Title: Bile acid transporters and regulatory nuclear receptors in the liver and beyond
Abstract: Bile acid (BA) transporters are critical for maintenance of the enterohepatic BA circulation where BAs exert their multiple physiological functions including stimulation of bile flow, intestinal absorption of lipophilic nutrients, solubilization and excretion of cholesterol, as well as antimicrobial and metabolic effects. Tight regulation of BA transporters via nuclear receptors is necessary to maintain proper BA homeostasis. Hereditary and acquired defects of BA transporters are involved in the pathogenesis of several hepatobiliary disorders including cholestasis, gallstones, fatty liver disease and liver cancer, but also play a role in intestinal and metabolic disorders beyond the liver. Thus, pharmacological modification of BA transporters and their regulatory nuclear receptors opens novel treatment strategies for a wide range of disorders. Bile acid (BA) transporters are critical for maintenance of the enterohepatic BA circulation where BAs exert their multiple physiological functions including stimulation of bile flow, intestinal absorption of lipophilic nutrients, solubilization and excretion of cholesterol, as well as antimicrobial and metabolic effects. Tight regulation of BA transporters via nuclear receptors is necessary to maintain proper BA homeostasis. Hereditary and acquired defects of BA transporters are involved in the pathogenesis of several hepatobiliary disorders including cholestasis, gallstones, fatty liver disease and liver cancer, but also play a role in intestinal and metabolic disorders beyond the liver. Thus, pharmacological modification of BA transporters and their regulatory nuclear receptors opens novel treatment strategies for a wide range of disorders. IntroductionTo exert their unique physiologic functions bile acids (BAs) undergo enterohepatic circulation requiring active transport processes through the liver and digestive tract [[1]Hofmann A.F. The enterohepatic circulation of bile acids in mammals: form and functions.Front Biosci. 2009; 14: 2584-2598Crossref PubMed Scopus (77) Google Scholar] (Fig. 1). During this tightly regulated cycle, a minor fraction (less than 3–5%) of secreted BAs escapes intestinal reabsorption via feces and needs to be replaced by de novo synthesis [[1]Hofmann A.F. The enterohepatic circulation of bile acids in mammals: form and functions.Front Biosci. 2009; 14: 2584-2598Crossref PubMed Scopus (77) Google Scholar]. Maintenance of the enterohepatic BA circulation is vital for several liver and gastrointestinal functions including bile flow, solubilization and excretion of cholesterol, clearance of toxic molecules, intestinal absorption of lipophilic nutrients, as well as metabolic and antimicrobial effects [[2]Hofmann A.F. Biliary secretion and excretion in health and disease: current concepts.Ann Hepatol. 2007; 6: 15-27PubMed Google Scholar]. Moreover, the enterohepatic circulation efficiently preserves these precious molecules, since BA synthesis from cholesterol involves 17 energy-consuming enzymatic steps [[3]Russell D.W. Fifty years of advances in bile acid synthesis and metabolism.J Lipid Res. 2009; 50: S120-125Crossref PubMed Scopus (91) Google Scholar]. In the body, BAs are mainly present in their conjugated form, which prevents unrestricted diffusion; therefore, BAs must be transported via energy-driven transport systems across the membranes of cells involved in the enterohepatic circulation [[4]Trauner M. Boyer J.L. Bile salt transporters: molecular characterization, function, and regulation.Physiol Rev. 2003; 83: 633-671Crossref PubMed Google Scholar]. BA transporters have different transport affinities for various BA species, but also for other endogenous and exogenous compounds such as drugs and toxins (Table 1). The expression of genes involved in BA homeostasis is tightly controlled by nuclear receptors (NRs) which sense the intracellular concentrations of BAs; in addition, post-transcriptional mechanisms such as insertion/retrieval of transporters into/from the cell membrane regulate the transport capacity via protein kinase C and mitogen-activated protein kinase activation by BAs [5Beuers U. Nathanson M.H. Isales C.M. Boyer J.L. Tauroursodeoxycholic acid stimulates hepatocellular exocytosis and mobilizes extracellular Ca2+ mechanisms defective in cholestasis.J Clin Invest. 