Enterohepatic transport of bile salts and genetics of cholestasis
2005; Elsevier BV; Volume: 43; Issue: 2 Linguagem: Inglês
10.1016/j.jhep.2005.03.017
ISSN1600-0641
AutoresChristiane Pauli–Magnus, Bruno Stieger, Yvonne Meier, Gerd A. Kullak‐Ublick, Peter J. Meier,
Tópico(s)Pharmacogenetics and Drug Metabolism
ResumoThe intestinal conservation mechanism of bile salts is highly efficient. From 20–40 g of bile salts excreted daily into bile, only 0.5 g are lost through fecal excretion and have to be replaced by de novo bile acid synthesis. This conservation is achieved through enterohepatic circulation of bile salts, which depends on the coordinated action of numerous transporter proteins expressed at the basolateral and apical membrane of liver, biliary and small intestinal epithelial cells. The following paragraphs introduce the major hepatobiliary transport systems involved in hepatobiliary circulation and briefly describe their role in hepatocellular physiology and bile formation. The reader is also referred to several complementary reviews that have appeared recently and that are referenced throughout the manuscript. Bile acid synthesis starts from cholesterol and can be subdivided into a classical or neutral and an alternative or acidic pathway (reviewed in: [[1]Russell D.W. The enzymes, regulation, and genetics of bile acid synthesis.Annu Rev Biochem. 2003; 72: 137-174Crossref PubMed Scopus (438) Google Scholar]). The classical pathway results in the formation of cholic acid and accounts for 90% of bile acid synthesis. It includes the hydroxylation of cholesterol at the 7α and 12α positions via the cytochrome P450 (CYP) enzymes CYP7A1 and CYP8B1, respectively, followed by hydroxylation via mitochondrial CYP27A1 [2Cali J.J. Russell D.W. Characterization of human sterol 27-hydroxylase. A mitochondrial cytochrome P-450 that catalyzes multiple oxidation reaction in bile acid biosynthesis.J Biol Chem. 1991; 266: 7774-7778Abstract Full Text PDF PubMed Google Scholar, 3Eggertsen G. Olin M. Andersson U. Ishida H. Kubota S. Hellman U. et al.Molecular cloning and expression of rabbit sterol 12alpha-hydroxylase.J Biol Chem. 1996; 271: 32269-32275Crossref PubMed Scopus (49) Google Scholar]. In contrast, the alternative pathway leads to the formation of chenodeoxycholic acid (CDCA). Here, 7α-hydroxylation is preceded by the formation of different oxysterols, which are further metabolized via CYP7B1 and CYP39A1[4Schwarz M. Lund E.G. Lathe R. Bjorkhem I. Russell D.W. Identification and characterization of a mouse oxysterol 7alpha-hydroxylase cDNA.J Biol Chem. 1997; 272: 23995-24001Crossref PubMed Scopus (115) Google Scholar, 5Li-Hawkins J. Lund E.G. Bronson A.D. Russell D.W. Expression cloning of an oxysterol 7alpha-hydroxylase selective for 24-hydroxycholesterol.J Biol Chem. 2000; 275: 16543-16549Crossref PubMed Scopus (87) Google Scholar]. Under physiological conditions, 70% of the human bile acid pool is composed of cholic acid and cholic acid metabolites while 30% are constituted by CDCA [[6]Kullak-Ublick G.A. Paumgartner G. Berr F. Long-term effects of cholecystectomy on bile acid metabolism.Hepatology. 1995; 21: 41-45Crossref PubMed Google Scholar]. After their synthesis, bile acids are conjugated with glycine and taurine, which improves their solubility in the bile fluid and in the intestinal lumen. These conjugated bile acids are present as anionic salts under physiological pH conditions and are therefore called bile salts. After their synthesis in hepatocytes, conjugated bile salts are secreted into the bile canaliculus via specialized transporter systems expressed at the canalicular membrane of hepatocytes. The canalicular excretion of bile salts constitutes the rate limiting step in bile formation and the first step in the enterohepatic circulation pathway. With the exception of FIC1 (ATP8B1), which is thought to play a role in the regulation of the enterohepatic bile acid pool and in the elimination of hydrophobic substances from the enterohepatic circulation (for review see: [[7]Stieger B. FIC1: another bile salt carrier within the enterohepatic circulation?.J Hepatol. 