Parks D.J. Blanchard S.G. Bledsoe R.K. Chandra G. Consler T.G. Kliewer S.A. Stimmel J.B. Willson T.M. Zavacki A.M. Moore D.D. et al.Bile acids: natural ligands for an orphan nuclear receptor.Science. 1999; 284: 1365-1368Crossref PubMed Scopus (1622) Google Scholar), has generated high interest in bile acid research. New functions of bile acids in metabolic regulation have been unraveled. It is now well recognized that bile acids are important signaling molecules that coordinately regulate a network of metabolic pathways, including lipid, glucose, drug, and energy metabolism (reviewed in Refs. 8Zollner G. Marschall H.U. Wagner M. Trauner M. Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations.Mol. Pharm. 2006; 3: 231-251Crossref PubMed Scopus (257) Google Scholar, 9Nguyen A. Bouscarel B. Bile acids and signal transduction: role in glucose homeostasis.Cell. Signal. 2008; 20: 2180-2197Crossref PubMed Scopus (111) Google Scholar, 10Houten S.M. Watanabe M. Auwerx J. Endocrine functions of bile acids.EMBO J. 2006; 25: 1419-1425Crossref PubMed Scopus (377) Google Scholar, 11Keitel V. Kubitz R. Haussinger D. Endocrine and paracrine role of bile acids.World J. Gastroenterol. 2008; 14: 5620-5629Crossref PubMed Scopus (82) Google Scholar, 12Thomas C. Pellicciari R. Pruzanski M. Auwerx J. Schoonjans K. Targeting bile-acid signalling for metabolic diseases.Nat. Rev. Drug Discov. 2008; 7: 678-693Crossref PubMed Scopus (732) Google Scholar, 13Lefebvre P. Cariou B. Lien F. Kuipers F. Staels B. Role of bile acids and bile acid receptors in metabolic regulation.Physiol. Rev. 2009; 89: 147-191Crossref PubMed Scopus (969) Google Scholar, 14Eloranta J.J. Kullak-Ublick G.A. The role of FXR in disorders of bile acid homeostasis.Physiology (Bethesda). 2008; 23: 286-295Crossref PubMed Scopus (72) Google Scholar, 15Modica S. Murzilli S. Salvatore L. Schmidt D.R. Moschetta A. Nuclear bile acid receptor FXR protects against intestinal tumorigenesis.Cancer Res. 2008; 68: 9589-9594Crossref PubMed Scopus (158) Google Scholar). The enterohepatic circulation of bile acids serves as an important physiological route not only for recycling of bile acids and absorption of nutrients but also for regulation of whole-body lipid metabolism. However, the mechanism underlying this remarkably efficient and complex physiological process has only recently been unraveled. This review will provide an update on the current understanding of the molecular mechanism of regulation of bile acid synthesis, with a focus on the most critical regulatory gene in the pathway, CYP7A1. It should be emphasized that the bile acid pool in mice consists mostly of hydrophilic bile acids, muricholic acids, and cholic acid and is very different from the hydrophobic bile acid pool consisting predominantly chenodeoxycholic acid (CDCA), cholic acid (CA), and deoxycholic acid (DCA) in humans. Hydrophobic, but not hydrophilic, bile acids are efficacious endogenous ligands of the nuclear receptors FXR (NR1H4), pregnane X receptor (PXR; NR1I2), and vitamin D receptor (VDR; NR1I1) that play critical roles in the regulation of bile acid synthesis and metabolism. Therefore, results from studying bile acid synthesis in the mouse models may not be extrapolated to humans without verification in suitable human models. This review will focus on the regulation of bile acid synthesis in human livers and will address the species differences in regulation. Bile acids are derived from