1993; 92: 2984-2993Crossref PubMed Scopus (137) Google Scholar, 6Beuers U. Nathanson M.H. Boyer J.L. Effects of tauroursodeoxycholic acid on cytosolic Ca2+ signals in isolated rat hepatocytes.Gastroenterology. 1993; 104: 604-612Abstract PubMed Scopus (0) Google Scholar, 7Beuers U. Bilzer M. Chittattu A. Kullak-Ublick G.A. Keppler D. Paumgartner G. et al.Tauroursodeoxycholic acid inserts the apical conjugate export pump, Mrp2, into canalicular membranes and stimulates organic anion secretion by protein kinase C-dependent mechanisms in cholestatic rat liver.Hepatology. 2001; 33: 1206-1216Crossref PubMed Scopus (165) Google Scholar, 8Schliess F. Kurz A.K. Vom Dahl S. Haussinger D. Mitogen-activated protein kinases mediate the stimulation of bile acid secretion by tauroursodeoxycholate in rat liver.Gastroenterology. 1997; 113: 1306-1314Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar]. Together with transcriptional regulation, such post-transcriptional changes fine-tune transporter expression and activity at the plasma membrane (recently reviewed in [[9]Klaassen C.D. Aleksunes L.M. Xenobiotic, bile acid, and cholesterol transporters: function and regulation.Pharmacol Rev. 2010; 62: 1-96Crossref PubMed Scopus (290) Google Scholar]). In addition to NRs as intracellular BA sensors, some cells also contain BA receptors at the cell surface including a G-protein coupled receptor (TGR5/M-BAR/GPBAR1) [[10]Maruyama T. Miyamoto Y. Nakamura T. Tamai Y. Okada H. Sugiyama E. et al.Identification of membrane-type receptor for bile acids (M-BAR).Biochem Biophys Res Commun. 2002; 298: 714-719Crossref PubMed Scopus (303) Google Scholar] and the epidermal growth factor receptor (EGFR) [[11]Rao Y.P. Studer E.J. Stravitz R.T. Gupta S. Qiao L. Dent P. et al.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 (74) Google Scholar]. Under physiological conditions, these regulatory networks preserve the enterohepatic BA circulation and limit intracellular levels of potentially toxic BAs. Disturbances of this delicate balance may contribute to cholestasis, gallstone disease, malabsorption and intestinal bacterial overgrowth (Fig. 1). By determining the distribution of BAs as signaling molecules with hormonal functions, transporter alterations also play a key role in fatty liver disease, insulin resistance, liver regeneration and cancer (Fig. 1). Modification of transporters and regulatory NRs may be utilized to develop novel therapeutic and preventive pharmacological strategies for these diseases. This review provides a comprehensive summary of the latest advances in understanding the function of hepatobiliary transporters and their key regulatory NRs for BA homeostasis in health and diseases, highlighting the potential clinical and therapeutic implications.Table 1Summary of hepatobiliary transporters in hepatocytes, their function, regulation through nuclear receptors and genetic alterations.ABCG5/8, cholesterol efflux pump, ATP-binding cassette, subfamily G, member 5/8; BAs, bile acids; BCRP (ABCG2), breast cancer resistance protein, ATP-binding cassette, subfamily G, member 2; BRIC, benign recurrent intrahepatic cholestasis; BSEP (ABCB11), bile salt export pump; CA, cholic acid; CAR (NR1I3), constitutive androstane receptor; FXR (NR1H4), farnesoid X receptor/bile acid receptor; GR (NR3C1), glucocorticoid receptor; HCC, hepatocellular carcinoma; HNF4α (NR2A1), hepatocyte nuclear factor 4 alpha; IBD, inflammatory bowel disease, ICP, intrahepatic cholestasis of pregnancy; LXRα (NR1H3), liver X receptor alpha; MDR1 (ABCB1), p-glycoprotein, multidrug resistance protein 1, ATP-binding cassette, subfamily B, member 1; MDR2/3 (ABCB4), multidrug resistance protein 2/3; MRP2 (ABCC2), multidrug