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• W2023488062 abstract "Proper bile formation and bile flow is essential for a number of important physiological functions, e.g. fat digestion and assimilation of lipid-soluble nutrients in the small intestine and cholesterol homeostasis. In order to fulfil these needs, a concerted adequate functioning of membrane transport systems in liver, bile ducts and the intestine is required. In 1993, the landmark discovery of Smit and colleagues [[1]Smit J.J.M. Schinkel A.H. Oude Elferink R.P.J. Groen A.K. Wagenaar E. van Deemter L. et al.Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from and to liver disease.Cell. 1993; 75: 451-462Abstract Full Text PDF PubMed Scopus (1318) Google Scholar] showed that homozygous disruption of the Mdr2 gene in mice produced bile virtually free of phospholipids and cholesterol being dramatically reduced. Subsequent studies demonstrated not only the role of Mdr2 for bile acid metabolism, but also reported reduced cholesterol absorption, low HDL cholesterol levels and increased fecal cholesterol excretion in mice lacking Mdr2 expression [2Oude Elferink R.P.J. Ottenhoff R. van Wijland M. Smit J.J.M. Schinkel A.H. Groen A.K. Regulation of biliary lipid secretion by mdr2 P-glycoprotein in the mouse.J Clin Invest. 1995; 95: 31-38Crossref PubMed Google Scholar, 3Voshol P.J. Havinga R. Wolters H. Ottenhoff R. Princen H.M.G. Oude Elferink R.P.J. et al.Reduced plasma cholesterol and increased fecal sterol loss in multidrug resistance gene 2 p-glycoprotein-deficient mice.Gastroenterology. 1998; 114: 1024-1034Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 4Koopen N.R. Wolters H. Voshol P. Stieger B. Vonk R.J. Meier P.J. et al.Decreased Na+-dependent taurocholate uptake and low expression of the sinusoidal Na+-taurocholate cotransporting protein (Ntcp) in livers of mdr2 P-glycoprotein-deficient mice.J Hepatol. 1999; 30: 14-21Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar].In this issue of the Journal of Hepatology, Voshol et al. [[5]Voshol P.J. Koopen N.R. de Vree J.M.L. Havinga R. Princen H.M.G. Oude Elferink R.P.J. et al.Dietary cholesterol does not normalize low plasma cholesterol levels but induces hyperbilirubinemia and hypercholanemia in Mdr2 P-glycoprotein-deficient mice.J Hepatol. 2001; 34: 202-209Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar] present a study in Mdr2 (−/−) mice designed to investigate whether dietary supplementation of phospholipids and/or cholesterol is capable to restore normal HDL cholesterol levels and whether the liver can handle excess dietary cholesterol despite a dramatically lowered biliary cholesterol secretion. Much to their surprise, the investigators noticed that plasma of Mdr2 (−/−) mice became jaundiced within 3 days of cholesterol feeding and this was associated with elevated plasma bile salt and bilirubin levels. Based on this finding one would have expected cholestasis, however, the puzzling finding was that neither bile flow or bile salt secretion was decreased by dietary cholesterol. How can we explain this amazing observation in the Mdr2 (−/−) mouse?The physiologist defines cholestasis as cessation or impairment of bile flow. Therefore, cholesterol fed Mdr2 (−/−) mice with elevated plasma bile salt and bilirubin levels despite a normal bile flow are not cholestatic in a strict physiological sense. Interestingly, a similar observation has been made in a mouse model of erythropoietic protoporphyria [[6]Meerman L. Koopen N.R. Bloks V. van Goor H. Havinga R. Wolthers B.G. et al.Biliary fibrosis associated with altered bile composition in a mouse model of erythropoietic protoporphyria.Gastroenterology. 