SIRT2 Deficiency Exacerbates Hepatic Steatosis via a Putative Role of the ER Stress Pathway

Abstract

Nonalcoholic fatty liver disease (NAFLD), a condition strongly associated with obesity and insulin resistance, is characterized by hepatic lipid accumulation and activation of the endoplasmic reticulum (ER) stress response. The sirtuin 2 (SIRT2) protein deacetylase is emerging as a new player in metabolic homeostasis, but its role in the development of hepatic steatosis and its link with ER stress activation remains unknown. SIRT2-knockout (SIRT2-KO) and wild-type mice were fed either a control or a high-fat diet (HFD) for 4 weeks. Genetic manipulation of SIRT2 levels was performed in human hepatic cells. Although apparently normal under a control diet, SIRT2-KO mice showed accelerated body weight gain and adiposity on a HFD, accompanied by severe insulin resistance. Importantly, SIRT2-KO mice exhibited worsened hepatic steatosis independently from diet, consistent with upregulated gene expression of lipogenic enzymes and increased expression of ER stress markers. Exposure of hepatic cells to palmitate induced lipid accumulation, increased ER stress, and decreased SIRT2 expression. Moreover, SIRT2-silenced cells showed enhanced lipid accumulation and ER stress activation under basal conditions, whereas SIRT2 overexpression abrogated palmitate-induced lipid deposition and ER stress activation. Our findings reveal a role for SIRT2 in the regulation of hepatic lipid homeostasis, potentially through the ER stress response, suggesting that SIRT2 activation might constitute a therapeutic strategy against obesity and its metabolic complications.

AICAR Ameliorates Non-Alcoholic Fatty Liver Disease via Modulation of the HGF/NF-κB/SNARK Signaling Pathway and Restores Mitochondrial and Endoplasmic Reticular Impairments in High-Fat Diet-Fed Rats

“…In the present study, AICAR reduced hepatic HIF1-α protein expression in HFD-fed rats. HIF-1α represses SIRT2 expression and promotes obesity, while SIRT2 knock-out animals develop obesity, hepatic steatosis, and ER stress [ 2 , 22 ]. This is relevant to our observed low SIRT2 expressions in in vivo and in vitro steatosis, which were upregulated by AICAR independent of AMPK.…”

“…Non-alcoholic fatty liver disease (NAFLD) is a global chronic metabolic disorder characterized by triacylglycerol (TAG) accumulation in the liver with minute or no alcohol consumption; it is commonly associated with metabolic risk factors, including obesity, dyslipidemia, insulin resistance, and diabetes mellitus [ 1 , 2 ]. NAFLD is highly prevalent worldwide, with higher rates in the Middle East (32%) [ 1 , 3 , 4 ].…”

“…The combined action of the PERK/IRE-1α/ATF6 pathways leads to either recovery from ER stress or progression to hepatic steatosis and steatohepatitis. Targeting these pathways has been proven to halt NAFLD progression [ 2 , 11 , 12 ].…”

“…To prevent and treat NAFLD, different drugs are currently used (or are in clinical trials) to alleviate hepatic mitochondrial dysfunction. Drugs that increase cellular NAD + and activate Sirtuin 2 (SIRT2), an NAD + -dependent deacetylase, have improved mitochondrial dysfunction [ 2 , 22 ]. The AMP-activated protein kinase (AMPK) activators such as metformin are widely used in NAFLD management, but the exact mechanism of action remains largely ill-defined [ 1 ].…”

Endoplasmic reticulum stress-mediated cell death in liver injury

“… [ 130 ] HFD/Palmitate SIRT2 (−) C57BL/6 mice Exacerbating ERS, causing lipid deposition, leading to obesity. [ 131 ] KO SIDT2 (−) Mice Activate ERS, cause lipid deposition, lead to hepatic steatosis. [ 132 ] Sorafenib STAT3 (−) Huh7, Hep3B & C57BL/6 J mice Exacerbating ERS and inducing cell death.…”