The NAD+-dependent deacetylase SIRT2 attenuates oxidative stress and mitochondrial dysfunction and improves insulin sensitivity in hepatocytes

Abstract

Insulin resistance is a major predictor of the development of metabolic disorders. Sirtuins (SIRTs) have emerged as potential targets that can be manipulated to counteract age-related diseases, including type 2 diabetes. SIRT2 has been recently shown to exert important metabolic effects, but whether SIRT2 regulates insulin sensitivity in hepatocytes is currently unknown. The aim of this study is to investigate this possibility and to elucidate underlying molecular mechanisms. Here, we show that SIRT2 is downregulated in insulin-resistant hepatocytes and livers, and this was accompanied by increased generation of reactive oxygen species, activation of stress-sensitive ERK1/2 kinase, and mitochondrial dysfunction. Conversely, SIRT2 overexpression in insulin-resistant hepatocytes improved insulin sensitivity, mitigated reactive oxygen species production and ameliorated mitochondrial dysfunction. Further analysis revealed a reestablishment of mitochondrial morphology, with a higher number of elongated mitochondria rather than fragmented mitochondria instigated by insulin resistance. Mechanistically, SIRT2 was able to increase fusion-related protein Mfn2 and decrease mitochondrial-associated Drp1. SIRT2 also attenuated the downregulation of TFAM, a key mtDNA-associated protein, contributing to the increase in mitochondrial mass. Importantly, we found that SIRT2 expression in PBMCs of human subjects was negatively correlated with obesity and insulin resistance. These results suggest a novel function for hepatic SIRT2 in the regulation of insulin sensitivity and raise the possibility that SIRT2 activators may offer novel opportunities for preventing or treating insulin resistance and type 2 diabetes.

Sirt2-SUMOylation is essential for its tumor-suppressor function in neuroblastoma

“…In this work, we identi ed a novel PTM-SUMOylation on Sirt2 at both K183 and K340 sites, which makes a great contribution to its tumor-suppressor function as well as the cell signal transduction. Because Sirt2 is an NAD + -dependent deacetylase [41,42], we also revealed that Sirt2-SUMOylation can be speci cally and positively regulated by NAD + in the cell, which logically highlights the importance of SUMOylation to Sirt2 protein function (Fig. 1F & G).…”

Poly(ADP-Ribose) Polymerases in Host-Pathogen Interactions, Inflammation, and Immunity

“…In mammals, this protein is highly expressed in the brain (340). Like SIRT1, SIRT2 is upregulated during calorie restriction and downregulated under conditions of energy excess (341,342). Recent applications to its function as a deacetylase of microtubules link it to aging brains and neuroprotective effects (343).…”

miR-486-3p Influences the Neurotoxicity of a-Synuclein by Targeting the SIRT2 Gene and the Polymorphisms at Target Sites Contributing to Parkinson’s Disease

“…It has been reported that SIRT2, as a strong deacetylase [23][24][25][26], is highly expressed in the brain and is markedly associated with aging [27,28]; additionally, SIRT2 was evaluated in the brains of PD patients, suggesting a potential role in PD development [29]. It has been confirmed that selective inhibitors of SIRT2 can protect against α-syn-mediated toxicity and dopaminergic cell death, both in vitro and in a Drosophila model of PD [19].…”