Fasting induces basolateral uptake transporters of the SLC family in the liver via HNF4α and PGC1α

Fasting induces numerous adaptive changes in metabolism by several central signaling pathways, the most important represented by the HNF4 alpha/ PGC-1 alpha-pathway. Because HNF4 alpha has been identified as central regulator of basolateral bile acid transporters and a previous study reports increased basolateral bile acid uptake into the liver during fasting, we hypothesized that HNF4 alpha is involved in fasting-induced bile acid uptake via upregulation of basolateral bile acid transporters. In rats, mRNA of Ntcp, Oatp1, and Oatp2 were significantly increased after 48 h of fasting. Protein expression as determined by Western blot showed significant increases for all three transporters 72 h after the onset of fasting. Whereas binding activity of HNF1 alpha in electrophoretic mobility shift assays remained unchanged, HNF4 alpha binding activity to the Ntcp promoter was increased significantly. In line with this result, we found significantly increased mRNA expression of HNF4 alpha and PGC-1 alpha. Functional studies in HepG2 cells revealed an increased endogenous NTCP mRNA expression upon cotransfection with either HNF4 alpha, PGC-1 alpha, or a combination of both. We conclude that upregulation of the basolateral bile acid transporters Ntcp, Oatp1, and Oatp2 in fasted rats is mediated via the HNF4 alpha/ PGC-1 alpha pathway.