Hormonal regulation of hepatic organic anion transporters

A critical function of the liver is the formation and maintenance of bile flow. Bile salts, a major constituent of bile, are transported across hepatocyte membranes by plasma membrane-bound transporters. In parallel, hepatocyte transporters also facilitate the movement of many endogenous and xenobiotic organic anions into and out of hepatocytes for the purposes of metabolism and elimination in bile. Changes in transporter expression levels due to disease or physiological state often result in altered bile flow and/or organic anion metabolism. The focus of this study, therefore, was the examination of the hormonal control of two groups of basolateral hepatocyte transporters, namely, the sodium taurocholate cotransporting polypeptide (Ntcp) and the organic anion transporting polypeptides (Oatp/OATP), via the Jak2/Stat5 signal transduction pathway.;Using cultures of primary hepatocytes isolated from young rats at 1, 2, 3, and 4 weeks of age, we showed that both prolactin and growth hormone activate Stat5 in females and males at all ages. PRL and GH induction of Ntcp mRNA expression, however, was not consistent until at least 3 weeks of age. These findings indicate that factors other than Stat5 appear to be required for induction of Ntcp in young rat liver. In studies of hormonal control of Oatps/OATPs, we showed that both PRL and GH induce Oatp1b2 mRNA expression in cultures of primary hepatocytes isolated from female and male rats. Additional transient cotransfection studies in HepG2 cells were used to determine the mechanism of PRL and GH Oatp/OATP induction. Results showed that (1) PRL and GH increase Oatp1b2 and OATP1B3 promoter activity, (2) both receptor (PRLR or GHR) and Stat5 are required for promoter induction, (3) mutation of promoter Stat5 binding sites abrogates PRL and GH induction of promoter activity, and (4) PRL increases binding of Stat5 to the OATP1B3 promoter. These Oatps/OATPs are the first known organic anion transporting polypeptides identified as targets of Stat5-mediated induction.