2001; 35: 522-524Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar]), canalicular transporters involved in bile formation belong to different members of the superfamily of ATP-Binding Cassette (ABC) transporters. In the liver, this family includes members of the multidrug resistance (MDR) protein family (ABCB-gene family), the multidrug resistance associated (MRP) protein family (ABCC-gene family) as well as of the family of ABC-half transporters (ABCG-gene family) (Fig. 1). Within the family of multidrug resistance proteins, the bile salt export pump BSEP (ABCB11) and the multidrug resistance protein 3 (MDR3, ABCB4) are two highly conserved members, which are involved in the secretion of cholephilic compounds from the liver cell into the bile canaliculus (reviewed in:[8Kullak-Ublick G.A. Stieger B. Meier P.J. Enterohepatic bile salt transporters in normal physiology and liver disease.Gastroenterology. 2004; 126: 322-342Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar, 9Meier P.J. Stieger B. Molecular Mechanisms in Bile Formation.News Physiol Sci. 2000; 15: 89-93PubMed Google Scholar, 10Meier P.J. Stieger B. Bile salt transporters.Annu Rev Physiol. 2002; 64: 635-661Crossref PubMed Scopus (270) Google Scholar]). BSEP constitutes the predominant bile salt efflux system of hepatocytes and mediates the cellular excretion of numerous conjugated bile salts such as taurine- or glycine-conjugated cholate, chenodeoxycholate and deoxycholate [11Byrne J.A. Strautnieks S.S. Mieli-Vergani G. Higgins C.F. Linton K.J. Thompson R.J. The human bile salt export pump: characterization of substrate specificity and identification of inhibitors.Gastroenterology. 2002; 123: 1649-1658Abstract Full Text Full Text PDF PubMed Google Scholar, 12Noe J. Stieger B. Meier P.J. Functional expression of the canalicular bile salt export pump of human liver.Gastroenterology. 2002; 123: 1659-1666Abstract Full Text Full Text PDF PubMed Google Scholar]. MDR3 was shown to function as an ATP-dependent phospholipid flippase, translocating phosphatidylcholine from the inner to the outer leaflet of the canalicular membrane (reviewed in: [[13]Borst P. Elferink R.O. Mammalian A.B.C. transporters in health and disease.Annu Rev Biochem. 2002; 71: 537-592Crossref PubMed Scopus (851) Google Scholar]). Canalicular phospholipids are then solubilized by canalicular bile salts to form mixed micelles, thereby protecting cholangiocytes from the detergent properties of bile salts. In addition to these processes, MRP2, the only canalicular member of the multidrug resistance associated protein family, mediates the canalicular transport of glucuronidated and sulfated bile salts. MRP2 is the main driving force for bile-salt independent bile flow through canalicular excretion of reduced glutathione. Furthermore, MRP2 transports a wide spectrum of organic anions, including bilirubin-diglucuronide, glutathione-conjugates, leukotriene C4 and divalent bile salt conjugates as well as drug substrates, such as cancer chemotherapeutic agents, uricosurics and antibiotics (reviewed in: [13Borst P. Elferink R.O. Mammalian A.B.C. transporters in health and disease.Annu Rev Biochem. 2002; 71: 537-592Crossref PubMed Scopus (851) Google Scholar, 14Keppler D. Konig J. Hepatic secretion of conjugated drugs and endogenous substances.Semin Liver Dis. 2000; 20: 265-272Crossref PubMed Google Scholar]). Only recently, hepatic expression of ABC half transporters could be demonstrated and localized to the canalicular membrane of hepatocytes. The heterodimeric transporter ABCG5/ ABCG8 (ABCG5 and ABCG8) has been identified as the apical transport system involved in the hepatobiliary excretion of plant sterols and cholesterol (reviewed in: [13Borst P. Elferink R.O. Mammalian A.B.C. transporters in health and disease.Annu Rev Biochem. 2002; 71: 537-592Crossref PubMed Scopus (851) Google Scholar, 15Wittenburg H. Carey M.C. Biliary cholesterol secretion by the twinned sterol half-transporters ABCG5 and ABCG8.J Clin Invest. 2002; 110: 605-609Crossref PubMed Google Scholar, 16Klett E.L. Patel S. Genetic defenses against noncholesterol sterols.Curr Opin Lipidol. 