title: Lipotoxic Stress Induces Pancreatic β-Cell Apoptosis through Modulation of Bcl-2 Proteins by the Ubiquitin-Proteasome System.
abstract: Pancreatic β-cell loss induced by saturated free fatty acids (FFAs) is believed to contribute to type 2 diabetes. Previous studies have shown induction of endoplasmic reticulum (ER) stress, increased ubiquitinated proteins, and deregulation of the Bcl-2 family in the pancreas of type 2 diabetic patients. However, the precise mechanism of β-cell death remains unknown. In the present study we demonstrate that the FFA palmitate blocks the ubiquitin-proteasome system (UPS) and causes apoptosis through induction of ER stress and deregulation of Bcl-2 proteins. We found that palmitate and the proteasome inhibitor MG132 induced ER stress in β-cells, resulting in decreased expression of the prosurvival proteins Bcl-2, Mcl-1, and Bcl-XL, and upregulation of the prodeath BH3-only protein PUMA. On the other hand, pharmacological activation of the UPS by sulforaphane ameliorated ER stress, upregulated prosurvival Bcl-2 proteins, and protected β-cells from FFA-induced cell death. Furthermore, transgenic overexpression of Bcl-2 protected islets from FFA-induced cell death in vitro and improved glucose-induced insulin secretion in vivo. Together our results suggest that targeting the UPS and Bcl-2 protein expression may be a valuable strategy to prevent β-cell demise in type 2 diabetes.
authors.affiliation: St Vincent's Institute of Medical Research, Melbourne, VIC 3065, Australia.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Litwak
authors.affiliation: St Vincent's Institute of Medical Research, Melbourne, VIC 3065, Australia ; Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Melbourne, VIC 3065, Australia.
authors.forename: Jibran A
authors.initials: JA
authors.lastname: Wali
authors.affiliation: St Vincent's Institute of Medical Research, Melbourne, VIC 3065, Australia ; Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Melbourne, VIC 3065, Australia.
authors.forename: Evan G
authors.initials: EG
authors.lastname: Pappas
authors.affiliation: St Vincent's Institute of Medical Research, Melbourne, VIC 3065, Australia ; Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Melbourne, VIC 3065, Australia.
authors.forename: Hamdi
authors.initials: H
authors.lastname: Saadi
authors.affiliation: St Vincent's Institute of Medical Research, Melbourne, VIC 3065, Australia ; Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Melbourne, VIC 3065, Australia.
authors.forename: William J
authors.initials: WJ
authors.lastname: Stanley
authors.affiliation: St Vincent's Institute of Medical Research, Melbourne, VIC 3065, Australia ; Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Melbourne, VIC 3065, Australia.
authors.forename: L Chitra
authors.initials: LC
authors.lastname: Varanasi
authors.affiliation: St Vincent's Institute of Medical Research, Melbourne, VIC 3065, Australia ; Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Melbourne, VIC 3065, Australia.
authors.forename: Thomas W H
authors.initials: TW
authors.lastname: Kay
authors.affiliation: St Vincent's Institute of Medical Research, Melbourne, VIC 3065, Australia ; Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Melbourne, VIC 3065, Australia.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Thomas
authors.affiliation: St Vincent's Institute of Medical Research, Melbourne, VIC 3065, Australia ; Department of Medicine, St. Vincent's Hospital, The University of Melbourne, Melbourne, VIC 3065, Australia.
authors.forename: Esteban N
authors.initials: EN
authors.lastname: Gurzov
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D019308:Palmitic Acid / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D007976:Leupeptins; D019253:Proto-Oncogene Proteins c-bcl-2; D025801:Ubiquitin; D019308:Palmitic Acid; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde