The formation of bile is a vital function, and its impairmentby drugs or infectious, autoimmune, metabolic, or genetic disordersresults in the syndrome commonly known as cholestasis.1 Thesecretion of bile normally depends on the function of a numberof membrane transport systems in hepatocytes and bile-duct epithelialcells (cholangiocytes) and on the structural and functionalintegrity of the bile-secretory apparatus. This review summarizesthe molecular defects in hepatocellular membrane transportersthat are associated with various forms of cholestatic liverdisease in humans.
Molecular Mechanisms of Bile Formation
Bile formation is an osmotic secretory process that is drivenby the active concentration of bile . . . [Full Text of this Article]
Experimental Models and Their Clinical Correlates
Molecular Mechanisms of Cholestasis
Hepatocellular Transporters
Cholangiocyte Transporters
Other Structural and Functional Defects: Altered Cytoskeleton, Tight Junctions, Vesicular Transport, and Signal Transduction
Therapeutic Implications and Future Perspectives
Pharmacologic Therapy
Gene Therapy
Conclusions
Source Information
From the Division of Gastroenterology and Hepatology, Department of Medicine, Karl Franzens University, Graz, Austria (M.T.); the Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, Zurich, Switzerland (P.J.M.); and the Department of Medicine and Liver Center, Yale University School of Medicine, New Haven, Conn. (J.L.B.).
Address reprint requests to Dr. Boyer at the Yale University School of Medicine, P.O. Box 208109, New Haven, CT 06520-8019.
References
This article has been cited by other articles:
Chiang, J. Y. L.
(2009). Bile acids: regulation of synthesis. J. Lipid Res.
50: 1955-1966
[Abstract][Full Text]
Kis, E., Ioja, E., Nagy, T., Szente, L., Heredi-Szabo, K., Krajcsi, P.
(2009). Effect of Membrane Cholesterol on BSEP/Bsep Activity: Species Specificity Studies for Substrates and Inhibitors. Drug Metab. Dispos.
37: 1878-1886
[Abstract][Full Text]
Li, F.-C., Liu, Y., Huang, G.-T., Chiou, L.-L., Liang, J.-H., Sun, T.-L., Dong, C.-Y., Lee, H.-S.
(2009). In vivo dynamic metabolic imaging of obstructive cholestasis in mice. Am. J. Physiol. Gastrointest. Liver Physiol.
296: G1091-G1097
[Abstract][Full Text]
Tanaka, Y., Aleksunes, L. M., Cui, Y. J., Klaassen, C. D.
(2009). ANIT-Induced Intrahepatic Cholestasis Alters Hepatobiliary Transporter Expression via Nrf2-Dependent and Independent Signaling. Toxicol Sci
108: 247-257
[Abstract][Full Text]
Liu, S., Yang, W., Shen, L., Turner, J. R., Coyne, C. B., Wang, T.
(2009). Tight Junction Proteins Claudin-1 and Occludin Control Hepatitis C Virus Entry and Are Downregulated during Infection To Prevent Superinfection. J. Virol.
83: 2011-2014
[Abstract][Full Text]
Volz, D. C., Kullman, S. W., Howarth, D. L., Hardman, R. C., Hinton, D. E.
(2008). Protective Response of the Ah Receptor to ANIT-Induced Biliary Epithelial Cell Toxicity in See-Through Medaka. Toxicol Sci
102: 262-277
[Abstract][Full Text]
Beilke, L. D., Besselsen, D. G., Cheng, Q., Kulkarni, S., Slitt, A. L., Cherrington, N. J.
(2008). Minimal Role of Hepatic Transporters in the Hepatoprotection against LCA-Induced Intrahepatic Cholestasis. Toxicol Sci
102: 196-204
[Abstract][Full Text]
Okada, K., Shoda, J., Kano, M., Suzuki, S., Ohtake, N., Yamamoto, M., Takahashi, H., Utsunomiya, H., Oda, K., Sato, K., Watanabe, A., Ishii, T., Itoh, K., Yamamoto, M., Yokoi, T., Yoshizato, K., Sugiyama, Y., Suzuki, H.
(2007). Inchinkoto, a herbal medicine, and its ingredients dually exert Mrp2/MRP2-mediated choleresis and Nrf2-mediated antioxidative action in rat livers. Am. J. Physiol. Gastrointest. Liver Physiol.
