title: Overexpression of glutathione peroxidase 4 prevents β-cell dysfunction induced by prolonged elevation of lipids in vivo.
abstract: We have shown that oxidative stress is a mechanism of free fatty acid (FFA)-induced β-cell dysfunction. Unsaturated fatty acids in membranes, including plasma and mitochondrial membranes, are substrates for lipid peroxidation, and lipid peroxidation products are known to cause impaired insulin secretion. Therefore, we hypothesized that mice overexpressing glutathione peroxidase-4 (GPx4), an enzyme that specifically reduces lipid peroxides, are protected from fat-induced β-cell dysfunction. GPx4-overexpressing mice and their wild-type littermate controls were infused intravenously with saline or oleate for 48 h, after which reactive oxygen species (ROS) were imaged, using dihydrodichlorofluorescein diacetate in isolated islets, and β-cell function was assessed ex vivo in isolated islets and in vivo during hyperglycemic clamps. Forty-eight-hour FFA elevation in wild-type mice increased ROS and the lipid peroxidation product malondialdehyde and impaired β-cell function ex vivo in isolated islets and in vivo, as assessed by decreased disposition index. Also, islets of wild-type mice exposed to oleate for 48 h had increased ROS and lipid peroxides and decreased β-cell function. In contrast, GPx4-overexpressing mice showed no FFA-induced increase in ROS and lipid peroxidation and were protected from the FFA-induced impairment of β-cell function assessed in vitro, ex vivo and in vivo. These results implicate lipid peroxidation in FFA-induced β-cell dysfunction.
authors.affiliation: Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Khajag
authors.initials: K
authors.lastname: Koulajian
authors.forename: Alexander
authors.initials: A
authors.lastname: Ivovic
authors.forename: Kaitai
authors.initials: K
authors.lastname: Ye
authors.forename: Tejas
authors.initials: T
authors.lastname: Desai
authors.forename: Anu
authors.initials: A
authors.lastname: Shah
authors.forename: I George
authors.initials: IG
authors.lastname: Fantus
authors.forename: Qitao
authors.initials: Q
authors.lastname: Ran
authors.forename: Adria
authors.initials: A
authors.lastname: Giacca
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology; D005230:Fatty Acids, Nonesterified / Q000633:toxicity*; D015309:Glucose Clamp Technique; D005979:Glutathione Peroxidase / Q000096:biosynthesis* / Q000502:physiology*; D007262:Infusions, Intravenous; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D007515:Islets of Langerhans / Q000201:enzymology / Q000502:physiology; D015227:Lipid Peroxidation / Q000502:physiology; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009829:Oleic Acids / Q000633:toxicity; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D017382:Reactive Oxygen Species / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D008563:Membrane Lipids; D009829:Oleic Acids; D017382:Reactive Oxygen Species; D017392:Thiobarbituric Acid Reactive Substances; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase
keywords: glutathione peroxidase 4; in vivo; lipid peroxide; lipotoxicity; oxidative stress; β-cell dysfunction