Submitted on April 19, 2007
Accepted on July 16, 2007
Fasting induces basolateral uptake transporters of the SLC family in the liver via HNF4
and PGC1
Christoph G. Dietrich1, Ina V. Martin1, Anne C. Porn1, Sebastian Voigt1, Carsten Gartung1, Christian Trautwein1, and Andreas Geier1*
1 Internal Medicine III, Aachen University Hospital (UKA), Aachen, NRW, Germany
* To whom correspondence should be addressed. E-mail: ageier{at}ukaachen.de.
Fasting induces numerous adaptive changes in metabolism using several central signalling pathways, the most important represented by the HNF4
/PGC-1-pathway. As 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 2 were significantly increased after 48 hours of fasting. Protein expression as determined by Western Blot showed significant increases for all three transporters 72 hours after the onset of fasting. While 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, Oatp 1 and 2 in fasted rats is mediated via the HNF4/PGC-1 pathway.
