@article{5cb78c12dc274f8f86f578728403ce35,
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 andinhibits 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.",
author = "Ga{\"e}lle Laurent and German, {Natalie J.} and Saha, {Asish K.} and {de Boer}, {Vincent C.J.} and Michael Davies and Koves, {Timothy R.} and Noah Dephoure and Frank Fischer and Gina Boanca and Bhavapriya Vaitheesvaran and Lovitch, {Scott B.} and Sharpe, {Arlene H.} and Kurland, {Irwin J.} and Clemens Steegborn and Gygi, {Steven P.} and Muoio, {Deborah M.} and Ruderman, {Neil B.} and Haigis, {Marcia C.}",
note = "Funding Information: We thank Hong Lu for technical assistance and Carla Harris (Vanderbilt MMPC Lipid Lab, DK59637) for lipid composition analysis. We thank the Nikon Imaging Center at Harvard Medical School. We thank Lydia Finley and the members of the Haigis lab for helpful discussions and constructive comments on the paper. G.L. was supported by Human Frontier Science Program, N.J.G. by National Science Fondation graduate research fellowship, V.C.J.d.B. by grants from the Netherlands Organization for Scientific Research (grants 916.10.065 and 825.07.005), and M.D. by NIDDK grant 1F32DK093256-01. I.J.K. was supported by grants DK58132-01A2, U19AI091175-01, and P60DK020541 (Einstein DRTC). N.B.R. and A.K.S. were supported by USPHS grants RO1DK19514 and RO1DK67509. T.R.K. was supported by Ellison Foundation grant AG-NS-0548-09. D.M.M. was supported by NIH grants 1RO1HL101189 and 2PO1DK05398. M.C.H. was supported by funding from NIH grant AG032375, Ellison Foundation AG-NS-0573-09, Glenn Foundation for Medical Research, and funding from SIRTRIS-GSK. ",
year = "2013",
month = jun,
day = "6",
doi = "10.1016/j.molcel.2013.05.012",
language = "English (US)",
volume = "50",
pages = "686--698",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "5",
}