2003; 14: 341-345Crossref PubMed Scopus (20) Google Scholar]). Mutations in ABCG5/G8 have been shown to cause sitosterolemia, a condition which is characterized by increased intestinal absorption and decreased biliary excretion of dietary sterols, leading to hypercholesterolemia and premature atherosclerosis [[17]Lu K. Lee M.H. Hazard S. Brooks-Wilson A. Hidaka H. Kojima H. et al.Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively.Am J Hum Genet. 2001; 69: 278-290Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar]. Overexpression of ABCG5/ABCG8 in transgenic mice led to an increase in biliary cholesterol secretion and a reduction of intestinal absorption of dietary cholesterol, providing strong evidence for ABCG5/ABCG8 being involved in hepatocellular secretion and intestinal efflux of cholesterol [[16]Klett E.L. Patel S. Genetic defenses against noncholesterol sterols.Curr Opin Lipidol. 2003; 14: 341-345Crossref PubMed Scopus (20) Google Scholar]. The breast cancer resistance protein BCRP (ABCG2) is another ABC half transporter expressed at the canalicular membrane of hepatocytes, although its highest expression levels were found in mammary epithelium and placenta. In addition to its role in conferring a multidrug resistance phenotype against a variety of xenobiotics, BCRP has recently been shown to in-vitro transport sulfated bile salt conjugates such as taurolithocholate sulfate [[18]Suzuki M. Suzuki H. Sugimoto Y. Sugiyama Y. ABCG2 transports sulfated conjugates of steroids and xenobiotics.J Biol Chem. 2003; 278: 22644-22649Crossref PubMed Scopus (189) Google Scholar]. BCRP might therefore contribute to the hepatocellular excretion of bile salts. In addition to these canalicular efflux transporters, the hepatocyte also localizes basolateral excretion systems for bile constituents, which belong to the family of multidrug resistance associated proteins. Five members of this family (MRP1 (ABCC1), MRP3 (ABCC3), MRP4 (ABCC4), MRP5 (ABCC5) and MRP6 (ABCC6)) have been located at the basolateral membrane of hepatocytes. MRP1 is almost absent in normal liver, while MRP3 and MRP4 expression is variable [[13]Borst P. Elferink R.O. Mammalian A.B.C. transporters in health and disease.Annu Rev Biochem. 2002; 71: 537-592Crossref PubMed Scopus (851) Google Scholar]. MRPs have been implicated in the cellular efflux of various organic anions including drug-glutathione, -glucuronide and -sulfate conjugates (MRP1), the efflux of bile salts and bile salt conjugates (MRP3, MRP4), the transport of nucleoside analog drugs such as zidovudine, lamivudine and stavudine (MRP4) and of the cyclic nucleosides cAMP and cGMP as well as methotrexate and the purine analogs 6-mercaptopurine and 6-thioguanine (MRP4 and MRP5) [[13]Borst P. Elferink R.O. Mammalian A.B.C. transporters in health and disease.Annu Rev Biochem. 2002; 71: 537-592Crossref PubMed Scopus (851) Google Scholar]. The efflux of bile salts by MRP4 is coupled to the cotransport of reduced glutathione or S-methyl-glutathione [[19]Rius M. Nies A.T. Hummel-Eisenbeiss J. Jedlitschky G. Keppler D. Cotransport of reduced glutathione with bile salts by MRP4 (ABCC4) localized to the basolateral hepatocyte membrane.Hepatology. 2003; 38: 374-384Crossref PubMed Scopus (198) Google Scholar]. Cholangiocytes play an important role in physiological bile secretion and express several transporter systems for secretory and absorptive functions. Uptake of bile salts from canalicular bile into cholangiocytes is mediated by the apical sodium dependent bile salt transporter ASBT (SCL10A2). ASBT belongs to the superfamily of solute carriers and is identical with the gene product expressed in the terminal ileum of small intestine (reviewed in: [[20]Hagenbuch B. Dawson P. The sodium bile salt cotransport family SLC10.Pflugers Arch. 2004; 447: 566-570Crossref PubMed Scopus (98) Google Scholar]). Furthermore, the apical uptake of bile salts involves the organic anion transporting polypeptide 1A2 (OATP1A2), which belongs to the OATP superfamily of sodium independent solute transporters (SCLO; former nomenclature: SLC21)) [21Hagenbuch B. Meier P.J. Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties.Pflugers Arch. 2004; 447: 653-665Crossref PubMed Scopus (440) Google Scholar, 22Chignard N. Mergey M. Veissiere D. Parc R. Capeau J. Poupon R. et al.Bile acid transport and regulating functions in the human biliary epithelium.Hepatology. 