292: G1450-G1463
[Abstract][Full Text]
Mochizuki, K., Kagawa, T., Numari, A., Harris, M. J., Itoh, J., Watanabe, N., Mine, T., Arias, I. M.
(2007). Two N-linked glycans are required to maintain the transport activity of the bile salt export pump (ABCB11) in MDCK II cells. Am. J. Physiol. Gastrointest. Liver Physiol.
292: G818-G828
[Abstract][Full Text]
Wasmuth, H E, Glantz, A, Keppeler, H, Simon, E, Bartz, C, Rath, W, Mattsson, L-A, Marschall, H-U, Lammert, F
(2007). Intrahepatic cholestasis of pregnancy: the severe form is associated with common variants of the hepatobiliary phospholipid transporter ABCB4 gene. Gut
56: 265-270
[Abstract][Full Text]
Li, Z., Mizuno, S., Nakamura, T.
(2007). Antinecrotic and antiapoptotic effects of hepatocyte growth factor on cholestatic hepatitis in a mouse model of bile-obstructive diseases. Am. J. Physiol. Gastrointest. Liver Physiol.
292: G639-G646
[Abstract][Full Text]
Michael, M., Thompson, M., Hicks, R. J., Mitchell, P. L., Ellis, A., Milner, A. D., Di Iulio, J., Scott, A. M., Gurtler, V., Hoskins, J. M., Clarke, S. J., Tebbut, N. C., Foo, K., Jefford, M., Zalcberg, J. R.
(2006). Relationship of Hepatic Functional Imaging to Irinotecan Pharmacokinetics and Genetic Parameters of Drug Elimination. JCO
24: 4228-4235
[Abstract][Full Text]
Navarro, V. J., Senior, J. R.
(2006). Drug-Related Hepatotoxicity. NEJM
354: 731-739
[Full Text]
Ogawa, A, Tagawa, T, Nishimura, H, Yajima, T, Abe, T, Arai, T, Taniguchi, M, Takeda, K, Akira, S, Nimura, Y, Yoshikai, Y
(2006). Toll-like receptors 2 and 4 are differentially involved in Fas dependent apoptosis in Peyer's patch and the liver at an early stage after bile duct ligation in mice. Gut
55: 105-113
[Abstract][Full Text]
Hartmann, G., Vassileva, V., Piquette-Miller, M.
(2005). IMPACT OF ENDOTOXIN-INDUCED CHANGES IN P-GLYCOPROTEIN EXPRESSION ON DISPOSITION OF DOXORUBICIN IN MICE. Drug Metab. Dispos.
33: 820-828
[Abstract][Full Text]
Fiorucci, S., Clerici, C., Antonelli, E., Orlandi, S., Goodwin, B., Sadeghpour, B. M., Sabatino, G., Russo, G., Castellani, D., Willson, T. M., Pruzanski, M., Pellicciari, R., Morelli, A.
(2005). Protective Effects of 6-Ethyl Chenodeoxycholic Acid, a Farnesoid X Receptor Ligand, in Estrogen-Induced Cholestasis. J. Pharmacol. Exp. Ther.
313: 604-612
[Abstract][Full Text]
Cullen, J. M.
(2005). Mechanistic Classification of Liver Injury. Toxicol Pathol
33: 6-8
[Abstract][Full Text]
Simon, F. R., Fortune, J., Iwahashi, M., Qadri, I., Sutherland, E.
(2004). Multihormonal regulation of hepatic sinusoidal Ntcp gene expression. Am. J. Physiol. Gastrointest. Liver Physiol.
287: G782-G794
[Abstract][Full Text]
Bennink, R. J., Dinant, S., Erdogan, D., Heijnen, B. H., Straatsburg, I. H., van Vliet, A. K., van Gulik, T. M.
(2004). Preoperative Assessment of Postoperative Remnant Liver Function Using Hepatobiliary Scintigraphy. JNM
45: 965-971
[Abstract][Full Text]
Kubitz, R., Saha, N., Kuhlkamp, T., Dutta, S., vom Dahl, S., Wettstein, M., Haussinger, D.
(2004). Ca2+-dependent Protein Kinase C Isoforms Induce Cholestasis in Rat Liver. J. Biol. Chem.
279: 10323-10330
[Abstract][Full Text]
Han, X., Fink, M. P., Uchiyama, T., Yang, R., Delude, R. L.
(2004). Increased iNOS activity is essential for hepatic epithelial tight junction dysfunction in endotoxemic mice. Am. J. Physiol. Gastrointest. Liver Physiol.