1999; 117: 696-705Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar]. By increasing bile flow, the liver most likely aims at keeping bile salt concentrations low to prevent damage to the biliary tree [7Mauad T. van Nieuwkerk C.M.J. Dingemans K.P. Smit J.J.M. Schinkel A.H. Notenboom R.G.E. et al.Mice with homozygous disruption of the mdr2 P-glycoprotein gene: a novel animal model for studies of nonsuppurative inflammatory cholangitis and hepatocarcinogenesis.Am J Pathol. 1994; 145: 1237-1245PubMed Google Scholar, 8van Nieuwkerk C.M. Elferink R.P. Groen A.K. Ottenhoff R. Tytgat G.N. Dingemans K.P. et al.Effects of ursodeoxycholate and cholate feeding on liver disease in FVB mice with a disrupted mdr2 P-glycoprotein gene.Gastroenterology. 1996; 111: 165-171Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar]. Indeed, such a mechanism appears to occur in guinea pigs with low biliary phospholipids and a bile acid pool that is more hydrophobic than that of mice [[9]Guertin F. Loranger A. Lepage G. Roy C.C. Yousef I.M. Domingo N. et al.Bile formation and hepatic plasma membrane composition in guinea pigs and rats.Comp Biochem Physiol B Biochem Mol Biol. 1995; 111: 523-531Crossref PubMed Scopus (12) Google Scholar]. Because bile salt secretion is not impaired in cholesterol-fed Mdr2 (−/−) mice, transporting bile salts from bile back to the systemic circulation by means of cholehepatic shunting may prevent further damage to the biliary tree. If this holds true, one would expect a higher choleretic activity of tauroursodeoxycholate in Mdr2 (−/−) mice, and an increased expression of the intestinal bile salt transporter on cholangiocytes [[10]Lazaridis K.N. Pham L. Tietz P. Marinelli R.A. deGroen P.C. Levine S. et al.Rat cholangiocytes absorb bile acids at their apical domain via the ileal sodium-dependent bile acid transporter.J Clin Invest. 1997; 100: 2714-2721Crossref PubMed Scopus (225) Google Scholar] would provide the molecular basis. As suggested by the work of Voshol et al. [[5]Voshol P.J. Koopen N.R. de Vree J.M.L. Havinga R. Princen H.M.G. Oude Elferink R.P.J. et al.Dietary cholesterol does not normalize low plasma cholesterol levels but induces hyperbilirubinemia and hypercholanemia in Mdr2 P-glycoprotein-deficient mice.J Hepatol. 2001; 34: 202-209Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar], decreased expression of the sodium dependent taurocholate cotransporter Ntcp in chow-fed Mdr2 (−/−) mice [[4]Koopen N.R. Wolters H. Voshol P. Stieger B. Vonk R.J. Meier P.J. et al.Decreased Na+-dependent taurocholate uptake and low expression of the sinusoidal Na+-taurocholate cotransporting protein (Ntcp) in livers of mdr2 P-glycoprotein-deficient mice.J Hepatol. 1999; 30: 14-21Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar] may be attenuated by cholesterol feeding mediated through putative bile salt and sterol regulatory elements in the Ntcp promoter [[11]Karpen S.J. Sun A.-Q. Kudish B. Hagenbuch B. Meier P.J. Ananthanarayanan M. et al.Multiple factors regulate the rat liver basolateral sodium-dependent bile acid cotransporter gene promoter.J Biol Chem. 1996; 271: 15211-15221Crossref PubMed Scopus (108) Google Scholar].Because in the Mdr2 (−/−) mouse unconjugated and conjugated bilirubin levels were elevated, hemolysis due to elevated plasma bile salt levels can not be the only explanation. Biliary excretion of conjugated bilirubin requires Mrp2, evident by hyperbilirubinemia in patients with Dubin–Johnson syndrome and mutations in the MRP2 gene [[12]Wada M. Toh S. Taniguchi K. Nakamura T. Uchiumi T. Kohno K. et al.Mutations in the canalicular multispecific organic anion transporter (cMOAT) gene, a novel ABC transporter, in patients with hyperbilirubinemia II/Dubin–Johnson syndrome.Hum Mol Genet. 