2001; 33: 496-503Crossref PubMed Scopus (42) Google Scholar, 23Soroka C.J. Lee J.M. Azzaroli F. Boyer J.L. Cellular localization and up-regulation of multidrug resistance-associated protein 3 in hepatocytes and cholangiocytes during obstructive cholestasis in rat liver.Hepatology. 2001; 33: 783-791Crossref PubMed Scopus (182) Google Scholar]. After their uptake into cholangiocytes, bile salts are effluxed at the basolateral cholangiocyte membrane into the peribiliary plexus via an anion exchange mechanism [[24]Benedetti A. Di Sario A. Marucci L. Svegliati-Baroni G. Schteingart C.D. Ton-Nu H.T. et al.Carrier-mediated transport of conjugated bile acids across the basolateral membrane of biliary epithelial cells.Am J Physiol. 1997; 272: G1416-G1424PubMed Google Scholar]. From here, bile salts reach the portal circulation and undergo the cholehepatic shunt pathway. MRP3, a basolaterally expressed member of the family of multidrug resistance associated proteins contributes to the efflux of bile salts from cholangiocytes [[25]Rost D. Konig J. Weiss G. Klar E. Stremmel W. Keppler D. Expression and localization of the multidrug resistance proteins MRP2 and MRP3 in human gallbladder epithelia.Gastroenterology. 2001; 121: 1203-1208Abstract Full Text Full Text PDF PubMed Google Scholar]. Moreover, MRP2 was recently localized in gallbladder-derived biliary epithelial cells, where it might contribute to taurocholate homeostasis [[25]Rost D. Konig J. Weiss G. Klar E. Stremmel W. Keppler D. Expression and localization of the multidrug resistance proteins MRP2 and MRP3 in human gallbladder epithelia.Gastroenterology. 2001; 121: 1203-1208Abstract Full Text Full Text PDF PubMed Google Scholar]. In addition, a splicing variant of rat asbt could be localized to the basolateral membrane of cholangiocytes, where it is proposed to function as a bile salt efflux protein. However, the contribution of this truncated protein to bile salt efflux in human cholangiocytes has not been established [[26]Lazaridis K.N. Tietz P. Wu T. Kip S. Dawson P.A. LaRusso N.F. Alternative splicing of the rat sodium/bile acid transporter changes its cellular localization and transport properties.Proc Natl Acad Sci USA. 2000; 97: 11092-11097Crossref PubMed Google Scholar]. The third step in enterohepatic circulation involves intestinal absorption of bile salts, cholesterol and phospholipids from the intestinal lumen of the terminal ileum. The uptake of conjugated bile salts in the terminal ileum is highly efficient and occurs mainly via the apical sodium dependent bile salt transporter ASBT (SLC10A2), which is identical to the transport system expressed in the apical membrane of cholangiocytes [[20]Hagenbuch B. Dawson P. The sodium bile salt cotransport family SLC10.Pflugers Arch. 2004; 447: 566-570Crossref PubMed Scopus (98) Google Scholar]. Furthermore, there is evidence that in addition to ASBT, OATP2B1 mediates the transport of taurocholic acid at acidic pH [[27]Nozawa T. Imai K. Nezu J. Tsuji A. Tamai I. Functional characterization of pH-sensitive organic anion transporting polypeptide OATP-B in human.J Pharmacol Exp Ther. 2004; 308: 438-445Crossref PubMed Scopus (168) Google Scholar]. In addition, sodium independent intestinal uptake of glycine-conjugated bile salts is mediated via Oatp1a5 in rats [[28]Walters H.C. Craddock A.L. Fusegawa H. Willingham M.C. Dawson P.A. Expression, transport properties, and chromosomal location of organic anion transporter subtype 3.Am J Physiol Gastrointest Liver Physiol. 2000; 279: G1188-G1200PubMed Google Scholar]. The relative contribution of the possible human Oatp1a5 orthologue OATP1A2 to bile salt uptake in human small intestinal cells has not yet been established. After intracellular transport of bile salts via the ileal bile acid binding protein (I-BABP), bile salts are effluxed at the basolateral membrane of enterocytes into portal circulation. Two carriers have been postulated to be responsible for transporting bile salts across the ileocyte basolateral membrane into the portal circulation. One potential candidate is MRP3, whose high expression in terminal ileum is suggestive for a role in bile salt transport into portal circulation [[29]Zimmermann C. Gutmann H. Hruz P. Gutzwiller J.P. Beglinger C. Drewe J. Mapping of multidrug resistance gene 1 and multidrug resistance-associated protein isoform 1 to 5 mRNA expression along the human intestinal tract.Drug Metab Dispos. 