title: Exendin-4 inhibits glucolipotoxic ER stress in pancreatic β cells via regulation of SREBP1c and C/EBPβ transcription factors.
abstract: Prolonged exposure to high glucose (HG) and palmitate (PA) results in increased ER stress and subsequently induces β-cell apoptosis. Exendin-4, a glucagon-like peptide-1 agonist, is known to protect β 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 β-cell apoptosis. Exendin-4 treatment protected INS-1 β cells from apoptosis in response to HG/PA (25 mM glucose+400 μM PA). HG/PA treatment increased cleaved caspase-3 and induced ER stress maker proteins such as PERK (EIF2AK3), ATF6, and phosphorylated forms of PERK, eIF2α, IRE1α (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/EBPβ (CEBPB) protein and its nuclear translocation. Exendin-4 treatment attenuated this increase. Knockdown of SREBP1c reduced the activation of C/EBPβ 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/EBPβ, which, in turn, may reduce glucolipotoxicity-induced ER stress and β-cell apoptosis.
authors.affiliation: Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 7-45 Songdo-dong, Yeonsu-ku, Incheon, Korea.
authors.forename: Yoon Sin
authors.initials: YS
authors.lastname: Oh
authors.forename: Youn-Jung
authors.initials: YJ
authors.lastname: Lee
authors.forename: Yup
authors.initials: Y
authors.lastname: Kang
authors.forename: Jaeseok
authors.initials: J
authors.lastname: Han
authors.forename: Oh-Kyung
authors.initials: OK
authors.lastname: Lim
authors.forename: Hee-Sook
authors.initials: HS
authors.lastname: Jun
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D000077270:Exenatide; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D014688:Venoms / Q000494:pharmacology*
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D010455:Peptides; D051780:Sterol Regulatory Element Binding Protein 1; D014688:Venoms; D000077270:Exenatide; D053148:Caspase 3