1998; 7: 203-207Crossref PubMed Scopus (235) Google Scholar]. Post-transcriptional regulation of Mrp2 in cholesterol-fed Mdr2 (−/−) mice would be in line with Mrp2 mRNA expression data presented by Voshol et al. [[5]Voshol P.J. Koopen N.R. de Vree J.M.L. Havinga R. Princen H.M.G. Oude Elferink R.P.J. et al.Dietary cholesterol does not normalize low plasma cholesterol levels but induces hyperbilirubinemia and hypercholanemia in Mdr2 P-glycoprotein-deficient mice.J Hepatol. 2001; 34: 202-209Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar] and further supported by analysis of the MRP2 promoter apparently lacking a sterol regulatory element binding protein recognition consensus site [[13]Tanaka T. Uchiumi T. Hinoshita E. Inokuchi A. Toh S. Wada M. et al.The human multidrug resistance protein 2 gene: functional characterization of the 5′-flanking region and expression in hepatic cells.Hepatology. 1999; 30: 1507-1512Crossref PubMed Scopus (84) Google Scholar]. As observed during hepatic inflammation [[14]Kubitz R. Wettsetin M Warskulat U. Häussinger D. Regulation of the multidrug resistance protein 2 in the rat liver by lipopolysaccharide and dexamethasone.Gastroenterology. 1999; 116: 401-410Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar], altered Mrp2 insertion and retrieval into and from the canalicular membrane may have contributed to some extent to elevated plasma bilirubin levels in mice with homozygous disruption of the Mdr2 gene. Studies with isolated canalicular liver plasma membranes or, more elegantly, by immunoelectronmicroscopy should provide clarification. Furthermore, increased expression of Mrp3 at the basolateral surface of hepatocytes [[15]König J. Rost D. Cui Y. Keppler D. Characterization of the human multidrug resistance protein isoform MRP3 localized to the basolateral hepatocyte membrane.Hepatology. 1999; 29: 1156-1163Crossref PubMed Scopus (429) Google Scholar] may also contribute to elevated conjugated bilirubin levels in plasma of cholesterol-fed Mdr2 (−/−) mice.The recent finding of heterozygous mutations in the MDR3 gene, the human orthologue of Mdr2, in female patients with intrahepatic cholestasis of pregnancy (reviewed in [[16]Lammert F. Marschall H.U. Glantz A. Matern S. Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management.J Hepatol. 2000; 33: 1012-1021Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar]) suggest that mutations in hepatobiliary transport proteins may predispose to this disease, probably due to a modulatory effect of progesterone on MDR3 activity [[17]Debry P. Nash E.A. Neklason D.W. Metherall J.E. Role of multidrug resistance P-glycoproteins in cholesterol esterification.J Biol Chem. 1997; 272: 1026-1031Crossref PubMed Scopus (127) Google Scholar]. It is tempting to speculate that estrogens may also alter MDR3 function and this may be accompanied by decreased NTCP gene expression as has been reported for pregnant rats [18Ganguly T.C. Liu Y. Hyde J.F. Hagenbuch B. Meier P.J. Vore M. Prolactin increases hepatic Na+/taurocholate co-transport activity and messenger RNA post partum.Biochem J. 1994; 303: 33-36Crossref PubMed Scopus (40) Google Scholar, 19Simon F.R. Fortune J. Iwahashi M. Gartung C. Wolkoff A. Sutherland E. Ethinyl estradiol cholestasis involves alterations in expression of liver sinusoidal transporters.Am J Physiol. 1996; 271: G1043-G1052PubMed Google Scholar]. No data are currently available for bile flow and biliary lipid secretion rates in pregnant women. Nevertheless, the Mdr2 (+/−) mouse may represent a suitable animal model to study the pathophysiology of intrahepatic cholestasis of pregnancy.The study by Voshol et al. [[5]Voshol P.J. Koopen N.R. de Vree J.M.L. Havinga R. Princen H.M.G. Oude Elferink R.P.J. et al.Dietary cholesterol does not normalize low plasma cholesterol levels but induces hyperbilirubinemia and hypercholanemia in Mdr2 P-glycoprotein-deficient mice.J Hepatol. 