ER-resident antioxidative GPx7 and GPx8 enzyme isoforms protect insulin-secreting INS-1E β-cells against lipotoxicity by improving the ER antioxidative capacity
| Autor: | Anne Jörns, Stephan Lortz, Sigurd Lenzen, Edward Avezov, Ilir Mehmeti |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty medicine.medical_treatment Palmitic Acid Gene Expression Apoptosis 030209 endocrinology & metabolism Oxidative phosphorylation Biology Endoplasmic Reticulum Transfection medicine.disease_cause Biochemistry Cell Line 03 medical and health sciences 0302 clinical medicine Insulin-Secreting Cells Physiology (medical) Internal medicine medicine Animals Transgenes Glutathione Peroxidase Insulin Endoplasmic reticulum Hydrogen Peroxide Endoplasmic Reticulum Stress Rats Oxidative Stress Glucose 030104 developmental biology Endocrinology Peroxidases Lipotoxicity Catalase biology.protein Unfolded protein response Oxidative stress Plasmids |
| Zdroj: | Free Radical Biology and Medicine. 112:121-130 |
| ISSN: | 0891-5849 |
| Popis: | Increased circulating levels of saturated fatty acids (FFAs) and glucose are considered to be major mediators of β-cell dysfunction and death in T2DM. Although it has been proposed that endoplasmic reticulum (ER) and oxidative stress play a crucial role in gluco/lipotoxicity, their interplay and relative contribution to β-cell dysfunction and apoptosis has not been fully elucidated. In addition it is still unclear how palmitate - the physiologically most abundant long-chain saturated FFA - elicits ER stress and which immediate signals commit β-cells to apoptosis. To study the underlying mechanisms of palmitate-mediated ER stress and β-cell toxicity, we exploited the observation that the recently described ER-resident GPx7 and GPx8 are not expressed in rat β-cells. Expression of GPx7 or GPx8 attenuated FFAs-mediated H2O2 generation, ER stress, and apoptosis induction. These results could be confirmed by a H2O2-specific inactivating ER catalase, indicating that accumulation of H2O2 in the ER lumen is critical in FFA-induced ER stress. Furthermore, neither the expression of GPx7 nor of GPx8 increased insulin content or facilitated disulfide bond formation in insulin-secreting INS-1E cells. Hence, reduction of H2O2 by ER-GPx isoforms is not rate-limiting in oxidative protein folding in rat β-cells. These data suggest that FFA-mediated ER stress is partially dependent on oxidative stress and selective expression of GPx7 or GPx8 improves the ER antioxidative capacity of rat β-cells without compromising insulin production and the oxidative protein folding machinery. |
| Databáze: | OpenAIRE |
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