Sirt3 Deficiency Increased the Vulnerability of Pancreatic Beta Cells to Oxidative Stress-Induced Dysfunction

Yu Zhou, Chi Kong Arthur CHUNG, Rongrong Fan, Heung Man Lee, Gang XU, Brian Tomlinson, Juliana C.N. Chan, Alice P.S. Kong*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)962-976
Number of pages15
JournalAntioxidants and Redox Signaling
Volume27
Issue number13
DOIs
Publication statusPublished - 1 Nov 2017

Scopus Subject Areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

User-Defined Keywords

  • High fat diet
  • Oxidative stress
  • Pancreatic beta cell
  • Sirt3

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