Sirt3 Deficiency Increased the Vulnerability of Pancreatic Beta Cells to Oxidative Stress-Induced Dysfunction
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AbstractAims: 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) nucleocytoplasmic 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.
Acceptance Date13/02/2017
All Author(s) ListZhou Y, Chung AC, Fan R, Lee HM, Xu G, Tomlinson B, Chan JC, Kong AP
Journal nameAntioxidants and Redox Signaling
Year2017
Month11
Day1
Volume Number27
Issue Number13
Pages962 - 976
ISSN1523-0864
eISSN1557-7716
LanguagesEnglish-United States

Last updated on 2020-27-06 at 00:25