Sirt3 Promotes the Urea Cycle and Fatty Acid Oxidation during Dietary Restriction

Hallows, William C.; Yu, Wei; Smith, Brian C.; Devries, Mark K.; Ellinger, James J.; Someya, Shinichi; Shortreed, Michael R.; Prolla, Tomas A.; Markley, John L.; Smith, Lloyd M.; Zhao, Shimin; Guan, Kun‐Liang; Denu, John M.

doi:10.1016/j.molcel.2011.01.002

Cited by 341 publications

(243 citation statements)

References 43 publications

Supporting

Mentioning

228

Contrasting

Unclassified

Order By: Relevance

“…As a predominant sirtuin for deacetylation of mitochondrial proteins (74 -76), Sirt3 plays a critical role in fatty acid oxidation, ketogenesis, and mitochondrial energy metabolism (35-38, 41, 74, 77-83). Sirt3 knock-out mice have increased levels of fatty acid oxidation intermediates and triglycerides and decreased levels of ␤-hydroxybutyrate (36,37,41). Sirt4, another mitochondrial sirtuin that has ADP-ribosyltransferase activity, has been reported to have an inhibitory function in the regulation of fatty acid oxidation and mitochondrial genes (40).…”

Section: Discussionmentioning

confidence: 99%

Hepatic FoxOs Regulate Lipid Metabolism via Modulation of Expression of the Nicotinamide Phosphoribosyltransferase Gene

Tao¹,

Wei²,

Gao

et al. 2011

Journal of Biological Chemistry

119

106

View full text Add to dashboard Cite

FoxO transcription factors have been implicated in lipid metabolism; however, the underlying mechanisms are not well understood. Here, in an effort to elucidate such mechanisms, we examined the phenotypic consequences of liver-specific deletion of three members of the FoxO family: FoxO1, FoxO3, and FoxO4. These liver-specific triply null mice, designated LTKO, exhibited elevated triglycerides in the liver on regular chow diet. More remarkably, LTKO mice developed severe hepatic steatosis following placement on a high fat diet. Further analyses revealed that hepatic NAD ؉ levels and Sirt1 activity were The O family members of Forkhead transcription factors (FoxOs) 3 are critical downstream effectors of the insulin/IGF-1 signaling pathway and play important roles in cellular growth and differentiation, protection against oxidative stress, and metabolic regulation (1-4). As a prototypical member of the FoxO family that includes four mammalian genes (FoxO1/3/ 4/6; FoxO2 is a pseudogene of FoxO3, and FoxO5 is the fish ortholog of FoxO3), FoxO1 has been implicated in nutrient and energy homeostasis (1-5). Although its function in glucose metabolism has been well documented (6 -12), the role of FoxO1 in hepatic lipid metabolism remains an area of active investigation (6,10,(12)(13)(14)(15)(16)(17). Adenovirus-mediated overexpression of the constitutively nuclear FoxO1 mutant (FoxO1ADA) increases triglycerides in the mouse liver but decreases triglycerides in the circulation (15). In line with this observation, deletion of FoxO1 in the liver of systemic insulin receptor (IR) knock-out mice reverses the development of hepatic steatosis (10). However, liver-specific FoxO1 knock-out mice manifest increased secretion of VLDL triglycerides in the streptozotocin-induced diabetic state (17). Moreover, the results from two transgenic lines harboring constitutively active FoxO1 alleles are contradictory in regard to its role in hepatic lipid metabolism (6,13,14). One line engineered with an S253A mutation (mouse FoxO1) leads to elevated serum and liver triglycerides (8, 13), whereas a triple substitution FOXO1TSS-A allele (T24A, S256A, and S319A in human FOXO1) exhibits lower levels of plasma triglycerides and normal levels of liver triglycerides (6). The latter finding is consistent with the observations from liver-specific IR or IR substrate (Irs1/2) knock-out mice, which have constitutively active FoxOs and lower levels of serum triglycerides due to deficiency of hepatic insulin signaling in these mice (12,18). In addition, liver-specific deletion of Akt2, the major inhibitory kinase for FoxOs, in the leptin-deficient ob/ob mice reduces fasted serum triglycerides and protects them from developing hepatic steatosis (19).In addition to phosphorylation by numerous kinases, such as Akt2, FoxOs are also subject to acetylation by several protein acetylases (20 -25). It is well known that FoxO acetylation can be reversed by NAD ϩ -dependent deacetylases (sirtuins, such as Sirt1 and Sirt2) (20 -25). Several sirtuins, including Sirt...

show abstract

Section: Discussionmentioning

confidence: 99%

Hepatic FoxOs Regulate Lipid Metabolism via Modulation of Expression of the Nicotinamide Phosphoribosyltransferase Gene

