Mol Cell Biol. 2013 Mar 25. 

Caron S, Samanez CH, Dehondt H, Ploton M, Briand O, Lien F, Dorchies E, Dumont J, Postic C, Cariou B, Lefebvre P, Staels B.

Abstract

The glucose-activated transcription factor Carbohydrate Response Element Binding Protein (ChREBP) induces the expression of hepatic glycolytic and lipogenic genes. The Farnesoid X Receptor (FXR) is a nuclear bile acid-receptor controlling bile acid, lipid and glucose homeostasis. FXR negatively regulates hepatic glycolysis and lipogenesis in mouse liver. The aim of this study is to determine whether FXR regulates the transcriptional activity of ChREBP in human hepatocytes and to unravel the underlying molecular mechanisms. Agonist-activated FXR inhibits glucose-induced transcription of several glycolytic genes, including Liver-type Pyruvate Kinase (L-PK), in the human hepatocyte IHH and HepaRG cell lines. This inhibition requires the L4L3 region of the L-PK promoter known to bind the transcription factors ChREBP and Hepatocyte Nuclear Factor-4 (HNF4). FXR interacts directly with ChREBP and HNF4 proteins. Analysis of the protein complex bound to the L4L3 region reveals the presence of ChREBP, HNF4, FXR and the transcriptional co-activators p300 and CBP at high glucose concentrations. FXR activation does not affect FXR neither HNF4 binding to the L4L3 region, but results in the concomitant release of ChREBP, p300 and CBP and in the recruitment of the transcriptional co-repressor SMRT. Thus, FXR transrepresses the expression of genes involved in glycolysis in human hepatocytes.