2001; 34: 202-209Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar] also demonstrated that dietary cholesterol is not capable to increase the low HDL cholesterol levels observed in Mdr2(−/−) mice. At first hand, the lack of hepatic up-regulation of the HDL receptor Srb1 [[20]Acton S. Rigotti A. Landschulz K.T. Xu S. Hobbs H.H. Krieger M. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor.Science. 1996; 271: 518-520Crossref PubMed Scopus (1986) Google Scholar] appears to exclude a contribution of Srb1 and the reverse cholesterol transport pathway to the low HDL cholesterol levels observed. However, altered HDL kinetics have not been ruled out and impaired chylomicron production by enterocytes of Mdr2 (−/−) mice [[21]Voshol P.J. Minich D.M. Havinga R. Oude Elferink R.P.J. Verkade H.J. Groen A.K. et al.Postprandial chylomicron formation and fat absorption in multidrug resistance gene 2 P-glycoprotein deficient mice.Gastroenterology. 2000; 118: 173-182Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar] may also be of relevance. Furthermore, desquamation of enterocytes as a result of lipid-free bile together with elevated intestinal cholesterol synthesis due to the lack of biliary cholesterol and increased intestinal cholesterol excretion through the action of Abc1 [[22]Repa J.J. Turley S.D. Lobaccaro J.M.A. Medina J. Li L. Lustig K. et al.Regulation of absorption and Abc1-mediated efflux of cholesterol by RXR heterodimers.Science. 2000; 289: 1524-1529Crossref PubMed Scopus (1144) Google Scholar] may provide another potential explanation.Despite the principal capacity of bile salts to extract cholesterol from plasma membranes of Mdr2 (−/−) mice [[2]Oude Elferink R.P.J. Ottenhoff R. van Wijland M. Smit J.J.M. Schinkel A.H. Groen A.K. Regulation of biliary lipid secretion by mdr2 P-glycoprotein in the mouse.J Clin Invest. 1995; 95: 31-38Crossref PubMed Google Scholar], dietary cholesterol is not capable of inducing biliary cholesterol secretion in Mdr2(−/−) mice. This finding together with elevated hepatic cholesterol levels may reflect an altered biliary cholesterol secretory process. One possible explanation may be impairment of free cholesterol delivery to the canalicular membrane which is thought to involve sterol carrier protein 2 [[23]Fuchs M. Lammert F. Wang D.Q.-H. Paigen B. Carey M.C. Cohen D.E. Sterol carrier protein 2 participates in hypersecretion of biliary cholesterol in genetically gallstone-susceptible mice.Biochem J. 1998; 336: 33-37Crossref PubMed Scopus (58) Google Scholar], fatty acid binding protein of liver [24Hafer A. Katzberg N. Münch C. Scheibner J. Stange E.F. Seedorf U. et al.Studies with sterol carrier protein 2 (Scp2) gene knockout mice identify liver fatty acid binding protein (Fabpl) as intracellular cholesterol transporter contributing to biliary cholesterol hyper-secretion and gallstone formation.Gastroenterology. 2000; 108: A135Google Scholar, 25Mok K.S. Hakvoort T. Frijters R. Tytgat G.N. Groen A.K. Identification of genes involved in hepatobiliary cholesterol transport.Gastroenterology. 1999; 116: 1249Google Scholar] or other yet unidentified transport processes. Alternatively, a decreased bile canalicular membrane fluidity due to cholesterol and sphingomyelin accumulation with a reduced phosphatidylcholine content of the outer membrane leaflet may come into play.In conclusion, the Mdr2 (−/−) mouse once again provided exciting findings with relevance to biliary physiology. Future studies should bring us not only another step closer towards understanding the molecular mechanisms of biliary cholesterol secretion, but also towards identification of the inter-relationship between hepatobiliary and intestinal transport processes. Proper bile formation and bile flow is essential for a number of important physiological functions, e.g. fat digestion and assimilation of lipid-soluble nutrients in the small intestine and cholesterol homeostasis. In order to fulfil these needs, a concerted adequate functioning of membrane transport systems in liver, bile ducts and the intestine is required. In 1993, the landmark discovery of Smit and colleagues [[1]Smit J.J.M. Schinkel A.H. Oude Elferink R.P.J. Groen A.K. Wagenaar E. van Deemter L. et al.Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from and to liver disease.Cell. 1993; 75: 451-462Abstract Full Text PDF PubMed Scopus (1318) Google Scholar] showed that homozygous disruption of the Mdr2 gene in mice produced bile virtually free of phospholipids and cholesterol being dramatically reduced. Subsequent studies demonstrated not only the role of Mdr2 for bile acid metabolism, but also reported reduced cholesterol absorption, low HDL cholesterol levels and increased fecal cholesterol excretion in mice lacking Mdr2 expression [2Oude Elferink R.P.J. Ottenhoff R. van Wijland M. Smit J.J.M. Schinkel A.H. Groen A.K. Regulation of biliary lipid secretion by mdr2 P-glycoprotein in the mouse.J Clin Invest. 1995; 95: 31-38Crossref PubMed Google Scholar, 3Voshol P.J. Havinga R. Wolters H. Ottenhoff R. Princen H.M.G. Oude Elferink R.P.J. et al.Reduced plasma cholesterol and increased fecal sterol loss in multidrug resistance gene 2 p-glycoprotein-deficient mice.Gastroenterology. 1998; 114: 1024-1034Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar, 4Koopen N.R. Wolters H. Voshol P. Stieger B. Vonk R.J. Meier P.J. et al.Decreased Na+-dependent taurocholate uptake and low expression of the sinusoidal Na+-taurocholate cotransporting protein (Ntcp) in livers of mdr2 P-glycoprotein-deficient mice.J Hepatol. 1999; 30: 14-21Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar]. In this issue of the Journal of Hepatology, Voshol et al. [[5]Voshol P.J. Koopen N.R. de Vree J.M.L. Havinga R. Princen H.M.G. Oude Elferink R.P.J. et al.Dietary cholesterol does not normalize low plasma cholesterol levels but induces hyperbilirubinemia and hypercholanemia in Mdr2 P-glycoprotein-deficient mice.J Hepatol. 2001; 34: 202-209Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar] present a study in Mdr2 (−/−) mice designed to investigate whether dietary supplementation of phospholipids and/or cholesterol is capable to restore normal HDL cholesterol levels and whether the liver can handle excess dietary cholesterol despite a dramatically lowered biliary cholesterol secretion. Much to their surprise, the investigators noticed that plasma of Mdr2 (−/−) mice became jaundiced within 3 days of cholesterol feeding and this was associated with elevated plasma bile salt and bilirubin levels. Based on this finding one would have expected cholestasis, however, the puzzling finding was that neither bile flow or bile salt secretion was decreased by dietary cholesterol. How can we explain this amazing observation in the Mdr2 (−/−) mouse? The physiologist defines cholestasis as cessation or impairment of bile flow. Therefore, cholesterol fed Mdr2 (−/−) mice with elevated plasma bile salt and bilirubin levels despite a normal bile flow are not cholestatic in a strict physiological sense. Interestingly, a similar observation has been made in a mouse model of erythropoietic protoporphyria [[6]Meerman L. Koopen N.R. Bloks V. van Goor H. Havinga R. Wolthers B.G. et al.Biliary fibrosis associated with altered bile composition in a mouse model of erythropoietic protoporphyria.Gastroenterology. 1999; 117: 696-705Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar]. By increasing bile flow, the liver most likely aims at keeping bile salt concentrations low to prevent damage to the biliary tree [7Mauad T. van Nieuwkerk C.M.J. Dingemans K.P. Smit J.J.M. Schinkel A.H. Notenboom R.G.E. et al.Mice with homozygous disruption of the mdr2 P-glycoprotein gene: a novel animal model for studies of nonsuppurative inflammatory cholangitis and hepatocarcinogenesis.Am J Pathol. 