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Oleate disrupts cAMP signaling, contributing to potent stimulation of pancreatic beta-cell autophagy


Autophagy is critical for maintaining cellular function via clearance of excess nutrients and damaged organelles. In pancreatic beta-cells, it helps counter the endoplasmic reticulum (ER) stress that impairs insulin secretory capacity during Type 2 diabetes. Chronic exposure of beta-cells to saturated fatty acids (FAs) such as palmitate stimulates ER stress and modulates autophagy, but the effects of unsaturated FAs such as oleate, which are also elevated during obesity, are less well understood. We therefore treated MIN6 cells and mouse islets for 8-48 h with either palmitate or oleate, and then monitored autophagic flux, signaling pathways, lysosomal biology, and phospholipid profiles. Compared with palmitate, oleate more effectively stimulated both autophagic flux and clearance of autophagosomes. The flux stimulation occurred independently of ER stress, nutrient-sensing (mTOR) and signaling pathways (protein kinases A, C, and D). Instead the mechanism involved the exchange factor directly activated by cAMP 2 (EPAC2). Oleate reduced cellular cAMP, and its effects on autophagic flux were reproduced or inhibited, respectively, by Epac2 knockdown or activation. Oleate also increased lysosomal acidity and increased phospholipid saturation, consistent with improved autophagosomal fusion with lysosomes. We conclude that a potent stimulation of autophagy might help explain the known benefits of unsaturated FAs in countering the toxicity of saturated FAs in beta-cells during obesity and lipid loading.

Type Journal
ISBN 1083-351X (Electronic) 0021-9258 (Linking)
Authors Chu, K. Y.; O'Reilly, L.; Mellet, N.; Meikle, P. J.; Bartley, C.; Biden, T. J.
Responsible Garvan Author Prof Trevor Biden
Published Date 2019-01-25
Published Volume 294
Published Issue 4
Published Pages 1218-1229
Status Published in-print
DOI 10.1074/jbc.RA118.004833
URL link to publisher's version
OpenAccess link to author's accepted manuscript version