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  • Title: Sirt3 Deficiency Increased the Vulnerability of Pancreatic Beta Cells to Oxidative Stress-Induced Dysfunction.
    Author: Zhou Y, Chung ACK, Fan R, Lee HM, Xu G, Tomlinson B, Chan JCN, Kong APS.
    Journal: Antioxid Redox Signal; 2017 Nov 01; 27(13):962-976. PubMed ID: 28375738.
    Abstract:
    AIMS: Hyperlipidemia-induced oxidative stress is considered to be one of the main pathogenic factors that contribute to pancreatic beta cell dysfunction in the development of type 2 diabetes (T2D). Sirtuin 3 (Sirt3) is abundantly expressed in the mitochondria as an NAD+-dependent deacetylase and regulates mitochondrial adaptive responses to oxidative stress. We examined the antioxidant defense mechanism of Sirt3 in pancreatic beta cells in the context of hyperlipidemia. RESULTS: Chronic high-fat diet (HFD) feeding caused elevated oxidative stress accompanied by reduced Sirt3 expression in the pancreatic beta cells of wild-type mice. Primary pancreatic islets of Sirt3 knockout (KO) mice and murine pancreatic MIN6 cells with downregulated Sirt3 expression showed increased superoxide dismutase 2 (SOD2) acetylation and reduced glucose-stimulated insulin secretion and glucose-stimulated adenosine triphosphate (ATP) generation. Moreover, Sirt3 deficiency sensitized the pancreatic islets and MIN6 cells to palmitate- and H2O2-induced beta cell dysfunction linked with aggravated c-Jun N-terminal kinase phosphorylation and cleaved caspase-3 expression. These negative effects were reversed by antioxidant chemical treatment or restoration of Sirt3 in KO islets. Finally, overexpression of Sirt3 in MIN6 cells partially rescued palmitate-induced reactive oxygen species generation, pancreatic and duodenal homeobox-1 (Pdx-1) nucleo-cytoplasmic translocation, and beta cell dysfunction. INNOVATION: We present that Sirt3 expression protected pancreatic beta cells from lipotoxicity by antagonizing oxidative stress-induced cell damage. CONCLUSION: These results suggest that Sirt3 may be a target for amelioration of beta cell dysfunction due to obesity and T2D. Antioxid. Redox Signal. 27, 962-976.
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