286: G126-G136
[Abstract][Full Text]
Hogan, W. J., Maris, M., Storer, B., Sandmaier, B. M., Maloney, D. G., Schoch, H. G., Woolfrey, A. E., Shulman, H. M., Storb, R., McDonald, G. B.
(2004). Hepatic injury after nonmyeloablative conditioning followed by allogeneic hematopoietic cell transplantation: a study of 193 patients. Blood
103: 78-84
[Abstract][Full Text]
Mottino, A. D., Veggi, L. M., Wood, M., Roman, J. M. V., Vore, M.
(2003). Biliary Secretion of Glutathione in Estradiol 17{beta}-D-Glucuronide-Induced Cholestasis. J. Pharmacol. Exp. Ther.
307: 306-313
[Abstract][Full Text]
Mesotten, D., Van den Berghe, G., Liddle, C., Coulter, S., McDougall, F., Baxter, R. C., Delhanty, P. J. D.
(2003). Growth Hormone Modulation of the Rat Hepatic Bile Transporter System in Endotoxin-Induced Cholestasis. Endocrinology
144: 4008-4017
[Abstract][Full Text]
Lee, W. M.
(2003). Drug-Induced Hepatotoxicity. NEJM
349: 474-485
[Full Text]
Beuers, U., Denk, G. U., Soroka, C. J., Wimmer, R., Rust, C., Paumgartner, G., Boyer, J. L.
(2003). Taurolithocholic Acid Exerts Cholestatic Effects via Phosphatidylinositol 3-Kinase-dependent Mechanisms in Perfused Rat Livers and Rat Hepatocyte Couplets. J. Biol. Chem.
278: 17810-17818
[Abstract][Full Text]
Cheng, J. B., Jacquemin, E., Gerhardt, M., Nazer, H., Cresteil, D., Heubi, J. E., Setchell, K. D. R., Russell, D. W.
(2003). Molecular Genetics of 3{beta}-Hydroxy-{Delta}5-C27-Steroid Oxidoreductase Deficiency in 16 Patients with Loss of Bile Acid Synthesis and Liver Disease. J. Clin. Endocrinol. Metab.
88: 1833-1841
[Abstract][Full Text]
Trauner, M., Boyer, J. L.
(2003). Bile Salt Transporters: Molecular Characterization, Function, and Regulation. Physiol. Rev.
83: 633-671
[Abstract][Full Text]
Clotman, F., Lannoy, V. J., Reber, M., Cereghini, S., Cassiman, D., Jacquemin, P., Roskams, T., Rousseau, G. G., Lemaigre, F. P.
(2003). The onecut transcription factor HNF6 is required for normal development of the biliary tract. Development
129: 1819-1828
[Abstract][Full Text]
Coffinier, C., Gresh, L., Fiette, L., Tronche, F., Schutz, G., Babinet, C., Pontoglio, M., Yaniv, M., Barra, J.
(2003). Bile system morphogenesis defects and liver dysfunction upon targeted deletion of HNF1{beta}. Development
129: 1829-1838
[Abstract][Full Text]
Hitzl, M., Klein, K., Zanger, U. M., Fritz, P., Nussler, A. K., Neuhaus, P., Fromm, M. F.
(2003). Influence of Omeprazole on Multidrug Resistance Protein 3 Expression in Human Liver. J. Pharmacol. Exp. Ther.
304: 524-530
[Abstract][Full Text]
Hartmann, G., Cheung, A. K. Y., Piquette-Miller, M.
(2002). Inflammatory Cytokines, but Not Bile Acids, Regulate Expression of Murine Hepatic Anion Transporters in Endotoxemia. J. Pharmacol. Exp. Ther.
303: 273-281
[Abstract][Full Text]
Chiang, J. Y. L.
(2002). Bile Acid Regulation of Gene Expression: Roles of Nuclear Hormone Receptors. Endocr. Rev.
23: 443-463
[Abstract][Full Text]
Beno, D. W. A., Uhing, M. R., Goto, M., Chen, Y., Jiyamapa-Serna, V. A., Kimura, R. E.
(2001). Endotoxin-induced reduction in biliary indocyanine green excretion rate in a chronically catheterized rat model. Am. J. Physiol. Gastrointest. Liver Physiol.
280: G858-G865
[Abstract][Full Text]
McGill, J. M., Yen, M. S., Cummings, O. W., Alpini, G., LeSage, G., Pollok, K. E., Miller, B., Engle, S. K., Stansfield, A. P.
(2001). Interleukin-5 inhibition of biliary cell chloride currents and bile flow. Am. J. Physiol. Gastrointest. Liver Physiol.
280: G738-G745
[Abstract][Full Text]
Staudinger, 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., Willson, T. M., Koller, B. H., Kliewer, S. A.
(2001). The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc. Natl. Acad. Sci. USA
98: 3369-3374
[Abstract][Full Text]
Funk, C., Ponelle, C., Scheuermann, G., Pantze, M.
(2001). Cholestatic Potential of Troglitazone as a Possible Factor Contributing to Troglitazone-Induced Hepatotoxicity: In Vivo and in Vitro Interaction at the Canalicular Bile Salt Export Pump (Bsep) in the Rat. Mol. Pharmacol.
59: 627-635
[Abstract][Full Text]
Miyoshi, H., Rust, C., Guicciardi, M. E., Gores, G. J.
(2001). NF-{{kappa}}B Is Activated in Cholestasis and Functions to Reduce Liver Injury. Am. J. Pathol.
158: 967-975
[Abstract][Full Text]
Tilg, H., Diehl, A. M.
(2000). Cytokines in Alcoholic and Nonalcoholic Steatohepatitis. NEJM
343: 1467-1476
[Full Text]
Rausa, F. M., Tan, Y., Zhou, H., Yoo, K. W., Stolz, D. B., Watkins, S. C., Franks, R. R., Unterman, T. G., Costa, R. H.
(2000). Elevated Levels of Hepatocyte Nuclear Factor 3beta in Mouse Hepatocytes Influence Expression of Genes Involved in Bile Acid and Glucose Homeostasis. Mol. Cell. Biol.
20: 8264-8282
[Abstract][Full Text]
Watkins, J. B. III, Gardner, P. A., Feczko, J. D., Klueber, K. M.
(2000). Streptozotocin and Insulin-Dependent Diabetes Induce Changes in Hepatic Cytoarchitecture in Mice. International Journal of Toxicology
19: 401-405
[Abstract]
Sodeman, T., Bronk, S. F., Roberts, P. J., Miyoshi, H., Gores, G. J.
(2000). Bile salts mediate hepatocyte apoptosis by increasing cell surface trafficking of Fas. Am. J. Physiol. Gastrointest. Liver Physiol.
278: G992-G999
[Abstract][Full Text]
Zsembery, A., Thalhammer, T., Graf, J.
(2000). Bile Formation: a Concerted Action of Membrane Transporters in Hepatocytes and Cholangiocytes. Physiology
15: 6-11
[Abstract][Full Text]
Kim, R. B., Leake, B., Cvetkovic, M., Roden, M. M., Nadeau, J., Walubo, A., Wilkinson, G. R.
(1999). Modulation by Drugs of Human Hepatic Sodium-Dependent Bile Acid Transporter (Sodium Taurocholate Cotransporting Polypeptide) Activity. J. Pharmacol. Exp. Ther.
291: 1204-1209
[Abstract][Full Text]
Soroka, C. J., Pate, M. K., Boyer, J. L.
(1999). Canalicular Export Pumps Traffic with Polymeric Immunoglobulin A Receptor on the Same Microtubule-associated Vesicle in Rat Liver. J. Biol. Chem.
274: 26416-26424
[Abstract][Full Text]
Wang, R., Salem, M., Yousef, I. M., Tuchweber, B., Lam, P., Childs, S. J., Helgason, C. D., Ackerley, C., Phillips, M. J., Ling, V.
(2001). Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis. Proc. Natl. Acad. Sci. USA
98: 2011-2016
[Abstract][Full Text]
Lazaridis, K. N., Tietz, P., Wu, T., Kip, S., Dawson, P. A., LaRusso, N. F.
(2000). Alternative splicing of the rat sodium/bile acid transporter changes its cellular localization and transport properties. Proc. Natl. Acad. Sci. USA
97: 11092-11097
[Abstract][Full Text]
Zinchuk, V. S., Okada, T., Akimaru, K., Seguchi, H.
(2002). Asynchronous expression and colocalization of Bsep and Mrp2 during development of rat liver. Am. J. Physiol. Gastrointest. Liver Physiol.
282: G540-G548
[Abstract][Full Text]