1994; 145: 1237-1245PubMed Google Scholar, 8van Nieuwkerk C.M. Elferink R.P. Groen A.K. Ottenhoff R. Tytgat G.N. Dingemans K.P. et al.Effects of ursodeoxycholate and cholate feeding on liver disease in FVB mice with a disrupted mdr2 P-glycoprotein gene.Gastroenterology. 1996; 111: 165-171Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar]. Indeed, such a mechanism appears to occur in guinea pigs with low biliary phospholipids and a bile acid pool that is more hydrophobic than that of mice [[9]Guertin F. Loranger A. Lepage G. Roy C.C. Yousef I.M. Domingo N. et al.Bile formation and hepatic plasma membrane composition in guinea pigs and rats.Comp Biochem Physiol B Biochem Mol Biol. 1995; 111: 523-531Crossref PubMed Scopus (12) Google Scholar]. Because bile salt secretion is not impaired in cholesterol-fed Mdr2 (−/−) mice, transporting bile salts from bile back to the systemic circulation by means of cholehepatic shunting may prevent further damage to the biliary tree. If this holds true, one would expect a higher choleretic activity of tauroursodeoxycholate in Mdr2 (−/−) mice, and an increased expression of the intestinal bile salt transporter on cholangiocytes [[10]Lazaridis K.N. Pham L. Tietz P. Marinelli R.A. deGroen P.C. Levine S. et al.Rat cholangiocytes absorb bile acids at their apical domain via the ileal sodium-dependent bile acid transporter.J Clin Invest. 1997; 100: 2714-2721Crossref PubMed Scopus (225) Google Scholar] would provide the molecular basis. As suggested by the work of Voshol et al. [[5]Voshol P.J. Koopen N.R. de Vree J.M.L. Havinga R. Princen H.M.G. Oude Elferink R.P.J. et al.Dietary cholesterol does not normalize low plasma cholesterol levels but induces hyperbilirubinemia and hypercholanemia in Mdr2 P-glycoprotein-deficient mice.J Hepatol. 2001; 34: 202-209Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar], decreased expression of the sodium dependent taurocholate cotransporter Ntcp in chow-fed Mdr2 (−/−) mice [[4]Koopen N.R. Wolters H. Voshol P. Stieger B. Vonk R.J. Meier P.J. et al.Decreased Na+-dependent taurocholate uptake and low expression of the sinusoidal Na+-taurocholate cotransporting protein (Ntcp) in livers of mdr2 P-glycoprotein-deficient mice.J Hepatol. 1999; 30: 14-21Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar] may be attenuated by cholesterol feeding mediated through putative bile salt and sterol regulatory elements in the Ntcp promoter [[11]Karpen S.J. Sun A.-Q. Kudish B. Hagenbuch B. Meier P.J. Ananthanarayanan M. et al.Multiple factors regulate the rat liver basolateral sodium-dependent bile acid cotransporter gene promoter.J Biol Chem. 1996; 271: 15211-15221Crossref PubMed Scopus (108) Google Scholar]. Because in the Mdr2 (−/−) mouse unconjugated and conjugated bilirubin levels were elevated, hemolysis due to elevated plasma bile salt levels can not be the only explanation. Biliary excretion of conjugated bilirubin requires Mrp2, evident by hyperbilirubinemia in patients with Dubin–Johnson syndrome and mutations in the MRP2 gene [[12]Wada M. Toh S. Taniguchi K. Nakamura T. Uchiumi T. Kohno K. et al.Mutations in the canalicular multispecific organic anion transporter (cMOAT) gene, a novel ABC transporter, in patients with hyperbilirubinemia II/Dubin–Johnson syndrome.Hum Mol Genet. 1998; 7: 203-207Crossref PubMed Scopus (235) Google Scholar]. Post-transcriptional regulation of Mrp2 in cholesterol-fed Mdr2 (−/−) mice would be in line with Mrp2 mRNA expression data presented by Voshol et al. [[5]Voshol P.J. Koopen N.R. de Vree J.M.L. Havinga R. Princen H.M.G. Oude Elferink R.P.J. et al.Dietary cholesterol does not normalize low plasma cholesterol levels but induces hyperbilirubinemia and hypercholanemia in Mdr2 P-glycoprotein-deficient mice.J Hepatol. 