cholesterol. Bile acid synthesis is the predominant metabolic pathway for catabolism of cholesterol in humans. Hydroxylation and modification of cholesterol to bile acids converts a hydrophobic membrane constituent to amphipathic molecules that can serve as powerful physiological detergents for absorption and transport of nutrients, fats, and vitamins but also as the versatile signaling molecules that are specific ligands for activation of nuclear and membrane receptors. Both free and conjugated bile acids bind to the ligand-binding domain of FXR, which forms a heterodimer with retinoid X receptor and binds to the inverted repeat of AGGTCA-like sequence with one nucleotide spacing (IR1) located in the promoters of the FXR target genes to stimulate gene transcription (5Makishima M. Okamoto A.Y. Repa J.J. Tu H. Learned R.M. Luk A. Hull M.V. Lustig K.D. Mangelsdorf D.J. Shan B. Identification of a nuclear receptor for bile acids.Science. 1999; 284: 1362-1365Crossref PubMed Scopus (1886) Google Scholar, 6Wang H. Chen J. Hollister K. Sowers L.C. Forman B.M. Endogenous bile acids are ligands for the nuclear receptor FXR/BAR.Mol. Cell. 1999; 3: 543-553Abstract Full Text Full Text PDF PubMed Scopus (1116) Google Scholar, 7Parks D.J. Blanchard S.G. Bledsoe R.K. Chandra G. Consler T.G. Kliewer S.A. Stimmel J.B. Willson T.M. Zavacki A.M. Moore D.D. et al.Bile acids: natural ligands for an orphan nuclear receptor.Science. 1999; 284: 1365-1368Crossref PubMed Scopus (1622) Google Scholar). FXR plays a central role in the regulation of bile acid synthesis, excretion, and transport (16Chiang J.Y. Bile acid regulation of gene expression: roles of nuclear hormone receptors.Endocr. Rev. 2002; 23: 443-463Crossref PubMed Scopus (348) Google Scholar, 17Chiang J.Y. Regulation of bile acid synthesis: pathways, nuclear receptors, and mechanisms.J. Hepatol. 2004; 40: 539-551Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar) as well as lipid, glucose, and energy metabolism (10Houten S.M. Watanabe M. Auwerx J. Endocrine functions of bile acids.EMBO J. 2006; 25: 1419-1425Crossref PubMed Scopus (377) Google Scholar, 12Thomas C. Pellicciari R. Pruzanski M. Auwerx J. Schoonjans K. Targeting bile-acid signalling for metabolic diseases.Nat. Rev. Drug Discov. 2008; 7: 678-693Crossref PubMed Scopus (732) Google Scholar, 13Lefebvre P. Cariou B. Lien F. Kuipers F. Staels B. Role of bile acids and bile acid receptors in metabolic regulation.Physiol. Rev. 2009; 89: 147-191Crossref PubMed Scopus (969) Google Scholar, 18Chiang J.Y. Nuclear receptor regulation of lipid metabolism: potential therapeutics for dyslipidemia, diabetes, and chronic heart and liver diseases.Curr. Opin. Investig. Drugs. 2005; 6: 994-1001PubMed Google Scholar, 19Watanabe M. Houten S.M. Mataki C. Christoffolete M.A. Kim B.W. Sato H. Messaddeq N. Harney J.W. Ezaki O. Kodama T. et al.Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation.Nature. 2006; 439: 484-489Crossref PubMed Scopus (1305) Google Scholar). The hydrophobic bile acid CDCA is the most efficacious endogenous FXR ligand, whereas hydrophilic bile acids, such as ursodeoxycholic acid and muricholic acids, do not activate FXR. Bile acids also bind and activate PXR (20Staudinger J.L. Goodwin B. Jones S.A. Hawkins-Brown D. MacKenzie K.I. LaTour A. Liu Y. Klaassen C.D. Brown K.K. Reinhard J. et al.The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.Proc. Natl. Acad. Sci. USA. 2001; 98: 3369-3374Crossref PubMed Scopus (1027) Google Scholar) and VDR (21Makishima M. Lu T.T. Xie W. Whitfield G.K. Domoto H. Evans R.M. Haussler M.R. Mangelsdorf D.J. Vitamin D receptor as an intestinal bile acid sensor.Science. 