@article{b3c76afb55f54bfd8ee0b62e35bc0e70,
title = "SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome",
abstract = "Acetylation is increasingly recognized as an important metabolic regulatory posttranslational protein modification, yet the metabolic consequence of mitochondrial protein hyperacetylation is unknown. We find that high-fat diet (HFD) feeding induces hepatic mitochondrial protein hyperacetylation in mice and downregulation of the major mitochondrial protein deacetylase SIRT3. Mice lacking SIRT3 (SIRT3KO) placed on a HFD show accelerated obesity, insulin resistance, hyperlipidemia, and steatohepatitis compared to wild-type (WT) mice. The lipogenic enzyme stearoyl-CoA desaturase 1 is highly induced in SIRT3KO mice, and its deletion rescues both WT and SIRT3KO mice from HFD-induced hepatic steatosis and insulin resistance. We further identify a single nucleotide polymorphism in the human SIRT3 gene that is suggestive of a genetic association with the metabolic syndrome. This polymorphism encodes a point mutation in the SIRT3 protein, which reduces its overall enzymatic efficiency. Our findings show that loss of SIRT3 and dysregulation of mitochondrial protein acetylation contribute to the metabolic syndrome.",
author = "Hirschey, {Matthew D.} and Tadahiro Shimazu and Enxuan Jing and Grueter, {Carrie A.} and Collins, {Amy M.} and Bradley Aouizerat and Alena Stan{\v c}{\'a}kov{\'a} and Eric Goetzman and Lam, {Maggie M.} and Bjoern Schwer and Stevens, {Robert D.} and Muehlbauer, {Michael J.} and Sanjay Kakar and Bass, {Nathan M.} and Johanna Kuusisto and Markku Laakso and Alt, {Frederick W.} and Newgard, {Christopher B.} and Farese, {Robert V.} and Kahn, {C. Ronald} and Eric Verdin",
note = "Funding Information: We thank C. Miller and J.D. Fish for histology preparation; C. Harris, L. Swift, and the MMPC (DK59637) for plasma and tissue lipid analysis; T. Tran for metabolic experiments; A. Wilson, G. Maki, and J. Carroll for figure preparation; and G. Howard and S. Ordway for editorial review. We thank the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN; a complete list of authors is located in the Supplemental Information ) for providing human patient samples. NASH CRN is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grants U01DK061718, U01DK061728, U01DK061731, U01DK061732, U01DK061734, U01DK061737, U01DK061738, U01DK061730, and U01DK061713) and by the National Institute of Child Health and Human Development (NICHD). Several NASH CRN clinical centers use support from General Clinical Research Centers or Clinical and Translational Science Awards in conduct of NASH CRN Studies (grants UL1RR024989, M01RR000750, M01RR00188, UL1RR02413101, M01RR000827, UL1RR02501401, M01RR000065, M01RR020359, and UL1RR025741). Funding for this work was supported in part by a University of California, San Francisco (UCSF) Postdoctoral Research Fellowship Award from the Sandler Foundation (M.D.H. and B.S.); from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research (KL2 RR024130) (B.A.); by grants from the Academy of Finland (contract 124243), The Finnish Heart Foundation, The Finnish Diabetes Research Foundation, TEKES (contract 1510/31/06), and Kuopio University Hospital (EVO grants 5232 and 5263), and a Senior Scholarship in Aging from the Elison Medical Foundation (F.W.A. and E.V.); the UCSF Liver Center though the NIDDK (P30 DK026743) (E.V.); an R24 grant from NIDDK (DK085610) (C.B.N., C.R.K., and E.V.); and institutional support from the J. David Gladstone Institutes (E.V.). F.W.A. is an Investigator of the Howard Hughes Medical Institute. ",
year = "2011",
month = oct,
day = "21",
doi = "10.1016/j.molcel.2011.07.019",
language = "English (US)",
volume = "44",
pages = "177--190",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "2",
}