2005; 33: 219-224Crossref PubMed Scopus (91) Google Scholar]. Only recently, the heteromeric organic solute transporter Ostα/Ostβ has been established as a new candidate basolateral bile salt carrier in mice and may be responsible for bile salt efflux in ileum and other Asbt-expressing tissues [[30]Dawson P.A. Hubbert M. Haywood J. Craddock A.L. Zerangue N. Christian W.V. et al.The heteromeric organic solute transporter alpha-beta, Ostalpha -Ostbeta, is an ileal basolateral bile acid transporter.J Biol Chem. 2004; 280: 6960-6968Crossref PubMed Scopus (142) Google Scholar]. Extraction of bile salts from portal circulation is the last step in the enterohepatic circulation pathway. Basolateral uptake transport is essential for bile formation, since 95% of the biliary excreted bile salts are reabsorbed in the small intestine and reentered into portal circulation. Sodium-dependent and sodium-independent transporter mechanisms mediate the hepatic uptake of endogenous and exogenous (xenobiotic) substances from sinusoidal blood plasma. The sodium dependent pathway is represented by the sodium-taurocholate cotransporting polypeptide NTCP (SLC10A1) [[20]Hagenbuch B. Dawson P. The sodium bile salt cotransport family SLC10.Pflugers Arch. 2004; 447: 566-570Crossref PubMed Scopus (98) Google Scholar], which is exclusively expressed at the basolateral membrane of hepatocytes. Substrate specificity of human NTCP is essentially limited to conjugated bile salts and certain sulfated steroids. NTCP accounts for more than 80% of conjugated (i.e. taurocholate and glycocholate) but of less than 50% of unconjugated (i.e. cholate) bile salt uptake [[20]Hagenbuch B. Dawson P. The sodium bile salt cotransport family SLC10.Pflugers Arch. 2004; 447: 566-570Crossref PubMed Scopus (98) Google Scholar]. In contrast, the sodium-independent system is represented by different members of the superfamily of organic anion transporting polypeptides (OATP/SLCO) (reviewed in: [[21]Hagenbuch B. Meier P.J. Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties.Pflugers Arch. 2004; 447: 653-665Crossref PubMed Scopus (440) Google Scholar]). The OATP superfamily comprises 9 human members, four of which could be detected in liver with, however, substantial differences in expression levels [[21]Hagenbuch B. Meier P.J. Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties.Pflugers Arch. 2004; 447: 653-665Crossref PubMed Scopus (440) Google Scholar]. Highest expression in liver is found for OATP1B1 (SLCO1B1) and its 80% sequence homologue OATP1B3 (SLCO1B3), which are both predominantly, if not exclusively expressed in the liver. OATPs transport a large variety of albumin-bound amphiphatic organic compounds. With the exception of OATP2B1 (SLCO2B1), whose substrate specificity seems to be limited to bromosulphophtalein (BSP) and steroid sulfates, OATP1A2 (SLCO1A2), OATP1B1 and OATP1B3 exhibit overlapping transport activities for conjugated and unconjugated bile salts, BSP, neutral steroids, steroid sulfates and glucuronides, and selected organic cations [[21]Hagenbuch B. Meier P.J. Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties.Pflugers Arch. 2004; 447: 653-665Crossref PubMed Scopus (440) Google Scholar]. Furthermore, numerous drugs are substrates of OATPs including the antihistamine fexofenadine, opioid peptides, digoxin, the HMG CoA-reductase inhibitor pravastatin, the angiotensin converting enzyme inhibitor enalapril or the antimetabolite methotrexate [[21]Hagenbuch B. Meier P.J. Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties.Pflugers Arch. 2004; 447: 653-665Crossref PubMed Scopus (440) Google Scholar]. In addition, cholecystokinin octapeptide, which is released postprandially from the small intestine is selectively transported by hepatic OATP1B3 [[31]Ismair M.G. Stieger B. Cattori V. Hagenbuch B. Fried M. Meier P.J. et al.Hepatic uptake of cholecystokinin octapeptide by organic anion-transporting polypeptides OATP4 and OATP8 of rat and human liver.Gastroenterology. 