Tao¹,

Wei²,

Gao

et al. 2011

Journal of Biological Chemistry

119

106

View full text Add to dashboard Cite

show abstract

“…As shown in mice, during times of low energy, Sirt3 expression in liver is induced to promote a metabolic switch to fatty acid oxidation (FAO) and ketone body production to provide alternative energy sources [53]. Activation of enzymes involved in fatty acid oxidation and ketogenesis, such as long-chain acyl coenzyme A dehydrogenase (LCAD) and 3-hydroxy-3-methylglutaryl CoA synthase 2 (HMGCS2), is required for ATP and ketone body production during periods of nutrient stress [53]. Another mouse study showed that Sirt3 not only promotes ketone body production in the liver, but also positively regulates ketone body utilization in the brain, emphasizing a crucial role for SIRT3 in metabolic fuel switching [54].…”

Section: Mitochondrial Sirtuins Protect Against Age-related Diseasesmentioning

confidence: 99%

Mitochondrial Sirtuins and Molecular Mechanisms of Aging

Ven

Santos

Haigis

2017

Trends in Molecular Medicine

250

175

View full text Add to dashboard Cite

Advancing age is the major risk factor for the development of chronic diseases and is accompanied with changes in metabolic processes and mitochondrial dysfunction. Mitochondrial sirtuins (SIRT3-5) are part of the sirtuin family of NAD+-dependent deacylases and ADP-ribosyl transferases. The dependence on NAD+ links sirtuin enzymatic activity to the metabolic state of the cell, poising them as stress sensors. Recent insights have revealed that SIRT3-5 orchestrate stress responses through coordinated regulation of substrate clusters rather than a few key metabolic enzymes. Additionally, mitochondrial sirtuin function has been implicated in the protection against age-related pathologies including neurodegeneration, cardiopathologies and insulin resistance. In this review, we highlight the molecular targets of SIRT3-5 and discuss their involvement in aging and age-related pathologies.

show abstract

“…SIRT3 directly deacetylates LACD at Lys42 and increases LACD activity (Hirschey et al ., 2010). In addition, SIRT3 may promote β-oxidation via multiple mechanisms, such as by deacetylating other β-oxidation enzymes, including the short-chain L-3-hydroxyacyl-CoA dehydrogenase and the very-long-chain acyl coenzyme A dehydrogenase (Hallows et al ., 2011), facilitating mitochondrial adaptation to fuel changes.…”

Section: Cellular Targets and Protective Mechanisms Of Sirtuinsmentioning

confidence: 99%

“…Ornithine transcarbamylase (OTC) catalyzes the second reaction of the urea cycle. A recent study showed that Sirt3 directly deacetylates this enzyme and stimulates its activity (Hallows et al ., 2011). Collectively, these results suggest that SIRT3 and SIRT5 may play a protective role by promoting amino acid catabolism and converting ammonia to non-toxic urea.…”

Section: Cellular Targets and Protective Mechanisms Of Sirtuinsmentioning

confidence: 99%

Protective effects and mechanisms of sirtuins in the nervous system

Zhang

Wang

Gan

et al. 2011

Progress in Neurobiology

182

130

View full text Add to dashboard Cite

Silent information regulator two proteins (sirtuins or SIRTs) are a group of histone deacetylases whose activities are dependent on and regulated by nicotinamide adenine dinucleotide (NAD+). They suppress genome-wide transcription, yet upregulate a select set of proteins related to energy metabolism and pro-survival mechanisms, and therefore play a key role in the longevity effects elicited by calorie restriction. Recently, a neuroprotective effect of sirtuins has been reported for both acute and chronic neurological diseases. The focus of this review is to summarize the latest progress regarding the protective effects of sirtuins, with a focus on SIRT1. We first introduce the distribution of sirtuins in the brain and how their expression and activity are regulated. We then highlight their protective effects against common neurological disorders, such as cerebral ischemia, axonal injury, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis. Finally, we analyze the mechanisms underlying sirtuin-mediated neuroprotection, centering on their non-histone substrates such as DNA repair enzymes, protein kinases, transcription factors, and coactivators. Collectively, the information compiled here will serve as a comprehensive reference for the actions of sirtuins in the nervous system to date, and will hopefully help to design further experimental research and expand sirtuins as therapeutic targets in the future.

show abstract

Sirt3 Promotes the Urea Cycle and Fatty Acid Oxidation during Dietary Restriction

Cited by 341 publications

References 43 publications

Hepatic FoxOs Regulate Lipid Metabolism via Modulation of Expression of the Nicotinamide Phosphoribosyltransferase Gene

Hepatic FoxOs Regulate Lipid Metabolism via Modulation of Expression of the Nicotinamide Phosphoribosyltransferase Gene

Mitochondrial Sirtuins and Molecular Mechanisms of Aging

Protective effects and mechanisms of sirtuins in the nervous system

Contact Info

Product

Resources

About