BSEP: Function and Role in Progressive Familial Intrahepatic Cholestasis

 

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ABSTRACT

Secretion of bile acids is the major driving force for bile flow in mammals. The recently described adenosine triphosphate (ATP)-dependent bile acid transporter, bile salt export pump (BSEP), formerly called sister of p-glycoprotein, is responsible for active transport of bile acids across the hepatocyte canalicular membrane into bile. It is now recognized that mutations in the gene encoding this protein (ABCB11) are responsible for a subgroup of infants and children with progressive familial cholestasis (PFIC-2), a cholestatic disorder causing extreme pruritus, growth failure, and progression to cirrhosis in the first decade of life. Understanding the structure and function of BSEP has improved our understanding of the mechanisms underlying bile secretion. Determining genotype/phenotype relationships in patients with mutations in this gene are currently ongoing.

REFERENCES

• 1 Nishida T, Gatmaitan Z, Che M. Rat liver canalicular membrane vesicles contain an ATP-dependent bile acid transport system.  Proc Natl Acad Sci U S A . 1991;  88 6590-6594
  CrossrefPubMedGoogle Scholar
• 2 Gerloff T, Stieger B, Hagenbuch B. The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver.  J Biol Chem . 1998;  273 10046-10050
  CrossrefPubMedGoogle Scholar
• 3 Strautnieks S S, Bull L N, Knisely A S. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis.  Nat Genet . 1998;  20 233-238
  CrossrefPubMedGoogle Scholar
• 4 Clayton R J, Iber F L, Ruebner B H, McKusick V A. Byler disease. Fatal familial intrahepatic cholestasis in an Amish kindred.  Am J Dis Child . 1969;  117 112-124
  PubMedGoogle Scholar
• 5 Whitington P F, Freese D K, Alonso E M. Clinical and biochemical findings in progressive familial intrahepatic cholestasis.  J Pediatr Gastroenterol Nutr . 1994;  18 134-141
  PubMedGoogle Scholar
• 6 Alonso E M, Snover D C, Montag A. Histologic pathology of the liver in progressive familial intrahepatic cholestasis.  J Pediatr Gastroenterol Nutr . 1994;  18 128-133
  CrossrefPubMedGoogle Scholar
• 7 Bull L N, van Eijk J M, Pawlikowska L. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis.  Nat Genet . 1998;  18 219-224
  CrossrefPubMedGoogle Scholar
• 8 Chobert M N, Bernard O, Bulle F. High hepatic gamma-glutamyltransferase (gamma-GT) activity with normal serum gamma-GT in children with progressive idiopathic cholestasis.  J Hepatol . 1989;  8 22-25
  CrossrefPubMedGoogle Scholar
• 9 Maggiore G, Bernard O, Hadchouel M. Diagnostic value of serum gamma-glutamyl transpeptidase activity in liver diseases in children.  J Pediatr Gastroenterol Nutr . 1991;  12 21-26
  PubMedGoogle Scholar
• 10 Paulusma C C, Kool M, Bosma P J. A mutation in the human canalicular multispecific organic anion transporter gene causes the Dubin-Johnson syndrome.  Hepatology . 1997;  25 1539-1542
  CrossrefPubMedGoogle Scholar
• 11 Stieger B, O'Neill B, Meier P J. ATP-dependent bile-salt transport in canalicular rat liver plasma- membrane vesicles.  Biochem J . 1992;  284 67-74
  PubMedGoogle Scholar
• 12 de Vree M J, Jacquemin E, Sturm E. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis.  Proc Natl Acad Sci U S A . 1998;  95 282-287
  CrossrefPubMedGoogle Scholar
• 13 Bull L N, Carlton V E, Stricker N L. Genetic and morphological findings in progressive familial intrahepatic cholestasis (Byler disease [PFIC-1] and Byler syndrome): evidence for heterogeneity.  Hepatology . 1997;  26 155-164
  CrossrefPubMedGoogle Scholar
• 14 Jansen P L, Strautnieks S S, Jacquemin E. Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis.  Gastroenterology . 1999;  117 1370-1379
