title: 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.
authors.affiliation: Université Lille Nord de France, Lille, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Caron
authors.forename: Carolina
authors.initials: C
authors.lastname: Huaman Samanez
authors.forename: Hélène
authors.initials: H
authors.lastname: Dehondt
authors.forename: Maheul
authors.initials: M
authors.lastname: Ploton
authors.forename: Olivier
authors.initials: O
authors.lastname: Briand
authors.forename: Fleur
authors.initials: F
authors.lastname: Lien
authors.forename: Emilie
authors.initials: E
authors.lastname: Dorchies
authors.forename: Julie
authors.initials: J
authors.lastname: Dumont
authors.forename: Catherine
authors.initials: C
authors.lastname: Postic
authors.forename: Bertrand
authors.initials: B
authors.lastname: Cariou
authors.forename: Philippe
authors.initials: P
authors.lastname: Lefebvre
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics* / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D006019:Glycolysis / Q000235:genetics; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D051379:Mice; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D021381:Protein Transport; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D012795:Sialoglycoproteins / Q000235:genetics / Q000378:metabolism; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D005947:Glucose; D051557:Hepatocyte Nuclear Factor 4; D006657:Histones; D008239:Lysine; D056985:Nuclear Receptor Co-Repressor 2; D010446:Peptide Fragments; D011770:Pyruvate Kinase; D018160:Receptors, Cytoplasmic and Nuclear; D012795:Sialoglycoproteins; D050880:p300-CBP Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C496592:HNF4A protein, human; C116385:MLXIPL protein, human; C539130:NCOR2 protein, human; C571744:bone sialoprotein (35-62), human