Polyunsaturated fatty acids suppress glycolytic and lipogenic genes through the inhibition of ChREBP nuclear protein translocation

J Clin Invest. 2005 Oct;115(10):2843-54. doi: 10.1172/JCI25256. Epub 2005 Sep 22.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases
  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
  • Cells, Cultured
  • Dietary Fats, Unsaturated / administration & dosage*
  • Dietary Fats, Unsaturated / pharmacology
  • Docosahexaenoic Acids / administration & dosage*
  • Docosahexaenoic Acids / pharmacology
  • Down-Regulation / drug effects
  • Down-Regulation / physiology
  • Eicosapentaenoic Acid / administration & dosage*
  • Eicosapentaenoic Acid / pharmacology
  • Fatty Acid Synthases / biosynthesis
  • Fatty Acid Synthases / genetics
  • Gene Expression Regulation, Enzymologic / drug effects
  • Gene Expression Regulation, Enzymologic / physiology
  • Glycolysis / drug effects*
  • Glycolysis / physiology
  • Hepatocytes / enzymology
  • Lipogenesis / drug effects*
  • Lipogenesis / physiology
  • Male
  • Mice
  • Multienzyme Complexes / metabolism
  • Nuclear Proteins / metabolism
  • Pentose Phosphate Pathway / drug effects
  • Pentose Phosphate Pathway / physiology
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyruvate Kinase / biosynthesis
  • Pyruvate Kinase / genetics
  • Transcription Factors / metabolism

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Dietary Fats, Unsaturated
  • Mlxipl protein, mouse
  • Multienzyme Complexes
  • Nuclear Proteins
  • Transcription Factors
  • Docosahexaenoic Acids
  • Eicosapentaenoic Acid
  • Fatty Acid Synthases
  • Pyruvate Kinase
  • Protein-Serine-Threonine Kinases
  • AMP-Activated Protein Kinases