resistanceassociated protein 2, ATP-binding cassette, subfamily C, member 2; MRP3 (ABCC3) multidrug resistance-associated protein 3, ATP-binding cassette, subfamily C, member 3; MRP4 (ABCC4) multidrug resistance-associated protein 4, ATP-binding cassette, subfamily C, member 4; NAFLD, non-alcoholic fatty liver disease; NTCP (SLC10A1), sodium/taurocholate cotransporting polypeptide, solute carrier family 10, member 1; OATP1A2 (SLCO1A2, OATP1, OATP-A, SLC21A3), solute carrier organic anion transporter family, member 1A2; OATP1B1 (SLCO1B1, OATP2, OATP-C, SLC21A6), solute carrier organic anion transporter family, member 1B1; OATP1B3 (SLCO1B3, OATP8, SLC21A8) solute carrier organic anion transporter family, member 1B3; OSTα/β, organic solute transporter alpha/beta; PBC, primary biliary cirrhosis; PFIC, progressive familial intrahepatic cholestasis; PPARα (NR1C1), peroxisome proliferator-activated receptor alpha; PSC, primary sclerosing cholangitis; PXR (NR1I2), pregnane X receptor; RXRα (NR2B1), retinoid X receptor alpha; SHP (NR0B2), short heterodimer partner; VDR (NR1I1), vitamin D receptor. Open table in a new tab Hepatocellular bile acid transporters and their regulation by nuclear receptorsBasolateral uptake systems in the liverBAs return to the liver via portal blood (and to a much lesser extent via the hepatic artery) and are efficiently removed during their first passage through the hepatic sinusoids by hepatocellular BA uptake systems [[12]Kullak-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 (379) Google Scholar], involving a sodium-dependent sodium/taurocholate co-transporting polypeptide (NTCP/SLC10A1) and a family of sodium-independent multispecific organic anion transporters (OATPs/SLCOs) [13Hagenbuch B. Meier P.J. Molecular cloning, chromosomal localization, and functional characterization of a human liver Na+/bile acid cotransporter.J Clin Invest. 1994; 93: 1326-1331Crossref PubMed Google Scholar, 14Kullak-Ublick G.A. Hagenbuch B. Stieger B. Wolkoff A.W. Meier P.J. Functional characterization of the basolateral rat liver organic anion transporting polypeptide.Hepatology. 1994; 20: 411-416PubMed Google Scholar] (Fig. 2; Table 1).Fig. 2Transcriptional regulation of hepatocellular bile formation. Expression of hepatobiliary transporters in hepatocytes determines hepatic bile acid (BA) flux and hepatocellular concentrations of these potentially toxic metabolites. To ensure the balance between synthesis, uptake and excretion, expression of hepatobiliary transporters is tightly regulated by nuclear receptors (NRs). NRs provide a network of negative feedback and positive feed-forward mechanisms, for the control of intracellular concentration of biliary constituents, which are often also ligands for these NRs. BA-activated FXR is a central player in this network, that represses (via interaction with HNF4 in rats and GR in humans) hepatic BA uptake (NTCP) and (via SHP) synthesis (CYP7A1), promotes bile secretion via induction of canalicular transporters (BSEP, MRP2, ABCG5/8, MDR3) and induces BA elimination via alternative export systems at the hepatic basolateral (sinusoidal) membrane (OSTα/β). Several NR pathways converge at the level of CYP7A1 as the rate limiting enzyme in BA synthesis. CAR and PXR facilitate adaptation to increased intracellular BA concentrations by upregulation of alternative hepatic export routes (MRP3 and MRP4) and induction of detoxification enzymes (not shown). Together with RAR, these xenobiotic receptors also regulate the canalicular expression of MRP2. Cholesterol sensor LXR promotes biliary cholesterol excretion via ABCG5/8. Stimulation of AE2 expression by GR stimulates biliary bicarbonate secretion thus reducing bile toxicity. Green arrows indicate stimulatory and red lines suppressive effects on target genes. In addition to these transcriptional mechanisms, post-transcriptional processes (e.g., vesicular targeting of transporters to the membrane, phosphorylation of transport proteins) and modification of the bile through cholangiocytes (e.g., bicarbonate secretion) also