2002; 296: 1313-1316Crossref PubMed Scopus (836) Google Scholar). These two receptors play important roles in detoxification of bile acids, drugs, and xenobiotics (20Staudinger J.L. Goodwin B. Jones S.A. Hawkins-Brown D. MacKenzie K.I. LaTour A. Liu Y. Klaassen C.D. Brown K.K. Reinhard J. et al.The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity.Proc. Natl. Acad. Sci. USA. 2001; 98: 3369-3374Crossref PubMed Scopus (1027) Google Scholar, 22Xie W. Radominska-Pandya A. Shi Y. Simon C.M. Nelson M.C. Ong E.S. Waxman D.J. Evans R.M. An essential role for nuclear receptors SXR/PXR in detoxification of cholestatic bile acids.Proc. Natl. Acad. Sci. USA. 2001; 98: 3375-3380Crossref PubMed Scopus (631) Google Scholar, 23Sonoda J. Xie W. Rosenfeld J.M. Barwick J.L. Guzelian P.S. Evans R.M. Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor (PXR).Proc. Natl. Acad. Sci. USA. 2002; 99: 13801-13806Crossref PubMed Scopus (240) Google Scholar). Bile acids have been shown to modulate cellular signaling pathways, including calcium mobilization, cyclic AMP synthesis, and protein kinase C activation (9Nguyen A. Bouscarel B. Bile acids and signal transduction: role in glucose homeostasis.Cell. Signal. 2008; 20: 2180-2197Crossref PubMed Scopus (111) Google Scholar). It has been reported that bile acids activate the protein kinase C/Janus N-termina kinase pathway (24Stravitz R.T. Vlahcevic Z.R. Gurley E.C. Hylemons P.B. Repression of cholesterol 7a-hydroxylase transcription by bile acids is mediated through protein kinase C in primary cultures of rat hepatocytes.J. Lipid Res. 1995; 36: 1359-1368Abstract Full Text PDF PubMed Google Scholar). Bile acids stimulate secretion of pro-inflammatory cytokines, tumor necrosis factor α (TNFα), and interleuken-1β (IL-1β) from Kupffer cells (resident macrophages in hepatocytes) that activate TNF receptor signaling and the mitogen-activated protein kinase (MAPK)/JNK pathway (25Miyake J.H. Wang S.L. Davis R.A. Bile acid induction of cytokine expression by macrophages correlates with repression of hepatic cholesterol 7alpha-hydroxylase.J. Biol. Chem. 2000; 275: 21805-21808Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, 26Gutierrez A. Ratliff E.P. Andres A.M. Huang X. McKeehan W.L. Davis R.A. Bile acids decrease hepatic paraoxonase 1 expression and plasma high-density lipoprotein levels via FXR-mediated signaling of FGFR4.Arterioscler. Thromb. Vasc. Biol. 2006; 26: 301-306Crossref PubMed Scopus (43) Google Scholar). Conjugated bile acids induce mitochondrial reactive oxidizing species, which activates the epidermal growth factor receptor and Raf-1/MEK/ERK signaling pathway (27Rao Y.P. Studer E.J. Stravitz R.T. Gupta S. Qiao L. Dent P. Hylemon P.B. Activation of the Raf-1/MEK/ERK cascade by bile acids occurs via the epidermal growth factor receptor in primary rat hepatocytes.Hepatology. 2002; 35: 307-314Crossref PubMed Scopus (87) Google Scholar, 28Fang Y. Han S.I. Mitchell C. Gupta S. Studer E. Grant S. Hylemon P.B. Dent P. Bile acids induce mitochondrial ROS, which promote activation of receptor tyrosine kinases and signaling pathways in rat hepatocytes.Hepatology. 