Exendin-4 inhibits glucolipotoxic ER stress in pancreatic β cells via regulation of SREBP1c and C/EBPβ transcription factors

Prolonged exposure to high glucose (HG) and palmitate (PA) results in increased ER stress and subsequently induces beta-cell apoptosis. Exendin-4, a glucagon-like peptide-1 agonist, is known to protect beta cells from toxicity induced by cytokines, HG, or fatty acids by reducing ER stress. However, the detailed molecular mechanisms for this protective effect are still not known. In this study, we investigated the role of exendin-4 in the inhibition of glucolipotoxicity-induced ER stress and beta-cell apoptosis. Exendin-4 treatment protected INS-1 beta cells from apoptosis in response to HG/PA (25 mM glucose+400 mu M PA). HG/PA treatment increased cleaved caspase-3 and induced ER stress maker proteins such as PERK (EIF2AK3), ATF6, and phosphorylated forms of PERK, eIF2 alpha, IRE1 alpha (ERN1), and JNK (MAPK8), and these increases were significantly inhibited by exendin-4 treatment. HG/PA treatment of INS-1 cells increased SREBP1 (SREBF1) protein and induced its nuclear translocation and subsequently increased C/EBP beta (CEBPB) protein and its nuclear translocation. Exendin-4 treatment attenuated this increase. Knockdown of SREBP1c reduced the activation of C/EBP beta and also blocked the expression of ER stress markers induced by HG/PA treatment. Our results indicate that exendin-4 inhibits the activation of SREBP1c and C/EBP beta, which, in turn, may reduce glucolipotoxicity-induced ER stress and beta-cell apoptosis.