play an important role in bile formation (not shown). BAs, bile acids; Bili-glu, bilirubin glucuronide; BSEP, bile salt export pump; CAR, constitutive androstane receptor; CYP7A1, cholesterol-7α-hydroxylase, FXR, farnesoid X receptor; GR, glucocorticoid receptor; HNF4, hepatocyte nuclear factor 4, LXR, liver X receptor; MDR3, multidrug resistance protein 3, phospholipid flippase; MRP2, multidrug resistance-associated protein 2; MRP3, multidrug resistance-associated protein 3; MRP4, multidrug resistance-associated protein 4; NTCP, sodium taurocholate co-transporting polypeptide; OSTα/β, organic solute transporter alpha and beta, PC, phosphatidylcholine; PXR, pregnane X receptor; PPARα, peroxisome proliferator-activated receptor alpha; RAR, retinoic acid receptor; SHP, small heterodimer partner.View Large Image Figure ViewerDownload Hi-res image Download (PPT)NTCP accounts for the bulk (about 90%) of BA uptake and was the first cloned BA transporter [[13]Hagenbuch B. Meier P.J. Molecular cloning, chromosomal localization, and functional characterization of a human liver Na+/bile acid cotransporter.J Clin Invest. 1994; 93: 1326-1331Crossref PubMed Google Scholar]. Its regulation under physiological and pathological conditions is therefore well understood thus serving as a paradigmatic model to understand transporter regulation. NTCP expression is controlled by BAs, hormones such as estrogen and prolactin, as well as pro-inflammatory cytokines (recently reviewed in [[15]Wagner M. Zollner G. Trauner M. Nuclear receptor regulation of the adaptive response of bile acid transporters in cholestasis.Semin Liver Dis. 2010; 30: 160-177Crossref PubMed Scopus (41) Google Scholar]). In cholestatic patients [16Zollner G. Fickert P. Silbert D. Fuchsbichler A. Marschall H.U. Zatloukal K. et al.Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis.J Hepatol. 2003; 38: 717-727Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar, 17Keitel V. Burdelski M. Warskulat U. Kuhlkamp T. Keppler D. Haussinger D. et al.Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis.Hepatology. 2005; 41: 1160-1172Crossref PubMed Scopus (138) Google Scholar] and animal models of cholestasis induced by biliary obstruction, estrogen or endotoxin, NTCP expression is universally reduced (reviewed in [[18]Zollner 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 (193) Google Scholar]). A key repressive mechanism involves activation of the farnesoid X receptor (FXR) through accumulating BAs, which then induces the small heterodimer partner (SHP) as repressor of hepatic nuclear factor 1 alpha and 4 alpha (HNF-1α and HNF-4α, and also interfering with retinoid X receptor (RXR), retinoic acid receptor (RAR) heterodimers in rats, or the glucocorticoid receptor in humans (recently reviewed in [[15]Wagner M. Zollner G. Trauner M. Nuclear receptor regulation of the adaptive response of bile acid transporters in cholestasis.Semin Liver Dis. 2010; 30: 160-177Crossref PubMed Scopus (41) Google Scholar]), which are all required for normal NTCP expression (Fig. 2, Table 1).Canalicular export systemsAt the canalicular membrane, highly specialized canalicular transporters mediate excretion of the individual components of bile such as BAs, phospholipids and cholesterol [[4]Trauner M. Boyer J.L. Bile salt transporters: molecular characterization, function, and regulation.Physiol Rev. 2003; 83: 633-671Crossref PubMed Google Scholar] (Fig. 2, Table 1). The bile salt export pump (BSEP, ABCB11 or sister of p-glycoprotein (Spgp)) is the major canalicular BA efflux system [[19]Gerloff T. Stieger B. Hagenbuch B. Madon J. Landmann L. Roth J. et al.The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver.J Biol Chem. 1998; 273: 10046-10050Crossref PubMed Scopus (668) Google Scholar]. The relevance of BSEP is emphasized by the severe progressive familial cholestatic syndrome (PFIC2) or benign recurrent intrahepatic cholestasis (BRIC2) resulting from BSEP mutations (Table 1). Importantly, the functional implications of BSEP deficiency may be underestimated in knockout mice (Table 1) where BA composition is less toxic than in humans, and BAs can be excreted by other canalicular transporters (Table 1). BSEP expression/activity is tightly controlled at transcriptional and post-transcriptional levels. FXR [[20]Makishima M. Okamoto A.Y. Repa J.J. Tu H. Learned R.M. Luk A. et al.Identification of a nuclear receptor for bile acids.Science. 