The GCN2 eIF2alpha kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid

Cell Metab. 2007 Feb;5(2):103-14. doi: 10.1016/j.cmet.2007.01.001.

Abstract

Metabolic adaptation is required to cope with episodes of protein deprivation and malnutrition. GCN2 eIF2alpha kinase, a sensor of amino acid deficiency, plays a key role in yeast and mammals in modulating amino acid metabolism as part of adaptation to nutrient deprivation. The role of GCN2 in adaptation to long-term amino acid deprivation in mammals, however, is poorly understood. We found that expression of lipogenic genes and the activity of fatty acid synthase (FAS) in the liver are repressed and lipid stores in adipose tissue are mobilized in wild-type mice upon leucine deprivation. In contrast, GCN2-deficient mice developed liver steatosis and exhibited reduced lipid mobilization. Liver steatosis in Gcn2(-/-) mice was found to be caused by unrepressed expression of lipogenic genes, including Srebp-1c and Fas. Thus, our study identifies a novel function of GCN2 in regulating lipid metabolism during leucine deprivation in addition to regulating amino acid metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Butyrolactone / analogs & derivatives
  • 4-Butyrolactone / pharmacology
  • Adipose Tissue / drug effects
  • Adipose Tissue / enzymology
  • Animals
  • Eukaryotic Initiation Factor-2 / metabolism
  • Fatty Acid Synthases / antagonists & inhibitors
  • Fatty Acid Transport Proteins / genetics
  • Fatty Acids / metabolism*
  • Fatty Liver / pathology
  • Female
  • Homeostasis* / drug effects
  • Leucine / deficiency*
  • Liver / drug effects
  • Liver / enzymology*
  • Liver / pathology
  • Male
  • Mice
  • Mitochondrial Trifunctional Protein
  • Multienzyme Complexes / genetics
  • Organ Size / drug effects
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Phosphorylation / drug effects
  • Protein-Serine-Threonine Kinases / deficiency
  • Protein-Serine-Threonine Kinases / metabolism*
  • Repressor Proteins / metabolism
  • Sterol Regulatory Element Binding Protein 1 / genetics
  • Sterol Regulatory Element Binding Protein 1 / metabolism
  • Triglycerides / biosynthesis
  • Up-Regulation / drug effects

Substances

  • 4-methylene-2-octyl-5-oxofuran-3-carboxylic acid
  • Eukaryotic Initiation Factor-2
  • Fatty Acid Transport Proteins
  • Fatty Acids
  • Multienzyme Complexes
  • PPAR gamma
  • Repressor Proteins
  • Sterol Regulatory Element Binding Protein 1
  • Triglycerides
  • Mitochondrial Trifunctional Protein
  • Fatty Acid Synthases
  • Eif2ak4 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Leucine
  • 4-Butyrolactone