Hepatic Transport of Bile Salts

ABSTRACT

The vectorial secretion of bile salts from blood into bile is a major driving force for bile formation. The basolateral hepatocyte membrane extracts bile salts from sinusoidal blood via Na⁺-dependent and Na⁺-independent membrane transporters. Na⁺-dependent uptake of bile salts is mediated by the Na⁺-taurocholate cotransporting polypeptide, a 51-kDa protein that is exclusively expressed in hepatocytes. Na⁺-independent uptake of bile salts is mediated by the organic anion transporting polypeptides, a superfamily of multispecific bile salt and amphipathic substrate transporters. Within the hepatocyte, bile salts are bound to cytosolic proteins and traverse the cell mainly by diffusion. Transport across the canalicular membrane is the rate-limiting step in overall hepatocellular bile salt excretion and is mediated by the bile salt export pump (BSEP), a homologue of the P-glycoproteins or multidrug resistance gene products. BSEP is a vulnerable target for inhibition by estrogen metabolites, drugs such as cyclosporine A, and abnormal bile salt metabolites, all of which can cause retention of bile salts and consequently intrahepatic cholestasis. Canalicular efflux of divalent sulfated or glucuronidated bile salts is mediated by the multidrug resistance protein 2 (MRP2), which is strongly decreased in cholestasis. Decreased MRP2 expression leads to compensatory increases in the basolateral expression of MRP1 and MRP3, which mediate the sinusoidal efflux of divalent bile salt conjugates and other organic anions. Thus, the hepatocyte can regulate expression levels of individual bile salt transporters during cholestasis to evade hepatotoxic injury.

KEYWORD

organic anions - bile acid transport - cholestasis

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