The GCN2 eIF2alpha kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid.
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.
Guo
Feifan
F
Department of Biology, Pennsylvania State University, University Park, PA 16802, USA.
Cavener
Douglas R
DR
D015107:4-Butyrolactone / Q000031:analogs & derivatives / Q000494:pharmacology; D000273:Adipose Tissue / Q000187:drug effects / Q000201:enzymology; D000818:Animals; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors; D050612:Fatty Acid Transport Proteins / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000473:pathology; D005260:Female; D006706:Homeostasis / Q000187:drug effects; D007930:Leucine / Q000172:deficiency*; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D063991:Mitochondrial Trifunctional Protein; D009097:Multienzyme Complexes / Q000235:genetics; D009929:Organ Size / Q000187:drug effects; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects
C406734:4-methylene-2-octyl-5-oxofuran-3-carboxylic acid; D015852:Eukaryotic Initiation Factor-2; D050612:Fatty Acid Transport Proteins; D005227:Fatty Acids; D009097:Multienzyme Complexes; D047495:PPAR gamma; D012097:Repressor Proteins; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D063991:Mitochondrial Trifunctional Protein; D064429:Fatty Acid Synthases; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases; D007930:Leucine; D015107:4-Butyrolactone