1999; 284: 1362-1365Crossref PubMed Scopus (1304) Google Scholar] upregulates BSEP expression (recently reviewed in [[21]Stieger B. The role of the sodium-taurocholate cotransporting polypeptide (NTCP) and of the bile salt export pump (BSEP) in physiology and pathophysiology of bile formation.Handb Exp Pharmacol. 2011; : 205-259Crossref PubMed Scopus (80) Google Scholar]). While BSEP is downregulated by inflammatory injury and estrogen, it is relatively well preserved in obstructive cholestasis, which may help limit intracellular BA accumulation, although a preserved bile flow may cause bile infarcts in biliary obstruction (recently reviewed in [[15]Wagner M. Zollner G. Trauner M. Nuclear receptor regulation of the adaptive response of bile acid transporters in cholestasis.Semin Liver Dis. 2010; 30: 160-177Crossref PubMed Scopus (41) Google Scholar]).The canalicular membrane also contains transport systems mediating excretion of biliary phospholipids (MDR3, Mdr2 in rodents, ABCB4) and cholesterol (two half transporters ABCG5/8 which are tightly coupled with BA excretion [[22]Lo Sasso G. Petruzzelli M. Moschetta A. A translational view on the biliary lipid secretory network.Biochim Biophys Acta. 2008; 1781: 79-96Crossref PubMed Scopus (14) Google Scholar] (Fig. 2, Table 1). Other canalicular transport systems (Fig. 2, Table 1) are less relevant for BA transport. Multidrug resistance-associated protein 2 (MRP2/ABCC2) mainly excretes bilirubin–glucuronides and glutathione conjugates, but also divalent sulfo-conjugated BAs into the bile (Fig. 2, Table 1) (Table 1). Multidrug resistance protein (MDR1, ABCB1) primarily excretes lipophilic cations including diverse drugs and carcinogens [[23]Cascorbi I. P-glycoprotein: tissue distribution, substrates, and functional consequences of genetic variations.Handb Exp Pharmacol. 2011; : 261-283Crossref PubMed Scopus (74) Google Scholar], while breast cancer resistance protein (BCRP, ABCG2) facilitates the transport of potentially toxic xenobiotics and food-derived carcinogens [[24]Meyer zu Schwabedissen H.E. Kroemer H.K. In vitro and in vivo evidence for the importance of breast cancer resistance protein transporters (BCRP/MXR/ABCP/ABCG2).Handb Exp Pharmacol. 2011; 2: 325-371Crossref Scopus (25) Google Scholar] (Table 1). Both transporters have also been implicated in BA transport when induced under cholestatic conditions, although this is still disputed in humans.Alternative basolateral efflux systems in hepatocytesDuring hepatocellular BA overload, BAs can also be transported back to the sinusoidal blood to protect the liver and for subsequent elimination via the urine. Usually this step is coordinated with phase I and II detoxification, providing less toxic and higher affinity substrates for the basolateral BA export systems [[18]Zollner 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 (193) Google Scholar]. This alternative basolateral BA export is mediated by the multidrug resistance-associated proteins MRP3 (ABCC3), MRP4 (ABCC4) and the heterodimeric organic solute transporter OSTα/OSTβ. Constitutive androstane receptor (CAR; NR1I3), pregnane X receptor (PXR; NR1I2), vitamin D receptor (VDR, NR1I1) and peroxisome proliferator-activated receptor alpha (PPARα, NR1C1) all increase MRP3 expression in mice, while MRP4 is induced by CAR and PPARα (recently reviewed in [[15]Wagner M. Zollner G. Trauner M. Nuclear receptor regulation of the adaptive response of bile acid transporters in cholestasis.Semin Liver Dis. 2010; 30: 160-177Crossref PubMed Scopus (41) Google Scholar]) (Fig. 2, Table 1). The heterodimeric transporters OSTα/OSTβ were initially identified as an intestinal BA efflux system in