title: Sirt3 Deficiency Increased the Vulnerability of Pancreatic Beta Cells to Oxidative Stress-Induced Dysfunction.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  We present that Sirt3 expression protected pancreatic beta cells from lipotoxicity by antagonizing oxidative stress-induced cell damage.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 1 Department of Medicine and Therapeutics, The Chinese University of Hong Kong , Prince of Wales Hospital, Hong Kong, Hong Kong .|2 Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong , Prince of Wales Hospital, Hong Kong, Hong Kong .|3 Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong , Prince of Wales Hospital, Hong Kong, Hong Kong .
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: 1 Department of Medicine and Therapeutics, The Chinese University of Hong Kong , Prince of Wales Hospital, Hong Kong, Hong Kong .|3 Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong , Prince of Wales Hospital, Hong Kong, Hong Kong .|4 Partner State Key Laboratory of Environmental and Biological Analysis and Department of Chemistry, The Hong Kong Baptist University , Hong Kong, Hong Kong .
authors.forename: Arthur C K
authors.initials: ACK
authors.lastname: Chung
authors.affiliation: 5 Department of Biosciences and Nutrition, Karolinska Institute , Stockholm, Sweden .
authors.forename: Rongrong
authors.initials: R
authors.lastname: Fan
authors.affiliation: 1 Department of Medicine and Therapeutics, The Chinese University of Hong Kong , Prince of Wales Hospital, Hong Kong, Hong Kong .|2 Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong , Prince of Wales Hospital, Hong Kong, Hong Kong .|3 Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong , Prince of Wales Hospital, Hong Kong, Hong Kong .
authors.forename: Heung Man
authors.initials: HM
authors.lastname: Lee
authors.affiliation: 1 Department of Medicine and Therapeutics, The Chinese University of Hong Kong , Prince of Wales Hospital, Hong Kong, Hong Kong .|3 Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong , Prince of Wales Hospital, Hong Kong, Hong Kong .|6 School of Chinese Medicine, The Hong Kong Baptist University , Hong Kong, Hong Kong .
authors.forename: Gang
authors.initials: G
authors.lastname: Xu
authors.affiliation: 1 Department of Medicine and Therapeutics, The Chinese University of Hong Kong , Prince of Wales Hospital, Hong Kong, Hong Kong .
authors.forename: Brian
authors.initials: B
authors.lastname: Tomlinson
authors.affiliation: 1 Department of Medicine and Therapeutics, The Chinese University of Hong Kong , Prince of Wales Hospital, Hong Kong, Hong Kong .|2 Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong , Prince of Wales Hospital, Hong Kong, Hong Kong .|3 Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong , Prince of Wales Hospital, Hong Kong, Hong Kong .
authors.forename: Juliana C N
authors.initials: JCN
authors.lastname: Chan
authors.affiliation: 1 Department of Medicine and Therapeutics, The Chinese University of Hong Kong , Prince of Wales Hospital, Hong Kong, Hong Kong .|2 Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong , Prince of Wales Hospital, Hong Kong, Hong Kong .|3 Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong , Prince of Wales Hospital, Hong Kong, Hong Kong .
authors.forename: Alice P S
authors.initials: APS
authors.lastname: Kong
mesh_terms: D000107:Acetylation; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects*; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D005947:Glucose / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D006949:Hyperlipidemias / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018384:Oxidative Stress; D010168:Palmitates / Q000009:adverse effects; D056566:Sirtuin 3 / Q000235:genetics* / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D000099156:Superoxide Dismutase 2
chemical_list: D000255:Adenosine Triphosphate; D005947:Glucose; D006861:Hydrogen Peroxide; D007328:Insulin; D010168:Palmitates; D056566:Sirtuin 3; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2; C525046:Sirt3 protein, mouse
keywords: Sirt3; high fat diet; oxidative stress; pancreatic beta cell