The Human Na+-Taurocholate Cotransporting Polypeptide Gene Is Activated by Glucocorticoid Receptor and Peroxisome Proliferator-Activated Receptor-γ Coactivator-1α, and Suppressed by Bile Acids via a Small Heterodimer Partner-Dependent Mechanism

Na+-taurocholate cotransporting polypeptide (NTCP) is the major bile acid uptake system in human hepatocytes. NTCP and the ileal transporter ASBT (apical sodium-dependent bile acid transporter) are two sodium-dependent transporters critical for the enterohepatic circulation of bile acids. The hASBT gene is known to be activated by the glucocorticoid receptor (GR). Here we show that GR also induces the endogenous hNTCP gene and transactivates the reporter-linked hNTCP promoter, in the presence of its ligand dexamethasone. Mutational analysis of the hNTCP promoter identified a functional GR response element, with which GR directly interacts within living cells. The GR/dexamethasone activation of endogenous hNTCP expression was suppressed by bile acids, in a manner dependent on the bile acid receptor farnesoid X receptor. Overexpression of the farnesoid X receptor-inducible transcriptional repressor small heterodimer partner also suppressed the GR/dexamethasone-activation of the hNTCP promoter. The peroxisom...