2001; 121: 1185-1190Abstract Full Text Full Text PDF PubMed Google Scholar]. The mechanisms involved in the intracellular movement of bile salts across hepatocytes are not fully elucidated. Under physiological conditions, the majority of bile salts are bound to intracellular binding proteins, while a smaller fraction of unbound bile salts rapidly diffuses through the hepatocyte (reviewed in [[32]Agellon L.B. Torchia E.C. Intracellular transport of bile acids.Biochim Biophys Acta. 2000; 1486: 198-209Crossref PubMed Scopus (47) Google Scholar]). In addition, hydrophobic bile salts may be partitioned into intracellular organelles such as endoplasmatic reticulum and Golgi apparatus, especially during episodes of high cellular bile salt loading [[32]Agellon L.B. Torchia E.C. Intracellular transport of bile acids.Biochim Biophys Acta. 2000; 1486: 198-209Crossref PubMed Scopus (47) Google Scholar]. Hepatocellular transport systems are subject to extensive regulation, mainly in response to the intracellular accumulation of bile salts or disease-associated changes in the activation of transcription factors (reviewed in: [33Trauner M. Boyer J.L. Bile salt transporters: molecular characterization, function, and regulation.Physiol Rev. 2003; 83: 633-671PubMed Google Scholar, 34Eloranta J.J. Kullak-Ublick G.A. Coordinate transcriptional regulation of bile acid homeostasis and drug metabolism.Arch Biochem Biophys. 2005; 433: 397-412Crossref PubMed Scopus (142) Google Scholar]). While posttranscriptional regulation mechanisms account for rapid changes in bile salt transporter activity, intermediate and long-term changes in transporter expression are achieved through regulation of gene transcription. The coordinated transcriptional and posttranscriptional regulation of hepatocellular transporters involved in hepatic uptake and efflux of bile constituents and of cytochrome P450 enzymes responsible for bile acid synthesis enables the liver to rapidly respond to changes in bile acid homeostasis. On a transcriptional level, expression of proteins involved in bile acid synthesis and transport processes is primarily mediated by a group of nuclear hormone receptors that belong to the superfamily of nuclear receptors. Based on their DNA-binding properties, this superfamily can be subdivided into four groups (reviewed in: [35Mangelsdorf D.J. Thummel C. Beato M. Herrlich P. Schutz G. Umesono K. et al.The nuclear receptor superfamily: the second decade.Cell. 1995; 83: 835-839Abstract Full Text PDF PubMed Google Scholar, 36Chiang J.Y. Bile acid regulation of gene expression: roles of nuclear hormone receptors.Endocr Rev. 2002; 23: 443-463Crossref PubMed Scopus (246) Google Scholar]). Nuclear receptors regulating bile acid synthesis and transporter function mostly belong to the group of class II receptors and include the Farnesoid X Receptor (FXR), the Retinoic Acid Receptor (RAR), the Peroxisome Proliferator-Activated Receptor (PPARα), the Liver X Receptor (LXR) and the Pregnane X Receptor (PXR), the human orthologue of which is the Steroid X Receptor (SXR). All of these class II receptors function as heterodimers with the Retinoid X Receptor (RXR), allowing high-affinity binding to specific DNA elements with subsequent activation of gene transcription (Fig. 1). Bile salts are ligands for FXR and regulate bile acid synthesis through negative and positive feedback mechanisms, leading to the inhibition of de novo bile acid synthesis and to the production of less toxic bile acid derivatives. FXR is abundantly expressed in the liver where it is activated by different bile acids such as chenodeoxycholic acid, deoxycholic acid, ursodeoxycholic acid and cholic acid [37Forman B.M. Goode E. Chen J. Oro A.E. Bradley D.J. Perlmann T. et al.Identification of a nuclear receptor that is activated by farnesol metabolites.Cell. 1995; 81: 687-693Abstract Full Text PDF PubMed Google Scholar, 38Lew J.L. Zhao A. Yu J. Huang L. De Pedro N. Pelaez F. et al.The farnesoid X receptor controls gene expression in a ligand- and