Biomedical subjects
Tim Hoffman
Publications and source records attributed to Tim Hoffman.
Estradiol represses prolactin-induced expression of Na+/taurocholate cotransporting polypeptide in liver cells through estrogen receptor-alpha and signal transducers and activators of transcription 5a.
Na(+)/taurocholate 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 signal transducers and activators of transcription (Stat)5a pathway. However, elevated levels of placental lactogen do not increase the expression of ntcp in pregnant rats. Because plasma estradiol (E(2)) levels are also elevated in pregnancy, we investigated the inhibitory effects of E(2) on PRL-induced ntcp activation. E(2) treatment inhibited the PRL-induced increase in liver ntcp mRNA to the same levels as in rats treated with E(2) alone. Estrogen receptor-alpha (ERalpha) mRNA and protein expression in liver were increased 2.6-fold and 2.2-fold, respectively, in pregnancy relative to controls. In HepG2 cells, E(2) repressed PRL-induced ntcp reporter gene expression in a dose-dependent manner in the presence of cotransfected ERalpha. The ERalpha antagonist ICI 182,780 reversed E(2)-induced repression, indicating specificity of inhibition by E(2). Overexpression of coactivator p300 did not reverse the inhibitory effects of E(2) and ERalpha. Western and gel shift analysis revealed that E(2)-bound ERalpha decreased the tyrosine phosphorylation and DNA-binding activity of Stat5a, indicating that the inhibitory effect of E(2) was mediated, at least in part, by interfering with PRL-mediated signal transduction. The present studies demonstrate the physiological significance of cross-talk between ERalpha and Stat5a in liver, in which 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.
Increased expression of ileal apical sodium-dependent bile acid transporter in postpartum rats.
The expression and activity of the apical ileal sodium-dependent bile acid transporter (asbt) was examined in the small intestine of control, pregnant, and lactating postpartum rats 2, 12, and 21 days after delivery. Western blot analysis of brush border membrane vesicles (BBMV) prepared from different regions of the small intestine demonstrated that expression of asbt was maximal in the most distal segments for all experimental groups, was not substantially affected in pregnant and 2-day postpartum rats, and was significantly increased in 12- and 21-day postpartum rats. Analysis of mRNA suggested that asbt protein was regulated at the posttranscriptional level in postpartum rats. Increased expression of asbt protein postpartum was maximal (approximately 2-fold) in the proximal region of the ileum, consistent with a 60% increase in taurocholate (TC) transport in BBMV from the proximal ileum in 14- to 21-day postpartum rats relative to control rats. Absorption of TC, determined from the intact proximal ileum using an intestinal loop model, demonstrated a 30% increase in TC uptake per unit weight of tissue in 14- to 21-day postpartum rats relative to control rats. Together with the marked increase in intestinal mass observed at peak lactation, these data indicate a significant increase in asbt-mediated reclamation of bile acids in the intestine of lactating rats.