"New" hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis.
De novo lipogenesis is an energy-expensive process whose role in adult mammals is poorly understood. We generated mice with liver-specific inactivation of fatty-acid synthase (FAS), a key lipogenic enzyme. On a zero-fat diet, FASKOL (FAS knockout in liver) mice developed hypoglycemia and fatty liver, which were reversed with dietary fat. These phenotypes were also observed after prolonged fasting, similarly to fasted PPARalpha-deficiency mice. Hypoglycemia, fatty liver, and defects in expression of PPARalpha target genes in FASKOL mice were corrected with a PPARalpha agonist. On either zero-fat or chow diet, FASKOL mice had low serum and hepatic cholesterol levels with elevated SREBP-2, decreased HMG-CoA reductase expression, and decreased cholesterol biosynthesis; these were also corrected with a PPARalpha agonist. These results suggest that products of the FAS reaction regulate glucose, lipid, and cholesterol metabolism by serving as endogenous activators of distinct physiological pools of PPARalpha in adult liver.
Chakravarthy
Manu V
MV
Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Pan
Zhijun
Z
Zhu
Yimin
Y
Tordjman
Karen
K
Schneider
Jochen G
JG
Coleman
Trey
T
Turk
John
J
Semenkovich
Clay F
CF
D000818:Animals; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics; D004041:Dietary Fats / Q000008:administration & dosage; D064429:Fatty Acid Synthases / Q000096:biosynthesis / Q000378:metabolism*; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D007003:Hypoglycemia / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors / Q000235:genetics
D004268:DNA-Binding Proteins; D004041:Dietary Fats; D005227:Fatty Acids; D047493:PPAR alpha; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D064429:Fatty Acid Synthases; D005947:Glucose