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Mammalian sirtuins and energy metabolism.

Li X, Kazgan N - Int. J. Biol. Sci. (2011)

Bottom Line: The seven mammalian sirtuins, SIRT1 to SIRT7, have emerged as key metabolic sensors that directly link environmental signals to mammalian metabolic homeostasis and stress response.Recent studies have shed light on the critical roles of sirtuins in mammalian energy metabolism in response to nutrient signals.This review focuses on the involvement of two nuclear sirtuins, SIRT1 and SIRT6, and three mitochondrial sirtuins, SIRT3, SIRT4, and SIRT5, in regulation of diverse metabolic processes.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. lix3@niehs.nih.gov

ABSTRACT
Sirtuins are highly conserved NAD+-dependent protein deacetylases and/or ADP-ribosyltransferases that can extend the lifespan of several lower model organisms including yeast, worms and flies. The seven mammalian sirtuins, SIRT1 to SIRT7, have emerged as key metabolic sensors that directly link environmental signals to mammalian metabolic homeostasis and stress response. Recent studies have shed light on the critical roles of sirtuins in mammalian energy metabolism in response to nutrient signals. This review focuses on the involvement of two nuclear sirtuins, SIRT1 and SIRT6, and three mitochondrial sirtuins, SIRT3, SIRT4, and SIRT5, in regulation of diverse metabolic processes.

Show MeSH
The diverse functions of SIRT1 in central nutrient sensing and peripheral energy metabolism. The activity of SIRT1 is regulated by the cellular metabolic status, small molecule activators, interacting proteins, as well as post-translational modifications. After activation, SIRT1 modulates a variety of metabolic activities systemically and locally through either direct protein deacetylation or indirect chromatin remodeling.
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Figure 2: The diverse functions of SIRT1 in central nutrient sensing and peripheral energy metabolism. The activity of SIRT1 is regulated by the cellular metabolic status, small molecule activators, interacting proteins, as well as post-translational modifications. After activation, SIRT1 modulates a variety of metabolic activities systemically and locally through either direct protein deacetylation or indirect chromatin remodeling.

Mentions: Recent reports have shown that SIRT1 is an important regulator of hepatic glucose and lipid metabolism (Figure 2). For instance, during short-term fasting phase, SIRT1 inhibits TORC2, a key mediator of early phase gluconeogenesis, leading to decreased gluconeogenesis 41. Prolonged fasting leads to increased SIRT1 deacetylation and activation of PGC-1α, an essential co-activator for a number of transcription factors, resulting in increased fatty acid oxidation and improved glucose homeostasis 42-44. SIRT1 also deacetylates and activates transcriptional factor Foxo1, resulting in increased gluconeogenesis 45. Consistently, adenoviral knockdown of SIRT1 reduces expression of fatty acid β-oxidation genes in the liver of fasted mice 46. Specific deletion of the exon 4 of the hepatic mouse SIRT1 gene, which resulted in a truncated non-functional SIRT1 protein, impairs fatty acid β-oxidation, thereby increasing the susceptibility of mice to high-fat diet induced dyslipidemia, hepatic steatosis, inflammation and endoplasmic reticulum (ER) stress 43. A complete deletion of hepatic SIRT1 by floxing exons 5 and 6 leads to the development of liver steatosis even under normal chow diet 47. Conversely, hepatic overexpression of SIRT1 mediated by adenovirus attenuates hepatic steatosis and ER stress, and restores glucose homeostasis in mice 48, confirming the essential role of SIRT1 in maintaining hepatic metabolic homeostasis.


Mammalian sirtuins and energy metabolism.

Li X, Kazgan N - Int. J. Biol. Sci. (2011)

The diverse functions of SIRT1 in central nutrient sensing and peripheral energy metabolism. The activity of SIRT1 is regulated by the cellular metabolic status, small molecule activators, interacting proteins, as well as post-translational modifications. After activation, SIRT1 modulates a variety of metabolic activities systemically and locally through either direct protein deacetylation or indirect chromatin remodeling.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3101526&req=5

Figure 2: The diverse functions of SIRT1 in central nutrient sensing and peripheral energy metabolism. The activity of SIRT1 is regulated by the cellular metabolic status, small molecule activators, interacting proteins, as well as post-translational modifications. After activation, SIRT1 modulates a variety of metabolic activities systemically and locally through either direct protein deacetylation or indirect chromatin remodeling.
Mentions: Recent reports have shown that SIRT1 is an important regulator of hepatic glucose and lipid metabolism (Figure 2). For instance, during short-term fasting phase, SIRT1 inhibits TORC2, a key mediator of early phase gluconeogenesis, leading to decreased gluconeogenesis 41. Prolonged fasting leads to increased SIRT1 deacetylation and activation of PGC-1α, an essential co-activator for a number of transcription factors, resulting in increased fatty acid oxidation and improved glucose homeostasis 42-44. SIRT1 also deacetylates and activates transcriptional factor Foxo1, resulting in increased gluconeogenesis 45. Consistently, adenoviral knockdown of SIRT1 reduces expression of fatty acid β-oxidation genes in the liver of fasted mice 46. Specific deletion of the exon 4 of the hepatic mouse SIRT1 gene, which resulted in a truncated non-functional SIRT1 protein, impairs fatty acid β-oxidation, thereby increasing the susceptibility of mice to high-fat diet induced dyslipidemia, hepatic steatosis, inflammation and endoplasmic reticulum (ER) stress 43. A complete deletion of hepatic SIRT1 by floxing exons 5 and 6 leads to the development of liver steatosis even under normal chow diet 47. Conversely, hepatic overexpression of SIRT1 mediated by adenovirus attenuates hepatic steatosis and ER stress, and restores glucose homeostasis in mice 48, confirming the essential role of SIRT1 in maintaining hepatic metabolic homeostasis.

Bottom Line: The seven mammalian sirtuins, SIRT1 to SIRT7, have emerged as key metabolic sensors that directly link environmental signals to mammalian metabolic homeostasis and stress response.Recent studies have shed light on the critical roles of sirtuins in mammalian energy metabolism in response to nutrient signals.This review focuses on the involvement of two nuclear sirtuins, SIRT1 and SIRT6, and three mitochondrial sirtuins, SIRT3, SIRT4, and SIRT5, in regulation of diverse metabolic processes.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. lix3@niehs.nih.gov

ABSTRACT
Sirtuins are highly conserved NAD+-dependent protein deacetylases and/or ADP-ribosyltransferases that can extend the lifespan of several lower model organisms including yeast, worms and flies. The seven mammalian sirtuins, SIRT1 to SIRT7, have emerged as key metabolic sensors that directly link environmental signals to mammalian metabolic homeostasis and stress response. Recent studies have shed light on the critical roles of sirtuins in mammalian energy metabolism in response to nutrient signals. This review focuses on the involvement of two nuclear sirtuins, SIRT1 and SIRT6, and three mitochondrial sirtuins, SIRT3, SIRT4, and SIRT5, in regulation of diverse metabolic processes.

Show MeSH