2004; 40: 961-971Crossref PubMed Scopus (101) Google Scholar). Conjugated bile acids activate the ERK and PI3K/AKT pathways via a pertussis toxin-sensitive mechanism involving Gαi protein-coupled receptor (29Dent P. Fang Y. Gupta S. Studer E. Mitchell C. Spiegel S. Hylemon P.B. Conjugated bile acids promote ERK1/2 and AKT activation via a pertussis toxin-sensitive mechanism in murine and human hepatocytes.Hepatology. 2005; 42: 1291-1299Crossref PubMed Scopus (84) Google Scholar, 30Fang Y. Studer E. Mitchell C. Grant S. Pandak W.M. Hylemon P.B. Dent P. Conjugated bile acids regulate hepatocyte glycogen synthase activity in vitro and in vivo via Galphai signaling.Mol. Pharmacol. 2007; 71: 1122-1128Crossref PubMed Scopus (32) Google Scholar). DCA activates the FAS receptor and the JNK pathway by induction of acidic sphingomyelinase-generated ceramide in rat primary hepatocytes (31Gupta S. Natarajan R. Payne S.G. Studer E.J. Spiegel S. Dent P. Hylemon P.B. Deoxycholic acid activates the c-Jun N-terminal kinase pathway via FAS receptor activation in primary hepatocytes: role of acidic sphingomyelinase-mediated ceramide generation in FAS receptor activation.J. Biol. Chem. 2004; 279: 5821-5828Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). Bile acids also stimulate insulin receptor signaling (32Han S.I. Studer E. Gupta S. Fang Y. Qiao L. Li W. Grant S. Hylemon P.B. Dent P. Bile acids enhance the activity of the insulin receptor and glycogen synthase in primary rodent hepatocytes.Hepatology. 2004; 39: 456-463Crossref PubMed Scopus (50) Google Scholar). In brown adipose tissue, bile acids activate TGR5, a Gαi protein-coupled receptor (33Kawamata Y. Fujii R. Hosoya M. Harada M. Yoshida H. Miwa M. Fukusumi S. Habata Y. Itoh T. Shintani Y. et al.A G protein-coupled receptor responsive to bile acids.J. Biol. Chem. 2003; 278: 9435-9440Abstract Full Text Full Text PDF PubMed Scopus (887) Google Scholar, 34Maruyama T. Miyamoto Y. Nakamura T. Tamai Y. Okada H. Sugiyama E. Itadani H. Tanaka K. Identification of membrane-type receptor for bile acids (M-BAR).Biochem. Biophys. Res. Commun. 2002; 298: 714-719Crossref PubMed Scopus (594) Google Scholar). TGR5 stimulates production of cAMP, which induces iodothyrone deiodinase (D2) and production of thyroid hormone T3, leading to stimulation of energy metabolism and improving glucose tolerance and insulin sensitivity (10Houten S.M. Watanabe M. Auwerx J. Endocrine functions of bile acids.EMBO J. 2006; 25: 1419-1425Crossref PubMed Scopus (377) Google Scholar, 12Thomas C. Pellicciari R. Pruzanski M. Auwerx J. Schoonjans K. Targeting bile-acid signalling for metabolic diseases.Nat. Rev. Drug Discov. 2008; 7: 678-693Crossref PubMed Scopus (732) Google Scholar, 19Watanabe M. Houten S.M. Mataki C. Christoffolete M.A. Kim B.W. Sato H. Messaddeq N. Harney J.W. Ezaki O. Kodama T. et al.Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation.Nature. 2006; 439: 484-489Crossref PubMed Scopus (1305) Google Scholar). TGR5 is not expressed in hepatocytes but has been localized in the sinusoid endothelial cells (35Keitel V. Reinehr R. Gatsios P. Rupprecht C. Gorg B. Selbach O. Haussinger D. Kubitz R. The G-protein coupled bile salt receptor TGR5 is expressed in liver sinusoidal endothelial cells.Hepatology. 2007; 45: 695-704Crossref PubMed Scopus (211) Google Scholar). In the enteroendocrine cells, TGR5 stimulates glucagon-like peptide 1 (36Katsuma S. Hirasawa A. Tsujimoto G. Bile acids promote glucagon-like peptide-1 secretion through TGR5 in a murine enteroendocrine cell line STC-1.Biochem. Biophys. Res. Commun. 