enterocytes (see below), but are also found in the liver; their expression is induced via FXR (reviewed in [[25]Dawson P.A. Lan T. Rao A. Bile acid transporters.J Lipid Res. 2009; 50: 2340-2357Crossref PubMed Scopus (160) Google Scholar]) (Fig. 2, Table 1).Cholangiocytes and bile acid transportBile duct epithelial cells (cholangiocytes) are important modifiers of bile formation by promoting bicarbonate excretion and line the bile ducts as drainage system for BAs to the intestine. Side chain modified BAs such as norUDCA with a relative resistance to conjugation, can bypass the enterohepatic circulation by a process termed cholehepatic shunting [[26]Hofmann A.F. Bile acids: trying to understand their chemistry and biology with the hope of helping patients.Hepatology. 2009; 49: 1403-1418Crossref PubMed Scopus (65) Google Scholar]. This process, together with potential direct effects of norUDCA on cholangiocyte secretion, induces bicarbonate-rich hypercholeresis that may represent a drugable protective mechanism in cholangiopathies [[27]Halilbasic E. Fiorotto R. Fickert P. Marschall H.U. Moustafa T. Spirli C. et al.Side chain structure determines unique physiologic and therapeutic properties of norursodeoxycholic acid in Mdr2−/− mice.Hepatology. 2009; 49: 1972-1981Crossref PubMed Scopus (63) Google Scholar]. In contrast, conjugated BAs require active transport into cholangiocytes via an apical sodium dependent BA transporter (ASBT), identical to the transport system in the ileum (see below). After uptake, BAs are exported into the adjacent peribiliary capillary plexus via OSTαβ and MRP3, and possibly a truncated version of ASBT (tABST) (recently reviewed in [[28]Claudel T. Zollner G. Wagner M. Trauner M. Role of nuclear receptors for bile acid metabolism, bile secretion, cholestasis, and gallstone disease.Biochim Biophys Acta. 2011; 1812: 867-878Crossref PubMed Scopus (23) Google Scholar]). Upregulation of cholangiocellular BA transport capacity in obstructive cholestasis ([[28]Claudel T. Zollner G. Wagner M. Trauner M. Role of nuclear receptors for bile acid metabolism, bile secretion, cholestasis, and gallstone disease.Biochim Biophys Acta. 2011; 1812: 867-878Crossref PubMed Scopus (23) Google Scholar]), partly by bile duct proliferation, may facilitate the removal of BAs from the stagnant bile. Under physiological conditions, a major role of BA transporters in cholangiocytes could be the regulation of intracellular concentrations of BAs as signaling molecules. Notably, several nuclear receptors such as FXR, RXR, LXR, VDR, PPARδ, and SHP, known to play a key role in the regulation of metabolic processes, are also expressed in cholangiocytes, although their role in bile duct (patho)biology remains to be clarified.Intestinal bile acid transportersApart from a relatively small proportion of passive uptake in the proximal small intestine and colon, BAs are mainly actively taken up in the terminal ileum via ASBT [29Shneider B.L. Intestinal bile acid transport: biology, physiology, and pathophysiology.J Pediatr Gastroenterol Nutr. 2001; 32: 407-417Crossref PubMed Scopus (82) Google Scholar, 30Dawson P.A. Haywood J. Craddock A.L. Wilson M. Tietjen M. Kluckman K. et al.Targeted deletion of the ileal bile acid transporter eliminates enterohepatic cycling of bile acids in mice.J Biol Chem. 2003; 278: 33920-33927Crossref PubMed Scopus (149) Google Scholar]. Notably, enterocytes, cholangiocytes and renal tubular cells share several BA transport systems including ASBT [[18]Zollner 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 (193) Google Scholar]. Unlike rats, human and mouse ASBT is under negative feedback regulation by BAs via FXR and SHP (reviewed in [[25]Dawson P.A. Lan T. Rao A. Bile acid transporters.J Lipid Res. 2009; 50: 2340-2357Crossref PubMed Scopus (160) Google Scholar]). After uptake, BAs are bound to the cytosolic ileal BA binding protein IBABP (also known as ileal lipid binding protein ILBP and fatty acid binding protein 6, FABP6) and exported into the portal blood via OSTα/OSTβ [[25]Dawson P.A. Lan T. Rao