Farnesoid X receptor inhibits the transcriptional activity of carbohydrate response element binding protein in human hepatocytes.

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 was 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 the liver-type pyruvate kinase gene (L-PK), in the immortalized 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 4α (HNF4α). FXR interacts directly with ChREBP and HNF4α proteins. Analysis of the protein complex bound to the L4L3 region reveals the presence of ChREBP, HNF4α, FXR, and the transcriptional coactivators p300 and CBP at high glucose concentrations. FXR activation does not affect either FXR or HNF4α binding to the L4L3 region but does result in the concomitant release of ChREBP, p300, and CBP and in the recruitment of the transcriptional corepressor SMRT. Thus, FXR transrepresses the expression of genes involved in glycolysis in human hepatocytes.

journal_name

Mol Cell Biol

authors

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

doi

10.1128/MCB.01004-12

subject

Has Abstract

pub_date

2013-06-01 00:00:00

pages

2202-11

issue

11

eissn

0270-7306

issn

1098-5549

pii

MCB.01004-12

journal_volume

33

pub_type

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