promoter-selective fashion.J Biol Chem. 2004; 279: 8856-8861Crossref PubMed Scopus (80) Google Scholar]. During states of high hepatocellular bile acid levels, FXR indirectly suppresses cholesterol-7α-hydroxylase (CYP7A1), the rate-limiting step of bile acid synthesis, through induction of the small heterodimeric partner 1 (SHP-1). SHP-1 is another member of the nuclear receptor family strongly expressed in the liver. SHP-1 acts as transcriptional repressor of Liver Receptor Homologue 1 (LRH-1), an orphan nuclear receptor, which is required for constitutive CYP7A1 expression [39Chiang J.Y. Kimmel R. Stroup D. Regulation of cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRalpha).Gene. 2001; 262: 257-265Crossref PubMed Scopus (223) Google Scholar, 40Goodwin B. Jones S.A. Price R.R. Watson M.A. McKee D.D. Moore L.B. et al.A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis.Mol Cell. 2000; 6: 517-526Abstract Full Text Full Text PDF PubMed Google Scholar, 41Lu T.T. Makishima M. Repa J.J. Schoonjans K. Kerr T.A. Auwerx J. et al.Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors.Mol Cell. 2000; 6: 507-515Abstract Full Text Full Text PDF PubMed Google Scholar]. On the other hand, high circulating cholesterol levels induce CYP7A1 expression levels through ligand-binding of specific cholesterol derivatives to LXR. Ligand activated LXR stimulates CYP7A1 transcription via binding to its specific response element within the CYP7A1 promoter [39Chiang J.Y. Kimmel R. Stroup D. Regulation of cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRalpha).Gene. 2001; 262: 257-265Crossref PubMed Scopus (223) Google Scholar, 42Gupta S. Pandak W.M. Hylemon P.B. LXR alpha is the dominant regulator of CYP7A1 transcription.Biochem Biophys Res Commun. 2002; 293: 338-343Crossref PubMed Scopus (55) Google Scholar]. Besides suppression of CYP1A7, FXR also downregulates the expression of sterol-12α-hydroxylase (CYP8B1) and the sterol-27-hydroxylase (CYP27A1), two other enzymes involved in bile acid synthesis via activation of SHP-1 [43Stroup D. Crestani M. Chiang J.Y. Identification of a bile acid response element in the cholesterol 7 alpha-hydroxylase gene CYP7A.Am J Physiol. 1997; 273: G508-G517PubMed Google Scholar, 44Chiang J.Y. Kimmel R. Weinberger C. Stroup D. Farnesoid X receptor responds to bile acids and represses cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription.J Biol Chem. 2000; 275: 10918-10924Crossref PubMed Scopus (169) Google Scholar, 45Zhang M. Chiang J.Y. Transcriptional regulation of the human sterol 12alpha-hydroxylase gene (CYP8B1): roles of heaptocyte nuclear factor 4alpha in mediating bile acid repression.J Biol Chem. 2001; 276: 41690-41699Crossref PubMed Scopus (122) Google Scholar, 46Yang Y. Zhang M. Eggertsen G. Chiang J.Y. On the mechanism of bile acid inhibition of rat sterol 12alpha-hydroxylase gene (CYP8B1) transcription: roles of alpha-fetoprotein transcription factor and hepatocyte nuclear factor 4alpha.Biochim Biophys Acta. 2002; 1583: 63-73Crossref PubMed Scopus (45) Google Scholar, 47del Castillo-Olivares A. Gil G. Role of FXR and FTF in bile acid-mediated suppression of cholesterol 7alpha-hydroxylase transcription.Nucleic Acids Res. 2000; 28: 3587-3593Crossref PubMed Google Scholar, 48Chen W. Chiang J.Y. Regulation of human sterol 27-hydroxylase gene (CYP27A1) by bile acids and hepatocyte nuclear factor 4alpha (HNF4alpha).Gene. 2003; 313: 71-82Crossref PubMed Scopus (34) Google Scholar, 49Garuti R. Croce M.A. Piccinini L. Tiozzo R. Bertolini S. Calandra S. Functional analysis of the promoter of human sterol 27-hydroxylase gene in HepG2 cells.Gene. 2002; 283: 133-143Crossref PubMed Scopus (22) Google Scholar]. In parallel, the gene encoding the enzyme uridine 5′diphosphate-glucuronosyltransferase 2B4 (UGT2B4), which converts hydrophobic bile acids into less toxic glucuronide derivatives is directly upregulated by FXR [[50]Barbier O. Torra I.P. Sirvent A. Claudel T. Blanquart C. Duran-Sandoval D. et al.FXR induces the UGT2B4 enzyme in hepatocytes: a potential mechanism of negative feedback control of FXR activity.Gastroenterology. 2003; 124: 1926-1940Abstr
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