title: Nutrient-dependent phosphorylation channels lipid synthesis to regulate PPARα.
abstract: Peroxisome proliferator-activated receptor (PPAR)α is a nuclear receptor that coordinates liver metabolism during fasting. Fatty acid synthase (FAS) is an enzyme that stores excess calories as fat during feeding, but it also activates hepatic PPARα by promoting synthesis of an endogenous ligand. Here we show that the mechanism underlying this paradoxical relationship involves the differential regulation of FAS in at least two distinct subcellular pools: cytoplasmic and membrane-associated. In mouse liver and cultured hepatoma cells, the ratio of cytoplasmic to membrane FAS-specific activity was increased with fasting, indicating higher cytoplasmic FAS activity under conditions associated with PPARα activation. This effect was due to a nutrient-dependent and compartment-selective covalent modification of FAS. Cytoplasmic FAS was preferentially phosphorylated during feeding or insulin treatment at Thr-1029 and Thr-1033, which flank a dehydratase domain catalytic residue. Mutating these sites to alanines promoted PPARα target gene expression. Rapamycin-induced inhibition of mammalian/mechanistic target of rapamycin complex 1 (mTORC1), a mediator of the feeding/insulin signal to induce lipogenesis, reduced FAS phosphorylation, increased cytoplasmic FAS enzyme activity, and increased PPARα target gene expression. Rapamycin-mediated induction of the same gene was abrogated with FAS knockdown. These findings suggest that hepatic FAS channels lipid synthesis through specific subcellular compartments that allow differential gene expression based on nutritional status.
authors.affiliation: Department of Medicine, Washington University School of Medicine , St. Louis, MO, USA.
authors.forename: Anne P L
authors.initials: AP
authors.lastname: Jensen-Urstad
authors.forename: Haowei
authors.initials: H
authors.lastname: Song
authors.forename: Irfan J
authors.initials: IJ
authors.lastname: Lodhi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Funai
authors.forename: Li
authors.initials: L
authors.lastname: Yin
authors.forename: Trey
authors.initials: T
authors.lastname: Coleman
authors.forename: Clay F
authors.initials: CF
authors.lastname: Semenkovich
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003593:Cytoplasm / Q000201:enzymology; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005502:Food; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008055:Lipids / Q000096:biosynthesis*; D008099:Liver / Q000201:enzymology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000378:metabolism; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D007328:Insulin; D008055:Lipids; D046912:Multiprotein Complexes; D047493:PPAR alpha; D064429:Fatty Acid Synthases; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: de novo lipogenesis; peroxisome proliferator-activated receptor α; starvation