2005; 329: 386-390Crossref PubMed Scopus (474) Google Scholar), which has antidiabetic activity. The liver is the only organ that has all 14 enzymes required for de novo synthesis of two primary bile acids in humans, CA (3α, 7α, 12α-trihydroxy-cholanoic acid) and CDCA (3α, 7α-dihydroxy-cholanoic acid) (Fig. 1) (37Russell D.W. The enzymes, regulation, and genetics of bile acid synthesis.Annu. Rev. Biochem. 2003; 72: 137-174Crossref PubMed Scopus (1124) Google Scholar). The classic bile acid biosynthetic pathway is initiated by CYP7A1 (38Chiang J.Y. Regulation of bile acid synthesis.Front. Biosci. 1998; 3: d176-d193Crossref PubMed Google Scholar). Sterol 12α-hydroxylase (CYP8B1) is required for synthesis of CA. Mitochondrial sterol 27 hydroxylase (CYP27A1) catalyzes sterol side chain oxidation, after which cleavage of a three-carbon unit in the peroxisomes leads to formation of a C24 bile acid. An alternative (acidic) pathway is initiated by CYP27A1, which in addition to the liver is expressed in macrophages and most other tissues, and may contribute significantly to total bile acid synthesis. Other minor pathways initiated by 25-hydroxylase in the liver and 24-hydroxylase in the brain also may contribute to bile acid synthesis. A nonspecific 7α-hydroxylase (CYP7B1) expressed in all tissues is involved in the generation of oxidized metabolites (oxysterols), which may be transported to the liver and converted to CDCA. Most bile acids are conjugated to glycine or taurine to decrease toxicity and increase solubility for secretion into bile. Bile acid:CoA synthase (BACS) and bile acid:amino acid transferase (BAT) are involved in amino acid conjugation of bile acids. In the intestine, glyco- and tauro-conjugated CA and CDCA are deconjugated, and 7α-dehydroxylase activity in bacteria flora removes a 7α-hydroxy group to form secondary bile acids DCA (3α, 12-dihydroxy) and lithocholic acid (LCA; 3α-monohydroxy), respectively. CA, CDCA, and DCA are reabsorbed in the intestine and transported back to the liver to inhibit bile acid synthesis. Most of the LCA is excreted in feces. A small amount of LCA circulated to the liver is sulfo-conjugated at the 3-hydroxy position by sulfotransferase (SULT2A1) and rapidly secreted into bile. Sulfation is the major pathway for detoxification of extremely hydrophobic bile acids in humans (39Hofmann A.F. Detoxification of lithocholic acid, a toxic bile acid: relevance to drug hepatotoxicity.Drug Metab. Rev. 2004; 36: 703-722Crossref PubMed Scopus (179) Google Scholar). Details of bile acid chemistry, biology, physiology, and synthesis have been reviewed recently (40Hofmann A.F. Hagey L.R. Bile acids: chemistry, pathochemistry, biology, pathobiology, and therapeutics.Cell. Mol. Life Sci. 2008; 65: 2461-2483Crossref PubMed Scopus (521) Google Scholar, 41Monte M.J. Marin J.J. Antelo A. Vazquez-Tato J. Bile acids: chemistry, physiology, and pathophysiology.World J. Gastroenterol. 2009; 15: 804-816Crossref PubMed Scopus (287) Google Scholar). Regulation of the rate-limiting enzyme in bile acid biosynthetic pathway CYP7A1 has been studied extensively. The CYP7A1 mRNA transcripts in the 3′-untranslated region are unusually long (3Li Y.C. Wang D.P. Chiang J.Y. Regulation of cholesterol 7α-hydroxylase in the liver. Cloning, sequencing, and regulation of cholesterol 7α-hydroxylase mRNA.J. Biol. 