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Submitted on June 13, 2003
Accepted on December 9, 2003
and Stat5a
1 Graduate Center for Toxicology, Department of Physiology, Department of Anatomy and Neurobiology, Chandler Medical Center, University of Kentucky, Lexington, KY 40536-0305, USA
* To whom correspondence should be addressed. E-mail: maryv{at}uky.edu.
Na+/taurocholate (TC) cotransporting polypeptide (ntcp) mediates the uptake of bile salts from plasma across the basolateral domain of the hepatocyte. We have demonstrated that ntcp expression can be induced by prolactin (PRL) and placental lactogen via the PRL-receptor and Stat5a pathway. However, elevated levels of placental lactogen do not increase the expression of ntcp in pregnant rats. Since plasma estradiol (E2) levels are also elevated in pregnancy, we investigated the inhibitory effects of E2 on PRL-induced ntcp activation. E2 treatment inhibited the PRL-induced increase in liver ntcp mRNA to the same levels as in rats treated with E2 alone. ER
mRNA and protein expression in liver were increased 2.6-fold and 2.2-fold, respectively, in pregnancy relative to controls. In HepG2 cells, E2 repressed PRL-induced ntcp reporter gene expression in a dose-dependent manner in the presence of cotransfected estrogen receptor- (ER). The ER antagonist ICI 182,780 reversed E2-induced repression, indicating specificity of inhibition by E2. Overexpression of co-activator p300 did not reverse the inhibitory effects of E2 and ER. Western and gel shift analysis revealed that E2-bound ER decreased the tyrosine phosphorylation and DNA-binding activity of Stat5a, indicating that the inhibitory effect of E2 was mediated, at least in part, by interfering with PRL-mediated signal transduction. The present studies demonstrate the physiological significance of cross talk between ER and Stat5a in liver, where both proteins are expressed. These data also establish a novel mechanism by which expression of ntcp, an important hepatic bile acid transporter, can be regulated by multiple hormones.
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