title: Protective Role of PPARdelta in Lipoapoptosis of Pancreatic β Cells.
abstract: Lipoapoptosis plays an important role in the pathogenesis of type 2 diabetes. Peroxisome proliferator-activated receptor delta (PPARdelta), a vital regulator of glucose and lipid metabolism, may reduce fatty acid-induced pancreatic β cell lipotoxicity in diabetes. However, the detailed molecular mechanisms underlying this process are not fully understood. In this study, we investigated the effect of activation of PPARdelta on palmitate-induced β cell apoptosis, and we explored the potential mechanism of the antiapoptotic effect. The cell apoptosis was determined by DNA fragmentation analysis and Hoechst 33342 staining. The expressing of glucagon-like peptide-1 receptor (GLP-1R) in INS-1 cells was assessed by Western blotting, quantification of PCR, and was further confirmed by immunofluorescence staining. The potential of PPARdelta to interact with homologous PPRE in the GLP-1R gene was determined by Chromatin immunoprecipitation (ChIP). Our results showed that exposure of INS-1 cells to palmitate for 24 h caused a significant increase in cell apoptosis, which was inhibited by GW501516. PPARdelta exerted anti-apoptotic effects in pancreatic β cells via the PI3 K/PKB/FoxO1 signaling pathway. Moreover, PPARdelta upregulated the GLP-1R expression under lipotoxic conditions. The ChIP assay revealed a direct binding of PPARdelta to a noncanonical PPRE motif of the GLP-1R gene in INS-1 cells. Our study suggested that the anti-apoptotic action of PPARdelta may involve its transcriptional regulation of GLP-1R and PI3 K/PKB/FoxO1 signaling. GW501516 and possible other GW-based strategies may confer additional benefit beyond improved glycemic control.
authors.affiliation: Department of Diabetes, The Second Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China.|Department of Endocrinology, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Diabetes, The Second Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China.
authors.forename: Jiangong
authors.initials: J
authors.lastname: Ren
authors.affiliation: Department of Endocrinology, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China.
authors.forename: Yuzhen
authors.initials: Y
authors.lastname: Tong
authors.affiliation: Department of Diabetes, The Second Hospital of Lanzhou University, Lanzhou, 730030, Gansu, China.
authors.forename: Xuejian
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Endocrinology, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China.
authors.forename: Qingguo
authors.initials: Q
authors.lastname: Lv
authors.affiliation: Department of Endocrinology, West China Hospital of Sichuan University, Chengdu, 610041, Sichuan, China. buddyjun@hotmail.com.
authors.forename: Nanwei
authors.initials: N
authors.lastname: Tong
mesh_terms: D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism; D047494:PPAR delta / Q000378:metabolism*; D010168:Palmitates / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D047494:PPAR delta; D010168:Palmitates
keywords: Apoptosis; GLP-1R; PPARdelta; Palmitate; Pancreatic β cells