MOLECULAR REGULATION OF SINUSOIDAL LIVER BILE-ACID TRANSPORTERS DURING CHOLESTASIS

Impairment of the hepatic transport of bile acids and other organic an ions will result in the clinically important syndrome of cholestasis. Cloning of a number of specific hepatic organic anion transporters has enabled studies of their molecular regulation during cholestasis. The best characterized transport system is a 50-51 kDa sodium-dependent t aurocholate cotransporting polypeptide (ntcp), which mediates the sodi um-dependent uptake of conjugated bile acids at the sinusoidal plasma membrane of hepatocytes. Under physiologic conditions and after deplet ion of biliary constituents, ntcp remains constitutively expressed thr oughout the liver acinus. However, both function and expression of ntc p are rapidly down-regulated in rat liver in various models of experim ental cholestasis, such as cholestasis induced by common bile duct lig ation, estrogen, endotoxin or cytokine treatment. In addition to ntcp, the sinusoidal organic anion transporting polypeptide oatp-1 is also down-regulated at the protein and steady-state mRNA levels in estrogen -cholestasis, but does not affect sodium-independent uptake of tauroch olate. The regulation of a recently cloned member of the organic anion transporter family (oatp-2), which is highly expressed in liver, rema ins to be studied under cholestatic conditions.