PRL, placental lactogen, and GH induce Na+/taurocholate-cotransporting polypeptide gene expression by activating signal transducer and activator of transcription-5 in liver cells

We investigated the transcriptional regulation of the Na+/taurocholate cotr ansporting polypeptide gene by PRL, placental lactogen, and GH. In primary hepatocytes, ovine PRL induced a dose-dependent phosphorylation and nuclear translocation of signal transducers and activators of transcription-5a and -5b, but not -1 or -3, whereas mouse placental lactogen I and rat GH activ ated -5a, -5b, and -1. In EMSAs, ovine PRL, mouse placental lactogen I, and rat GH increased the specific DNA binding of nuclear signal transducer and activator of transcription-5 to its consensus element in both transfected HepG2 cells and primary hepatocytes. PRL, placental lactogen I, and GH also increased Na+/taurocholate cotransporting polypeptide mRNA expression in h epatocytes from control and pregnant (mouse placental lactogen I) rats. Gen istein, a phosphotyrosine kinase inhibitor, inhibited PRL-induced signal tr ansducer and activator of transcription-5 activation and Na+/taurocholate-c otransporting polypeptide mRNA. In HepG2 cells transiently cotransfected wi th either the long form of the rat PRL receptor or rat GH receptor, signal transducer and activator of transcription-5a and a -5-responsive luciferase expression vector containing the Na+/taurocholate-cotransporting polypepti de promoter, mouse placental lactogen 1, like ovine PRL, activated -5a via the long form of the rat PRL receptor; whereas rat GH activated -5a via rat GH receptor, leading to transactivation of the Na+/taurocholate-cotranspor ting polypeptide promoter. These data establish that PRL and placental lact ogen I induce Na+/taurocholate-cotransporting polypeptide gene expression v ia signal transducer and activator of transcription-5 proteins in liver, an d indicate that these hormones play an important role in regulating liver m etabolic function.