Molecular aspects of hepatobiliary transport

M Muller*, PLM Jansen

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

308 Citations (Scopus)

Abstract

Generation of bile flow is a regulated, ATP-dependent process and depends on the coordinated action of a number of transporter proteins in the sinusoidal and canalicular domains of the hepatocyte. Dysfunction of any of these proteins leads to retention of substrates, with conjugated hyperbilirubinemia or cholestasis as a result. In recent years many of the transport proteins involved in bile formation have been identified, cloned, and functionally characterized. The hepatocyte sinusoidal membrane contains transport proteins for the hepatic uptake of organic anions and cations and for the uptake of bile acids. The multispecific organic anion transporting polypeptide (OATP) mediates the hepatic uptake of organic anions and a variety of organic amphiphilic compounds, including organic cations. The organic cation transporter OCT1 more specifically transports small organic cations. NTCP is the Na+-bile acid cotransporting protein that mediates the hepatic uptake of bile acids. The canalicular transport proteins are able to transport endogenous and exogenous metabolites into the bile against steep concentration gradients. Most of these transporters are members of the large ATP-binding cassette (ABC) superfamily, and their transport function directly depends on the hydrolysis of Mg2+/ATP. At least five ABC transporter proteins have been characterized so far: I) the human multidrug resistance protein MDR1 mediates the excretion of hydrophobic, mostly cationic, metabolites; 2) MDR3 is involved in phosphatidylcholine secretion; 3) the canalicular bile acid transporter cBAT mediates secretion of monovalent bile salts and provides the molecular basis of bile acid-dependent bile flow; 4) SPGP, product of the P-glycoprotein sister gene, is exclusively expressed in the liver but its function is currently unknown; and 5) the human multidrug resistance protein MRP2 mediates the excretion of multivalent anionic conjugates.

Original languageEnglish
Pages (from-to)G1285-G1303
Number of pages19
JournalAmerican Journal of Physiology-Gastrointestinal and Liver Physiology
Volume272
Issue number6
Publication statusPublished - Jun-1997

Keywords

  • ATP-dependent transport
  • volume regulation
  • multidrug resistance
  • ATP-binding cassette transporter
  • bile formation
  • RESISTANCE-ASSOCIATED PROTEIN
  • PERFUSED-RAT-LIVER
  • BILE-ACID TRANSPORT
  • HEPATOCYTE CANALICULAR MEMBRANE
  • ATP-DEPENDENT TRANSPORT
  • P-GLYCOPROTEIN GENE
  • ORGANIC ANION TRANSPORTER
  • DUCT EPITHELIAL-CELLS
  • XENOPUS-LAEVIS OOCYTES
  • MULTIDRUG-RESISTANCE

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