Farnesoid X receptor inhibits the transcriptional activity of carbohydrate response element binding protein in human hepatocytes.: Transrepression of ChREBP by FXR

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.
Type de document :
Article dans une revue
Molecular and Cellular Biology, American Society for Microbiology, 2013, 33 (11), pp.2202-11. 〈10.1128/MCB.01004-12〉
Liste complète des métadonnées

http://www.hal.inserm.fr/inserm-00806064
Contributeur : Marie-Hélène Derudas <>
Soumis le : vendredi 29 mars 2013 - 15:48:48
Dernière modification le : jeudi 26 avril 2018 - 01:05:27
Document(s) archivé(s) le : dimanche 30 juin 2013 - 04:01:38

Fichiers

CaronS_HuamanSamanezC_FIGURES....
Fichiers produits par l'(les) auteur(s)

Identifiants

Citation

Sandrine Caron, Carolina Huaman Samanez, Hélène Dehondt, Maheul Ploton, Olivier Briand, et al.. Farnesoid X receptor inhibits the transcriptional activity of carbohydrate response element binding protein in human hepatocytes.: Transrepression of ChREBP by FXR. Molecular and Cellular Biology, American Society for Microbiology, 2013, 33 (11), pp.2202-11. 〈10.1128/MCB.01004-12〉. 〈inserm-00806064〉

Partager

Métriques

Consultations de la notice

278

Téléchargements de fichiers

507