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One or more labile proteins regulate the stability of chimeric mRNAs containing the 3′-untranslated region of cholesterol 7α-hydroxylase mRNA.J. Biol. Chem. 2000; 275: 19985-19991Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 44Agellon L.B. Cheema S.K. The 3′-untranslated region of the mouse cholesterol 7α-hydroxylase mRNA contains elements responsive to post-transcriptional regulation by bile acids.Biochem. J. 1997; 328: 393-399Crossref PubMed Scopus (33) Google Scholar). Numerous studies have demonstrated that bile acids, steroid hormones, inflammatory cytokines, insulin, and growth factors inhibit CYP7A1 transcription through the 5′-upstream region of the promoter (45Crestani M. Sadeghpour A. Stroup D. Gali G. Chiang J.Y.L. Transcriptional activation of the cholesterol 7α-hydroxylase gene (CYP7A) by nuclear hormone receptors.J. Lipid Res. 1998; 39: 2192-2200Abstract Full Text Full Text PDF PubMed Google Scholar, 46Li T. Jahan A. Chiang J.Y. Bile acids and cytokines inhibit the human cholesterol 7α-hydroxylase gene via the JNK/c-jun pathway in human liver cells.Hepatology. 2006; 43: 1202-1210Crossref PubMed Scopus (100) Google Scholar, 47Li T. Kong X. Owsley E. Ellis E. Strom S. Chiang J.Y. Insulin regulation of cholesterol 7α-hydroxylase expression in human hepatocytes: roles of forkhead box O1 and sterol regulatory element-binding protein 1c.J. Biol. Chem. 2006; 281: 28745-28754Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 48Song K.H. Chiang J.Y. Glucagon and cAMP inhibit cholesterol 7alpha-hydroxylase (CYP7a1) gene expression in human hepatocytes: discordant regulation of bile acid synthesis and gluconeogenesis.Hepatology. 2006; 43: 117-125Crossref PubMed Scopus (44) Google Scholar, 49Song K.H. Ellis E. Strom S. Chiang J.Y. Hepatocyte growth factor signaling pathway inhibits cholesterol 7α-hydroxylase and bile acid synthesis in human hepatocytes.Hepatology. 2007; 46: 1993-2002Crossref PubMed Scopus (54) Google Scholar, 50Song K.H. Li T. Owsley E. Strom S. Chiang J.Y. Bile acids activate fibroblast growth factor 19 signaling in human hepatocytes to inhibit cholesterol 7alpha-hydroxylase gene expression.Hepatology. 2009; 49: 297-305Crossref PubMed Scopus (230) Google Scholar). Analysis of the proximal promoter of the rat Cyp7a1 identified two regions (footprints) that are putative binding sites for nuclear receptors (51Chiang J.Y.L. Stroup D. Identification and characterization of a putative bile acid responsive element in cholesterol 7α-hydroxylase gene promoter.J. Biol. Chem. 1994; 269: 17502-17507Abstract Full Text PDF PubMed Google Scholar), which are ligand-activated transcription factors that play important roles in embryogenesis, development, and metabolism (16Chiang J.Y. Bile acid regulation of gene expression: roles of nuclear hormone receptors.Endocr. Rev. 2002; 23: 443-463Crossref PubMed Scopus (348) Google Scholar). The sequence located at −73 to −55 of the rat CYP7A1 promoter is highly conserved and was identified as a putative bile acid response element (BARE-I) that might be involved in conferring bile acid inhibition. This sequence contains a DR4 (direct repeat spaced by four nucleotides) motif in all species except the human, which binds liver X receptor (LXRα or NR1H3), an oxysterol-activated nuclear receptor. The CYP7A1 is the first LXRα target gene identified (52Janowski B.A. Willy P.J. Devi T.R. Falck J.R. Mangelsdorf D.J. An oxysterol signalling pathway mediated by the nuclear receptor LXRα.Nature. 