PPARδ Activation Rescues Pancreatic β-Cell Line INS-1E from Palmitate-Induced Endoplasmic Reticulum Stress through Enhanced Fatty Acid Oxidation

One of the key factors responsible for the development of type 2 diabetes is the loss of functional pancreatic beta cells. This occurs due to a chronic exposure to a high fatty acid environment. ER stress is caused by an accumulation of irreversible misfold or unfold protein: these trigger the death of functional pancreatic beta cells. PPAR delta is an orphan nuclear receptor. It plays a pivotal role in regulating the metabolism of dietary lipids and fats. However, the correlation between PPAR delta of fatty acids and ER stress of pancreatic beta cells is not quite clear till date. Here, we show that PPAR delta attenuates palmitate-induced ER stress of pancreatic beta cells. On the other hand, PPAR delta agonist inhibits both abnormal changes in ER structure and activation of signaling cascade, which is downstream ER stress. Further, we illustrate that PPAR delta attenuates palmitate-induced ER stress by promoting fatty acid oxidation through treatment with etomoxir, an inhibitor of fatty acid oxidation. It dramatically abolishes PPAR delta-mediated inhibition of ER stress. Finally, we show that PPAR delta could protect pancreatic beta cells from palmitate-induced cell death and dysfunction of insulin secretion. Our work elucidates the protective effect of PPAR delta on the fatty-acid-induced toxicity of pancreatic beta cells.