A. Bile acid transporters.J Lipid Res. 2009; 50: 2340-2357Crossref PubMed Scopus (160) Google Scholar]. The colon is exposed to BAs escaping ileal reabsorption and possesses detoxification and efflux systems (e.g., OSTα/OSTβ) for defense against secondary (unconjugated) BAs formed by the intestinal flora [[18]Zollner 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 (193) Google Scholar].After uptake into enterocytes, BAs induce FGF15 in mice (a homolog of human FGF 19) which acts in an endocrine fashion to repress the BA synthesis in hepatocytes [[31]Inagaki T. Choi M. Moschetta A. Peng L. Cummins C.L. McDonald J.G. et al.Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis.Cell Metab. 2005; 2: 217-225Abstract Full Text Full Text PDF PubMed Scopus (622) Google Scholar], facilitates gallbladder refilling [[32]Choi M. Moschetta A. Bookout A.L. Peng L. Umetani M. Holmstrom S.R. et al.Identification of a hormonal basis for gallbladder filling.Nat Med. 2006; 12: 1253-1255Crossref PubMed Scopus (135) Google Scholar] and in a paracrine manner downregulates ASBT expression [[33]Sinha J. Chen F. Miloh T. Burns R.C. Yu Z. Shneider B.L. Beta-Klotho and FGF-15/19 inhibit the apical sodium-dependent bile acid transporter in enterocytes and cholangiocytes.Am J Physiol Gastrointest Liver Physiol. 2008; 295: G996-G1003Crossref PubMed Scopus (42) Google Scholar], altogether leading to reduction of circulating BAs. Although under physiological conditions FGF19 originates mainly from enterocytes, patients with obstructive cholestasis show a profound increase in hepatic FGF19 expression (not observed in rodents) that correlates with elevated serum FGF19 levels [[34]Schaap F.G. van der Gaag N.A. Gouma D.J. Jansen P.L. High expression of the bile salt-homeostatic hormone fibroblast growth factor 19 in the liver of patients with extrahepatic cholestasis.Hepatology. 2009; 49: 1228-1235Crossref PubMed Scopus (94) Google Scholar]. In addition, FGF15/19 may also be actively involved in energy homeostasis since it stimulates hepatic glycogen and protein synthesis, as well as β-oxidation without inducing lipogenesis [[35]Kir S. Beddow S.A. Samuel V.T. Miller P. Previs S.F. Suino-Powell K. et al.FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis.Science. 2011; 331: 1621-1624Crossref PubMed Scopus (146) Google Scholar]. Apart from its signal function in the portal axis, FGF19 is also secreted into the bile and could have other signaling functions in exposed cells of the biliary and enteric tract [[36]Zweers S.J. Booij K.A. Komuta M. Roskams T. Gouma D.J. Jansen P.L. et al.The human gallbladder secretes fibroblast growth factor 19 into bile: towards defining the role of fibroblast growth factor 19 in the enterobiliary tract.Hepatology. 2012; 55: 575-583Crossref PubMed Scopus (35) Google Scholar]. Secretion of glucagon-like peptide 1 (GLP-1) from enteroendocrine cells is mediated by the plasma membrane BA activated G-protein-coupled receptor TGR5 and represents a link between BA and glucose metabolism, since GLP-1, secreted after food intake, facilitates glucose-induced insulin secretion [[37]Thomas C. Gioiello A. Noriega L. Strehle A. Oury J. Rizzo G. et al.TGR5-mediated bile acid sensing controls glucose homeostasis.Cell Metab. 2009; 10: 167-177Abstract Full Text Full Text PDF PubMed Scopus (414) Google Scholar].Role of bile acid transporters in cholestasis – pathophysiological and therapeutic considerationsTransporter alterations in cholestasis may be primary/pro-cholestatic (e.g., genetic defects (Table 1), inhibition by drugs, repression by cytokines and oxidative stress), or more often represent secondary/adaptive changes attempting to minimize liver injury [[18]Zollner 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 (193) Google Scholar]. In addition to transcriptional and post-transcriptional transporter changes, impaired canalicular contractility and increased tight junction permeability may also contribute to cholestasis [[38]Trauner M. Meier P.J. Boyer J.L. Molecular pathogenesis of cholestasis.N Engl J Me