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LIVER AND BILIARY TRACT

Fasting induces basolateral uptake transporters of the SLC family in the liver via HNF4 and PGC1

Department of Internal Medicine III (Division of Gastroenterology and Hepatology), Aachen University Hospital (UKA), Aachen, Germany

Submitted 19 April 2007 ; accepted in final form 16 July 2007

Fasting induces numerous adaptive changes in metabolism by several central signaling pathways, the most important represented by the HNF4/PGC-1-pathway. Because HNF4 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 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 in electrophoretic mobility shift assays remained unchanged, HNF4 binding activity to the Ntcp promoter was increased significantly. In line with this result, we found significantly increased mRNA expression of HNF4 and PGC-1. Functional studies in HepG2 cells revealed an increased endogenous NTCP mRNA expression upon cotransfection with either HNF4, PGC-1, 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/PGC-1 pathway.

bile salt transport; HNF4; PGC-1; Ntcp; Oatp

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