1996; 383: 728-731Crossref PubMed Scopus (1356) Google Scholar, 53Lehmann J.M. Kliewer S.A. Moore L.B. Smith-Oliver T.A. Oliver B.B. Su J-L. Sundseth S.S. Winegar D.A. Blanchard D.E. Spencer T.A. et al.Activation of the nuclear receptor LXR by oxysterols defines a new hormone response pathway.J. Biol. Chem. 1997; 272: 3137-3140Abstract Full Text Full Text PDF PubMed Scopus (975) Google Scholar). This has been confirmed by the finding that when fed a high cholesterol diet, bile acid synthesis increases in wild-type mice but not in Lxrα null mice, which accumulate high levels of cholesterol in the liver (54Peet D.J. Turley S.D. Ma W. Janowski B.A. Lobaccaro J.M. Hammer R.E. Mangelsdorf D.J. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha.Cell. 1998; 93: 693-704Abstract Full Text Full Text PDF PubMed Scopus (1158) Google Scholar). In contrast, the human CYP7A1 promoter does not bind LXRα and is not induced by LXRα due to alteration of the DR4 motif in the BARE-I sequence (55Chiang J.Y. Kimmel R. Stroup D. Regulation of cholesterol 7α-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRα).Gene. 2001; 262: 257-265Crossref PubMed Scopus (288) Google Scholar). This has been confirmed by the finding that transgenic mice carrying a human CYP7A1 do not respond to a high cholesterol diet and that the transgene is not induced and bile acid synthesis is not stimulated in these mice (56Agellon L.B. Drover V.A. Cheema S.K. Gbaguidi G.F. Walsh A. Dietary cholesterol fails to stimulate the human cholesterol 7α-hydroxylase gene (CYP7A1) in transgenic mice.J. Biol. Chem. 2002; 277: 20131-20134Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar, 57Chen J.Y. Levy-Wilson B. Goodart S. Cooper A.D. Mice expressing the human CYP7A1 gene in the mouse CYP7A1 knock-out background lack induction of CYP7A1 expression by cholesterol feeding and have increased hypercholesterolemia when fed a high fat diet.J. Biol. Chem. 2002; 277: 42588-42595Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar). Another bile acid response element (BARE-II) is located in a region from −149 to −118 of the rat Cyp7a1 promoter, which has an 18-nucleotide sequence that is completely conserved in many species (58Stroup D. Crestani M. Chiang J.Y. Identification of a bile acid response element in the cholesterol 7α-hydroxylase gene CYP7A.Am. J. Physiol. 1997; 273: G508-G517PubMed Google Scholar). This sequence contains a DR1 motif, which binds hepatocyte nuclear factor 4α (HNF4α; NR2A1). HNF4α transactivates CYP7A1 promoter activity by interacting with a coactivator, peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Mutation of the DR1 sequence drastically reduced basal CYP7A1 promoter activity and its response to bile acid inhibition (45Crestani M. Sadeghpour A. Stroup D. Gali G. Chiang J.Y.L. Transcriptional activation of the cholesterol 7α-hydroxylase gene (CYP7A) by nuclear hormone receptors.J. Lipid Res. 1998; 39: 2192-2200Abstract Full Text Full Text PDF PubMed Google Scholar). Several earlier studies report that bile acid pool size increases in diabetic rats and insulin inhibits CYP7A1 and CYP8B1 activities (reviewed in Ref. 38Chiang J.Y. Regulation of bile acid synthesis.Front. Biosci. 1998; 3:" @default.
• W2087577664 created "2016-06-24" @default.
• W2087577664 creator A5002732282 @default.
• W2087577664 date "2009-10-01" @default.
• W2087577664 modified "2023-10-14" @default.
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