SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion

被引：283

作者：

Anderson, Kristin A. ^{[1
,2
,3
]}

Huynh, Frank K. ^{[1
,2
]}

Fisher-Wellman, Kelsey ^{[1
,2
]}

Stuart, J. Darren ^{[1
,2
]}

Peterson, Brett S. ^{[1
,2
]}

Douros, Jonathan D. ^{[1
,2
]}

Wagner, Gregory R. ^{[1
,2
]}

Thompson, J. Will ^{[3
,4
]}

Madsen, Andreas S. ^{[5
,6
]}

Green, Michelle F. ^{[1
,2
]}

Sivley, R. Michael ^{[7
]}

Ilkayeva, Olga R. ^{[1
,2
]}

Stevens, Robert D. ^{[1
,2
]}

Backos, Donald S. ^{[8
]}

Capra, John A. ^{[7
]}

Olsen, Christian A. ^{[5
,6
]}

Campbell, Jonathan E. ^{[1
,2
,3
,9
]}

Muoio, Deborah M. ^{[1
,2
,3
,9
]}

Grimsrud, Paul A. ^{[1
,2
]}

Hirschey, Matthew D. ^{[1
,2
,3
,9
]}

机构：

[1] Duke Univ, Med Ctr, Duke Mol Physiol Inst, Durham, NC 27701 USA

[2] Duke Univ, Med Ctr, Sarah W Stedman Nutr & Metab Ctr, Durham, NC 27701 USA

[3] Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA

[4] Duke Univ, Med Ctr, Duke Prote & Metab Shared Resource, Durham, NC 27710 USA

[5] Univ Copenhagen, Ctr Biopharmaceut, Fac Hlth & Med Sci, Univ Pk 2, DK-2100 Copenhagen, Denmark

[6] Univ Copenhagen, Dept Drug Design & Pharmacol, Fac Hlth & Med Sci, Univ Pk 2, DK-2100 Copenhagen, Denmark

[7] Vanderbilt Univ, Dept Biol Sci, Dept Biomed Informat, Vanderbilt Genet Inst,Ctr Struct Biol, 221 Kirkland Hall, Nashville, TN 37235 USA

[8] Univ Colorado, Skaggs Sch Pharm & Pharmaceut Sci, Computat Chem & Biol Core Facil, Anschutz Med Campus, Aurora, CO 80045 USA

[9] Duke Univ, Med Ctr, Dept Med, Div Endocrinol Metab & Nutr, Durham, NC 27710 USA

来源：

CELL METABOLISM | 2017年 / 25卷 / 04期

关键词：

AMINO-ACID CATABOLISM; GLUTAMATE-DEHYDROGENASE; PROTEIN; NAD; DEACETYLASE; HYPERINSULINEMIA; SIRTUINS; MUSCLE; ASSAY; LIVER;

D O I：

10.1016/j.cmet.2017.03.003

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

Sirtuins are NAD(+)-dependent protein deacylases that regulate several aspects of metabolism and aging. In contrast to the other mammalian sirtuins, the primary enzymatic activity of mitochondrial sirtuin 4 (SIRT4) and its overall role in metabolic control have remained enigmatic. Using a combination of phylogenetics, structural biology, and enzymology, we show that SIRT4 removes three acyl moieties from lysine residues: methylglutaryl (MG)-, hydroxymethylglutaryl (HMG)-, and 3-methylglutaconyl (MGc)-lysine. The metabolites leading to these post-translational modifications are intermediates in leucine oxidation, and we show a primary role for SIRT4 in controlling this pathway in mice. Furthermore, we find that dysregulated leucine metabolism in SIRT4KO mice leads to elevated basal and stimulated insulin secretion, which progressively develops into glucose intolerance and insulin resistance. These findings identify a robust enzymatic activity for SIRT4, uncover a mechanism controlling branched-chain amino acid flux, and position SIRT4 as a crucial player maintaining insulin secretion and glucose homeostasis during aging.

引用

页码：838 / +

页数：33

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