2001; 34: 202-209Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar] and further supported by analysis of the MRP2 promoter apparently lacking a sterol regulatory element binding protein recognition consensus site [[13]Tanaka T. Uchiumi T. Hinoshita E. Inokuchi A. Toh S. Wada M. et al.The human multidrug resistance protein 2 gene: functional characterization of the 5′-flanking region and expression in hepatic cells.Hepatology. 1999; 30: 1507-1512Crossref PubMed Scopus (84) Google Scholar]. As observed during hepatic inflammation [[14]Kubitz R. Wettsetin M Warskulat U. Häussinger D. Regulation of the multidrug resistance protein 2 in the rat liver by lipopolysaccharide and dexamethasone.Gastroenterology. 1999; 116: 401-410Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar], altered Mrp2 insertion and retrieval into and from the canalicular membrane may have contributed to some extent to elevated plasma bilirubin levels in mice with homozygous disruption of the Mdr2 gene. Studies with isolated canalicular liver plasma membranes or, more elegantly, by immunoelectronmicroscopy should provide clarification. Furthermore, increased expression of Mrp3 at the basolateral surface of hepatocytes [[15]König J. Rost D. Cui Y. Keppler D. Characterization of the human multidrug resistance protein isoform MRP3 localized to the basolateral hepatocyte membrane.Hepatology. 1999; 29: 1156-1163Crossref PubMed Scopus (429) Google Scholar] may also contribute to elevated conjugated bilirubin levels in plasma of cholesterol-fed Mdr2 (−/−) mice. The recent finding of heterozygous mutations in the MDR3 gene, the human orthologue of Mdr2, in female patients with intrahepatic cholestasis of pregnancy (reviewed in [[16]Lammert F. Marschall H.U. Glantz A. Matern S. Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management.J Hepatol. 2000; 33: 1012-1021Abstract Full Text Full Text PDF PubMed Scopus (353) Google Scholar]) suggest that mutations in hepatobiliary transport proteins may predispose to this disease, probably due to a modulatory effect of progesterone on MDR3 activity [[17]Debry P. Nash E.A. Neklason D.W. Metherall J.E. Role of multidrug resistance P-glycoproteins in cholesterol esterification.J Biol Chem. 1997; 272: 1026-1031Crossref PubMed Scopus (127) Google Scholar]. It is tempting to speculate that estrogens may also alter MDR3 function and this may be accompanied by decreased NTCP gene expression as has been reported for pregnant rats [18Ganguly T.C. Liu Y. Hyde J.F. Hagenbuch B. Meier P.J. Vore M. Prolactin increases hepatic Na+/taurocholate co-transport activity and messenger RNA post partum.Biochem J. 1994; 303: 33-36Crossref PubMed Scopus (40) Google Scholar, 19Simon F.R. Fortune J. Iwahashi M. Gartung C. Wolkoff A. Sutherland E. Ethinyl estradiol cholestasis involves alterations in expression of liver sinusoidal transporters.Am J Physiol. 1996; 271: G1043-G1052PubMed Google Scholar]. No data are currently available for bile flow and biliary lipid secretion rates in pregnant women. Nevertheless, the Mdr2 (+/−) mouse may represent a suitable animal model to study the pathophysiology of intrahepatic cholestasis of pregnancy. The study by Voshol et al. [[5]Voshol P.J. Koopen N.R. de Vree J.M.L. Havinga R. Princen H.M.G. Oude Elferink R.P.J. et al.Dietary cholesterol does not normalize low plasma cholesterol levels but induces hyperbilirubinemia and hypercholanemia in Mdr2 P-glycoprotein-deficient mice.J Hepatol. 2001; 34: 202-209Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar] also demonstrated that dietary cholesterol is not capable to increase the low HDL cholesterol levels observed in Mdr2(−/−) mice. At first hand, the lack of hepatic up-regulation of the HDL receptor Srb1 [[20]Acton S. Rigotti A. Landschulz K.T. Xu S. Hobbs H.H. Krieger M. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor.Science. 1996; 271: 518-520Crossref PubMed Scopus (1986) Google Scholar] appears to exclude a contribution of Srb1 and the reverse cholesterol transport pathway to the low HDL cholesterol levels observed. However, altered HDL kinetics have not been ruled out and impaired chylomicron production by enterocytes of Mdr2 (−/−) mice [[21]Voshol P.J. Minich D.M. Havinga R. Oude Elferink R.P.J. Verkade H.J. Groen A.K. et al.Postprandial chylomicron formation and fat absorption in multidrug resistance gene 2 P-glycoprotein deficient mice.Gastroenterology. 2000; 118: 173-182Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar] may also be of relevance. Furthermore, desquamation of enterocytes as a result of lipid-free bile together with elevated intestinal cholesterol synthesis due to the lack of biliary cholesterol and increased intestinal cholesterol excretion through the action of Abc1 [[22]Repa J.J. Turley S.D. Lobaccaro J.M.A. Medina J. Li L. Lustig K. et al.Regulation of absorption and Abc1-mediated efflux of cholesterol by RXR heterodimers.Science. 2000; 289: 1524-1529Crossref PubMed Scopus (1144) Google Scholar] may provide another potential explanation. Despite the principal capacity of bile salts to extract cholesterol from plasma membranes of Mdr2 (−/−) mice [[2]Oude Elferink R.P.J. Ottenhoff R. van Wijland M. Smit J.J.M. Schinkel A.H. Groen A.K. Regulation of biliary lipid secretion by mdr2 P-glycoprotein in the mouse.J Clin Invest. 1995; 95: 31-38Crossref PubMed Google Scholar], dietary cholesterol is not capable of inducing biliary cholesterol secretion in Mdr2(−/−) mice. This finding together with elevated hepatic cholesterol levels may reflect an altered biliary cholesterol secretory process. One possible explanation may be impairment of free cholesterol delivery to the canalicular membrane which is thought to involve sterol carrier protein 2 [[23]Fuchs M. Lammert F. Wang D.Q.-H. Paigen B. Carey M.C. Cohen D.E. Sterol carrier protein 2 participates in hypersecretion of biliary cholesterol in genetically gallstone-susceptible mice.Biochem J. 1998; 336: 33-37Crossref PubMed Scopus (58) Google Scholar], fatty acid binding protein of liver [24Hafer A. Katzberg N. Münch C. Scheibner J. Stange E.F. Seedorf U. et al.Studies with sterol carrier protein 2 (Scp2) gene knockout mice identify liver fatty acid binding protein (Fabpl) as intracellular cholesterol transporter contributing to biliary cholesterol hyper-secretion and gallstone formation.Gastroenterology. 2000; 108: A135Google Scholar, 25Mok K.S. Hakvoort T. Frijters R. Tytgat G.N. Groen A.K. Identification of genes involved in hepatobiliary cholesterol transport.Gastroenterology. 1999; 116: 1249Google Scholar] or other yet unidentified transport processes. Alternatively, a decreased bile canalicular membrane fluidity due to cholesterol and sphingomyelin accumulation with a reduced phosphatidylcholine content of the outer membrane leaflet may come into play. In conclusion, the Mdr2 (−/−) mouse once again provided exciting findings with relevance to biliary physiology. Future studies should bring us not only another step closer towards understanding the molecular mechanisms of biliary cholesterol secretion, but also towards identification of the inter-relationship between hepatobiliary and intestinal transport processes." @default.
• W2023488062 created "2016-06-24" @default.
• W2023488062 creator A5029630686 @default.
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• W2023488062 date "2001-02-01" @default.
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