SIRT3 Deacetylates Mitochondrial 3-Hydroxy-3-Methylglutaryl CoA Synthase 2 and Regulates Ketone Body Production

Shimazu, Tadahiro; Hirschey, Matthew D.; Hua, Lan; Dittenhafer‐Reed, Kristin E.; Schwer, Bjoern; Lombard, David B.; Yu, Li; Bunkenborg, Jakob; Alt, Frederick W.; Denu, John M.; Jacobson, Matthew P.; Verdin, Eric

doi:10.1016/j.cmet.2010.11.003

Cited by 422 publications

(321 citation statements)

References 39 publications

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“…Furthermore, hydroxymethylglutaryl-CoA synthase 2 is a known Sirt3 target 32 , again indicating that sirtuin targets could serve as signalling integration points (see above) and/or that different sirtuins might remove different acylations, such as acetylation and succinylation, which appear to affect the same target residues 17 . A Sirt5 function in stress response would be consistent with the hits Prx3 (Lys83, 93) and Prx1 (Lys197).…”

Section: Resultsmentioning

confidence: 99%

An acetylome peptide microarray reveals specificities and deacetylation substrates for all human sirtuin isoforms

et al. 2013

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Sirtuin enzymes regulate metabolism and aging processes through deacetylation of acetyllysines in target proteins. More than 6,800 mammalian acetylation sites are known, but few targets have been assigned to most sirtuin isoforms, hampering our understanding of sirtuin function. Here we describe a peptide microarray system displaying 6,802 human acetylation sites for the parallel characterisation of their modification by deacetylases. Deacetylation data for all seven human sirtuins obtained with this system reveal isoform-specific substrate preferences and deacetylation substrate candidates for all sirtuin isoforms, including Sirt4. We confirm malate dehydrogenase protein as a Sirt3 substrate and show that peroxiredoxin 1 and high-mobility group B1 protein are deacetylated by Sirt5 and Sirt1, respectively, at the identified sites, rendering them likely new in vivo substrates. Our microarray platform enables parallel studies on physiological acetylation sites and the deacetylation data presented provide an exciting resource for the identification of novel substrates for all human sirtuins.

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Section: Resultsmentioning

confidence: 99%

An acetylome peptide microarray reveals specificities and deacetylation substrates for all human sirtuin isoforms

et al. 2013

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“…Activity of HMGCS2, the enzyme-regulating flux through ketogenesis, is decreased by acetylation and succinylation, and increased by phosphorylation (Quant et al 1990, Shimazu et al 2010, Grimsrud et al 2012. HMGCS2 is phosphorylated by PKA, a downstream glucagon signaling molecule, and hyperphosphorylation of HMGCS2 occurs in obese rodents (Grimsrud et al 2012).…”

Section: Beta-oxidation and Ketogenesismentioning

confidence: 99%

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

Geisler

Renquist

2017

Journal of Endocrinology

146

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Fatty liver can be diet, endocrine, drug, virus or genetically induced. Independent of cause, hepatic lipid accumulation promotes systemic metabolic dysfunction. By acting as peroxisome proliferator-activated receptor (PPAR) ligands, hepatic non-esterified fatty acids upregulate expression of gluconeogenic, beta-oxidative, lipogenic and ketogenic genes, promoting hyperglycemia, hyperlipidemia and ketosis. The typical hormonal environment in fatty liver disease consists of hyperinsulinemia, hyperglucagonemia, hypercortisolemia, growth hormone deficiency and elevated sympathetic tone. These endocrine and metabolic changes further encourage hepatic steatosis by regulating adipose tissue lipolysis, liver lipid uptake, de novo lipogenesis (DNL), beta-oxidation, ketogenesis and lipid export. Hepatic lipid accumulation may be induced by 4 separate mechanisms: (1) increased hepatic uptake of circulating fatty acids, (2) increased hepatic de novo fatty acid synthesis, (3) decreased hepatic beta-oxidation and (4) decreased hepatic lipid export. This review will discuss the hormonal regulation of each mechanism comparing multiple physiological models of hepatic lipid accumulation. Nonalcoholic fatty liver disease (NAFLD) is typified by increased hepatic lipid uptake, synthesis, oxidation and export. Chronic hepatic lipid signaling through PPARgamma results in gene expression changes that allow concurrent activity of DNL and beta-oxidation. The importance of hepatic steatosis in driving systemic metabolic dysfunction is highlighted by the common endocrine and metabolic disturbances across many conditions that result in fatty liver. Understanding the mechanisms underlying the metabolic dysfunction that develops as a consequence of hepatic lipid accumulation is critical to identifying points of intervention in this increasingly prevalent disease state.

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“…Ketone bodies, in turn, serve as an important source of energy for tissues such as heart, skeletal muscle, and brain under fasting conditions. SIRT3-mediated HMGCS2 deacetylation promotes its activity and thus facilitates ketone body formation (144). Consequently, Sirt3 KO mice display reduced serum bhydroxybutyrate levels during prolonged fasting (144).…”

Section: Sirt3 Deacetylates Pdc E1a To Promote Glucose Oxidationmentioning

confidence: 99%

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

Kumar

Lombard²

2015

Antioxidants & Redox Signaling

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123

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Significance: Maintenance of metabolic homeostasis is critical for cellular and organismal health. Proper regulation of mitochondrial functions represents a crucial element of overall metabolic homeostasis. Mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5) play pivotal roles in promoting this homeostasis by regulating numerous aspects of mitochondrial metabolism in response to environmental stressors. Recent Advances: New work has illuminated multiple links between mitochondrial sirtuins and cancer. SIRT5 has been shown to regulate the recently described post-translational modifications succinyl-lysine, malonyllysine, and glutaryl-lysine. An understanding of these modifications is still in its infancy. Enumeration of SIRT3 and SIRT5 targets via advanced proteomic techniques promises to dramatically enhance insight into functions of these proteins. Critical Issues: In this review, we highlight the roles of mitochondrial sirtuins and their targets in cellular and organismal metabolic homeostasis. Furthermore, we discuss emerging roles for mitochondrial sirtuins in suppressing and/or promoting tumorigenesis, depending on the cellular and molecular context. Future Directions: Currently, hundreds of potential SIRT3 and SIRT5 molecular targets have been identified in proteomic experiments. Future studies will need to validate the major targets of these enzymes, and elucidate how acetylation and/or acylation modulate their functionality. A great deal of interest exists in targeting sirtuins pharmacologically; this endeavor will require development of sirtuin-specific modulators (activators and inhibitors) as potential treatments for cancer and metabolic disease. Antioxid.

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SIRT3 Deacetylates Mitochondrial 3-Hydroxy-3-Methylglutaryl CoA Synthase 2 and Regulates Ketone Body Production

Cited by 422 publications

References 39 publications

An acetylome peptide microarray reveals specificities and deacetylation substrates for all human sirtuin isoforms

An acetylome peptide microarray reveals specificities and deacetylation substrates for all human sirtuin isoforms

Hepatic lipid accumulation: cause and consequence of dysregulated glucoregulatory hormones

Mitochondrial Sirtuins and Their Relationships with Metabolic Disease and Cancer

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