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PRL, Placental Lactogen, and GH Induce Na⁺/Taurocholate-Cotransporting Polypeptide Gene Expression by Activating Signal Transducer and Activator of Transcription-5 in Liver Cells

Graduate Center for Toxicology (J.C., P.M.G., T.C.G., M.W., M.V.) and Department of Anatomy and Neurobiology (J.F.H.), College of Medicine, Chandler Medical Center, University of Kentucky, Lexington, Kentucky 40536-0305; and Department of Biology (F.T.), University of California, Santa Cruz, California 95064

Address all correspondence and requests for reprints to: Mary Vore, Graduate Center for Toxicology, 306 Health Science Research Building, University of Kentucky, Lexington, Kentucky 40536-0305. E-mail: maryv{at}pop.uky.edu

We investigated the transcriptional regulation of the Na⁺/taurocholate cotransporting 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 activated -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 hepatocytes from control and pregnant (mouse placental lactogen I) rats. Genistein, a phosphotyrosine kinase inhibitor, inhibited PRL-induced signal transducer and activator of transcription-5 activation and Na⁺/taurocholate-cotransporting polypeptide mRNA. In HepG2 cells transiently cotransfected with 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 polypeptide promoter, mouse placental lactogen I, 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-cotransporting polypeptide promoter. These data establish that PRL and placental lactogen I induce Na⁺/taurocholate-cotransporting polypeptide gene expression via signal transducer and activator of transcription-5 proteins in liver, and indicate that these hormones play an important role in regulating liver metabolic function.

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