期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 294, 期 16, 页码 6612-6620出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA118.007102
关键词
lipoxygenase pathway; pancreatic islet; diabetes; reactive oxygen species (ROS); oxidative stress
资金
- NIDDK, National Institutes of Health [R01 DK105588, P30 DK097512, K01 DK102492, R03 DK115990]
In type 1 diabetes, an autoimmune event increases oxidative stress in islet cells, giving rise to cellular dysfunction and apoptosis. Lipoxygenases are enzymes that catalyze the oxygenation of polyunsaturated fatty acids that can form lipid metabolites involved in several biological functions, including oxidative stress. 12-Lipoxygenase and 12/15-lipoxygenase are related but distinct enzymes that are expressed in pancreatic islets, but their relative contributions to oxidative stress in these regions are still being elucidated. In this study, we used mice with global genetic deletion of the genes encoding 12-lipoxygenase (arachidonate 12-lipoxygenase, 12S type [Alox12]) or 12/15-lipoxygenase (Alox15) to compare the influence of each gene deletion on cell function and survival in response to the cell toxin streptozotocin. Alox12(-/-) mice exhibited greater impairment in glucose tolerance following streptozotocin exposure than WT mice, whereas Alox15(-/-) mice were protected against dysglycemia. These changes were accompanied by evidence of islet oxidative stress in Alox12(-/-) mice and reduced oxidative stress in Alox15(-/-) mice, consistent with alterations in the expression of the antioxidant response enzymes in islets from these mice. Additionally, islets from Alox12(-/-) mice displayed a compensatory increase in Alox15 gene expression, and treatment of these mice with the 12/15-lipoxygenase inhibitor ML-351 rescued the dysglycemic phenotype. Collectively, these results indicate that Alox12 loss activates a compensatory increase in Alox15 that sensitizes mouse cells to oxidative stress.
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