Hepatocellular transport proteins and their role in liver disease

Abstract

TRANSPORT PROTEINS Basolateral transport systems Na-dependent bile salt uptake Uptake of bile salts into the liver was first characterized in experimental models such as the isolated perfused rat liver, isolated hepatocyte cultures and basolateral plasma membrane vesicles. These studies indicated that more than 80% of taurocholate uptake but less than 50% of cholate uptake into hepatocytes is sodiumdependent. Whereas unconjugated bile salts are uncharged molecules that can traverse membranes by passive nonionic diffusion, conjugation with glycine or taurine decreases their pKa values and necessitates the presence of a specific carrier protein for hepatocellular uptake. The chief uptake system for conjugated bile salts in mammalian liver was isolated by expression and molecular cloning strategies and has been called the Na + taurocholate cotransporting polypeptide (gene symbol: SLC10A1). Rat Ntcp consists of 362 amino acids with an apparent molecular mass of 51 kD and is expressed exclusively at the basolateral membrane of hepatocytes (Figure 1). Ntcp mediates sodium-dependent uptake of taurocholate and other bile salts when expressed in stably transfected COS-7, Chinese hamster ovary (CHO) and hepatoblastoma (HepG2) cells or in cRNA injected Xenopus laevis oocytes, with apparent Km values between 17-42 μmol/L. The only non-bile salt substrates that are transported by Ntcp are selected sulfated steroid conjugates such as estrone-3sulfate and dehydroepiandrosterone sulfate (DHEAS) . In human liver, NTCP represents a 349-amino acid protein. NTCP is structurally related to the intestinal bile salt transporter (IBAT), that also mediates the Nadependent uptake of bile saltsand that is expressed not only in ileum, but also in the kidney and in cholangiocytes. Na-dependent taurocholate uptake is reduced in experimental models of cholestasis such as bile duct l igat ion , endotoxinemia and par t ia l hepatectomy, is reduced in primary hepatocyte cultures and is absent in various hepatoma cell lines . These changes in hepatic Na dependent bile salt uptake correlate with expression levels of Ntcp. Thus, Ntcp mRNA and protein levels are decreased in bile duct ligation, endotoxinemia and ethinyl estradiol induced cholestasis. In patients with a diagnosis of extrahepatic biliary atresia and clinical evidence of cholestasis, NTCP mRNA levels are also decreased.