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

Kristin A Anderson; Frank K Huynh; Kelsey Fisher-Wellman; J Darren Stuart; Brett S Peterson; Jonathan D Douros; Gregory R Wagner; J Will Thompson; Andreas S Madsen; Michelle F Green; R Michael Sivley; Olga R Ilkayeva; Robert D Stevens; Donald S Backos; John A Capra; Christian A Olsen; Jonathan E Campbell; Deborah M Muoio; Paul A Grimsrud; Matthew D Hirschey

doi:10.1016/j.cmet.2017.03.003

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

Kristin A Anderson, Frank K Huynh, Kelsey Fisher-Wellman, J Darren Stuart, Brett S Peterson, Jonathan D Douros, Gregory R Wagner, J Will Thompson, Andreas S Madsen, Michelle F Green, R Michael Sivley, Olga R Ilkayeva, Robert D Stevens, Donald S Backos, John A Capra, Christian A Olsen, Jonathan E Campbell, Deborah M Muoio, Paul A Grimsrud, Matthew D Hirschey

126 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Cell Metabolism
Volume	25
Issue number	4
Pages (from-to)	838-855.e15
ISSN	1550-4131
DOIs	https://doi.org/10.1016/j.cmet.2017.03.003
Publication status	Published - 4 Apr 2017

Keywords

Amidohydrolases
Amino Acid Sequence
Animals
Carbon-Carbon Ligases
Glucose
HEK293 Cells
Homeostasis
Humans
Insulin
Insulin Resistance
Leucine
Lysine
Metabolic Flux Analysis
Mice, Inbred C57BL
Mice, Knockout
Mitochondrial Proteins
Models, Molecular
Phylogeny
Sirtuins
Journal Article

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Anderson, K. A., Huynh, F. K., Fisher-Wellman, K., Stuart, J. D., Peterson, B. S., Douros, J. D., Wagner, G. R., Thompson, J. W., Madsen, A. S., Green, M. F., Sivley, R. M., Ilkayeva, O. R., Stevens, R. D., Backos, D. S., Capra, J. A., Olsen, C. A., Campbell, J. E., Muoio, D. M., Grimsrud, P. A., & Hirschey, M. D. (2017). SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion. Cell Metabolism, 25(4), 838-855.e15. https://doi.org/10.1016/j.cmet.2017.03.003

Anderson, KA, Huynh, FK, Fisher-Wellman, K, Stuart, JD, Peterson, BS, Douros, JD, Wagner, GR, Thompson, JW, Madsen, AS, Green, MF, Sivley, RM, Ilkayeva, OR, Stevens, RD, Backos, DS, Capra, JA, Olsen, CA, Campbell, JE, Muoio, DM, Grimsrud, PA & Hirschey, MD 2017, 'SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion', Cell Metabolism, vol. 25, no. 4, pp. 838-855.e15. https://doi.org/10.1016/j.cmet.2017.03.003

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title = "SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion",

abstract = "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.",

keywords = "Amidohydrolases, Amino Acid Sequence, Animals, Carbon-Carbon Ligases, Glucose, HEK293 Cells, Homeostasis, Humans, Insulin, Insulin Resistance, Leucine, Lysine, Metabolic Flux Analysis, Mice, Inbred C57BL, Mice, Knockout, Mitochondrial Proteins, Models, Molecular, Phylogeny, Sirtuins, Journal Article",

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T1 - SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion

AU - Anderson, Kristin A

AU - Huynh, Frank K

AU - Fisher-Wellman, Kelsey

AU - Stuart, J Darren

AU - Peterson, Brett S

AU - Douros, Jonathan D

AU - Wagner, Gregory R

AU - Thompson, J Will

AU - Madsen, Andreas S

AU - Green, Michelle F

AU - Sivley, R Michael

AU - Ilkayeva, Olga R

AU - Stevens, Robert D

AU - Backos, Donald S

AU - Capra, John A

AU - Olsen, Christian A

AU - Campbell, Jonathan E

AU - Muoio, Deborah M

AU - Grimsrud, Paul A

AU - Hirschey, Matthew D

PY - 2017/4/4

Y1 - 2017/4/4

N2 - 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.

AB - 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.

KW - Amidohydrolases

KW - Amino Acid Sequence

KW - Animals

KW - Carbon-Carbon Ligases

KW - Glucose

KW - HEK293 Cells

KW - Homeostasis

KW - Humans

KW - Insulin

KW - Insulin Resistance

KW - Leucine

KW - Lysine

KW - Metabolic Flux Analysis

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Mitochondrial Proteins

KW - Models, Molecular

KW - Phylogeny

KW - Sirtuins

KW - Journal Article

U2 - 10.1016/j.cmet.2017.03.003

DO - 10.1016/j.cmet.2017.03.003

M3 - Journal article

C2 - 28380376

SN - 1550-4131

VL - 25

SP - 838-855.e15

JO - Cell Metabolism

JF - Cell Metabolism

IS - 4

ER -

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

Abstract

Keywords

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