Platelet-type 12-lipoxygenase deletion provokes a compensatory 12/15-lipoxygenase increase that exacerbates oxidative stress in mouse islet β cells
Autor: | Raghavendra G. Mirmira, Abass M. Conteh, Swetha Nakshatri, Marimar Hernandez-Perez, Ryan M. Anderson, Amelia K. Linnemann, Sarah A. Tersey, Christopher A. Reissaus |
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Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
medicine.medical_specialty Naphthalenes Arachidonate 12-Lipoxygenase medicine.disease_cause Biochemistry Gene Expression Regulation Enzymologic Streptozocin Mice 03 medical and health sciences Lipoxygenase Insulin-Secreting Cells Internal medicine medicine Animals Arachidonate 15-Lipoxygenase Molecular Biology Mice Knockout geography geography.geographical_feature_category 030102 biochemistry & molecular biology biology Chemistry Pancreatic islets Isoxazoles Cell Biology Islet Streptozotocin Lipids ALOX15 Oxidative Stress 030104 developmental biology Endocrinology medicine.anatomical_structure ALOX12 Apoptosis biology.protein Gene Deletion Oxidative stress medicine.drug |
Zdroj: | Journal of Biological Chemistry. 294:6612-6620 |
ISSN: | 0021-9258 |
Popis: | In type 1 diabetes, an autoimmune event increases oxidative stress in islet β 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 β cell function and survival in response to the β 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 β cells to oxidative stress. |
Databáze: | OpenAIRE |
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