  CrossrefPubMedGoogle Scholar
• 15 Whitington P F, Emerick K M, Suchy F J. Familial hepatocellular cholestasis. In: Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Disease in Children Philadelphia: Lippincott, Williams & Wilkins 2001: 315-325
  Google Scholar
• 16 Carlton V E, Knisely A S, Freimer N B. Mapping of a locus for progressive familial intrahepatic cholestasis (Byler disease) to 18q21-q22, the benign recurrent intrahepatic cholestasis region.  Hum Mol Genet . 1995;  4 1049-1053
  CrossrefPubMedGoogle Scholar
• 17 Houwen R H, Baharloo S, Blankenship K. Genome screening by searching for shared segments: mapping a gene for benign recurrent intrahepatic cholestasis.  Nat Genet . 1994;  8 380-386
  PubMedGoogle Scholar
• 18 Strautnieks S S, Kagalwalla A F, Tanner M S. Locus heterogeneity in progressive familial intrahepatic cholestasis.  J Med Genet . 1996;  33 833-836
  PubMedGoogle Scholar
• 19 Arnell H, Nemeth A, Anneren G. Progressive familial intrahepatic cholestasis (PFIC): evidence for genetic heterogeneity by exclusion of linkage to chromosome 18q21-q22.  Hum Genet . 1997;  100 378-381
  PubMedGoogle Scholar
• 20 Strautnieks S S, Kagalwalla A F, Tanner M S. Identification of a locus for progressive familial intrahepatic cholestasis PFIC2 on chromosome 2q24.  Am J Hum Genet . 1997;  61 630-633
  CrossrefPubMedGoogle Scholar
• 21 Becker A, Lucka L, Kilian C. Characterisation of the ATP-dependent taurocholate-carrier protein (gp110) of the hepatocyte canalicular membrane.  Eur J Biochem . 1993;  214 539-548
  CrossrefPubMedGoogle Scholar
• 22 Sippel C J, Suchy F J, Ananthanarayanan M. The rat liver ecto-ATPase is also a canalicular bile acid transport protein.  J Biol Chem . 1993;  268 2083-2091
  PubMedGoogle Scholar
• 23 Muller M, Ishikawa T, Berger U. ATP-dependent transport of taurocholate across the hepatocyte canalicular membrane mediated by a 110-kDa glycoprotein binding ATP and bile salt.  J Biol Chem . 1991;  266 18920-18926
  PubMedGoogle Scholar
• 24 Thompson N L, Hixson D C, Callanan H. A Fischer rat substrain deficient in dipeptidyl peptidase IV activity makes normal steady-state RNA levels and an altered protein. Use as a liver-cell transplantation model.  Biochem J . 1991;  273 497-502
  PubMedGoogle Scholar
• 25 Marguet D, Baggio L, Kobayashi T. Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26.  Proc Natl Acad Sci U S A . 2000;  97 6874-6879
  CrossrefPubMedGoogle Scholar
• 26 Childs S, Yeh R L, Georges E. Identification of a sister gene to P-glycoprotein.  Cancer Res . 1995;  55 2029-2034
  PubMedGoogle Scholar
• 27 Childs S, Yeh R L, Hui D. Taxol resistance mediated by transfection of the liver-specific sister gene of P-glycoprotein.  Cancer Res . 1998;  58 4160-4167
  PubMedGoogle Scholar
• 28 Cai S Y, Wang L, Ballatori N. Bile salt export pump is highly conserved during vertebrate evolution and its expression is inhibited by PFIC type II mutations.  Am J Physiol Gastrointest Liver Physiol . 2001;  281 G316-G322
  PubMedGoogle Scholar
• 29 Green R M, Hoda F, Ward K L. Molecular cloning and characterization of the murine bile salt export pump.  Gene . 2000;  241 117-123
  CrossrefPubMedGoogle Scholar
• 30 Noe J, Hagenbuch B, Meier P J. Characterization of the mouse bile salt export pump overexpressed in the baculovirus system.  Hepatology . 2001;  33 1223-1231
  CrossrefPubMedGoogle Scholar
• 31 Wang R, Salem M, Yousef I M. Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis.  Proc Natl Acad Sci U S A . 2001;  98 2011-2016
  CrossrefPubMedGoogle Scholar
• 32 Knisely A S. Progressive familial intrahepatic cholestasis: a personal perspective.  Pediatr Dev Pathol . 2000;  3 113-125
  PubMedGoogle Scholar