title: SIRT4 coordinates the balance between lipid synthesis and catabolism by repressing malonyl CoA decarboxylase.
abstract: Lipid metabolism is tightly controlled by the nutritional state of the organism. Nutrient-rich conditions increase lipogenesis, whereas nutrient deprivation promotes fat oxidation. In this study, we identify the mitochondrial sirtuin, SIRT4, as a regulator of lipid homeostasis. SIRT4 is active in nutrient-replete conditions to repress fatty acid oxidation while promoting lipid anabolism. SIRT4 deacetylates and inhibits malonyl CoA decarboxylase (MCD), an enzyme that produces acetyl CoA from malonyl CoA. Malonyl CoA provides the carbon skeleton for lipogenesis and also inhibits fat oxidation. Mice lacking SIRT4 display elevated MCD activity and decreased malonyl CoA in skeletal muscle and white adipose tissue. Consequently, SIRT4 KO mice display deregulated lipid metabolism, leading to increased exercise tolerance and protection against diet-induced obesity. In sum, this work elucidates SIRT4 as an important regulator of lipid homeostasis, identifies MCD as a SIRT4 target, and deepens our understanding of the malonyl CoA regulatory axis.
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Laurent
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: German
authors.forename: Asish K
authors.initials: AK
authors.lastname: Saha
authors.forename: Vincent C J
authors.initials: VC
authors.lastname: de Boer
authors.forename: Michael
authors.initials: M
authors.lastname: Davies
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Koves
authors.forename: Noah
authors.initials: N
authors.lastname: Dephoure
authors.forename: Frank
authors.initials: F
authors.lastname: Fischer
authors.forename: Gina
authors.initials: G
authors.lastname: Boanca
authors.forename: Bhavapriya
authors.initials: B
authors.lastname: Vaitheesvaran
authors.forename: Scott B
authors.initials: SB
authors.lastname: Lovitch
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Irwin J
authors.initials: IJ
authors.lastname: Kurland
authors.forename: Clemens
authors.initials: C
authors.lastname: Steegborn
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Muoio
authors.forename: Neil B
authors.initials: NB
authors.lastname: Ruderman
authors.forename: Marcia C
authors.initials: MC
authors.lastname: Haigis
mesh_terms: D000107:Acetylation; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D002262:Carboxy-Lyases / Q000378:metabolism*; D004032:Diet; D005227:Fatty Acids / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics; D008055:Lipids / Q000096:biosynthesis; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000209:etiology / Q000378:metabolism; D010084:Oxidation-Reduction; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*
chemical_list: D005227:Fatty Acids; D008055:Lipids; D024101:Mitochondrial Proteins; C514813:SIRT4 protein, mouse; D037761:Sirtuins; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase