title: Polyunsaturated fatty acids suppress glycolytic and lipogenic genes through the inhibition of ChREBP nuclear protein translocation.
abstract: Dietary polyunsaturated fatty acids (PUFAs) are potent inhibitors of hepatic glycolysis and lipogenesis. Recently, carbohydrate-responsive element-binding protein (ChREBP) was implicated in the regulation by glucose of glycolytic and lipogenic genes, including those encoding L-pyruvate kinase (L-PK) and fatty acid synthase (FAS). The aim of our study was to assess the role of ChREBP in the control of L-PK and FAS gene expression by PUFAs. We demonstrated in mice, both in vivo and in vitro, that PUFAs [linoleate (C18:2), eicosapentanoic acid (C20:5), and docosahexaenoic acid (C22:6)] suppressed ChREBP activity by increasing ChREBP mRNA decay and by altering ChREBP translocation from the cytosol to the nucleus, independently of an activation of the AMP-activated protein kinase, previously shown to regulate ChREBP activity. In contrast, saturated [stearate (C18)] and monounsaturated fatty acids [oleate (C18:1)] had no effect. Since glucose metabolism via the pentose phosphate pathway is determinant for ChREBP nuclear translocation, the decrease in xylulose 5-phosphate concentrations caused by a PUFA diet favors a PUFA-mediated inhibition of ChREBP translocation. In addition, overexpression of a constitutive nuclear ChREBP isoform in cultured hepatocytes significantly reduced the PUFA inhibition of both L-PK and FAS gene expression. Our results demonstrate that the suppressive effect of PUFAs on these genes is primarily caused by an alteration of ChREBP nuclear translocation. In conclusion, we describe a novel mechanism to explain the inhibitory effect of PUFAs on the genes encoding L-PK and FAS and demonstrate that ChREBP is a pivotal transcription factor responsible for coordinating the PUFA suppression of glycolytic and lipogenic genes.
authors.affiliation: Département d'Endocrinologie, Institut Cochin, INSERM U567 CNRS UMR8104, Université René Descartes, Paris, France.
authors.forename: Renaud
authors.initials: R
authors.lastname: Dentin
authors.forename: Fadila
authors.initials: F
authors.lastname: Benhamed
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Pégorier
authors.forename: Fabienne
authors.initials: F
authors.lastname: Foufelle
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.forename: Sophie
authors.initials: S
authors.lastname: Vaulont
authors.forename: Jean
authors.initials: J
authors.lastname: Girard
authors.forename: Catherine
authors.initials: C
authors.lastname: Postic
mesh_terms: D055372:AMP-Activated Protein Kinases; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism*; D002478:Cells, Cultured; D004042:Dietary Fats, Unsaturated / Q000008:administration & dosage* / Q000494:pharmacology; D004281:Docosahexaenoic Acids / Q000008:administration & dosage* / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D015118:Eicosapentaenoic Acid / Q000008:administration & dosage* / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000096:biosynthesis / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006019:Glycolysis / Q000187:drug effects* / Q000502:physiology; D022781:Hepatocytes / Q000201:enzymology; D050155:Lipogenesis / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051379:Mice; D009097:Multienzyme Complexes / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010427:Pentose Phosphate Pathway / Q000187:drug effects / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011770:Pyruvate Kinase / Q000096:biosynthesis / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004042:Dietary Fats, Unsaturated; C506001:Mlxipl protein, mouse; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D014157:Transcription Factors; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid; D064429:Fatty Acid Synthases; D011770:Pyruvate Kinase; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases