Activation of PPARdelta up-regulates fatty acid oxidation and energy uncoupling genes of mitochondria and reduces palmitate-induced apoptosis in pancreatic beta-cells.
Recent evidence indicates that decreased oxidative capacity, lipotoxicity, and mitochondrial aberrations contribute to the development of insulin resistance and type 2 diabetes. The goal of this study was to investigate the effects of peroxisome proliferator-activated receptor delta (PPARdelta) activation on lipid oxidation, mitochondrial function, and insulin secretion in pancreatic beta-cells. After HIT-T15 cells (a beta-cell line) were exposed to high concentrations of palmitate and GW501516 (GW; a selective agonist of PPARdelta), we found that administration of GW increased the expression of PPARdelta mRNA. GW-induced activation of PPARdelta up-regulated carnitine palmitoyltransferase 1 (CPT1), long-chain acyl-CoA dehydrogenase (LCAD), pyruvate dehydrogenase kinase 4 (PDK4), and uncoupling protein 2 (UCP2); alleviated mitochondrial swelling; attenuated apoptosis; and reduced basal insulin secretion induced by increased palmitate in HIT cells. These results suggest that activation of PPARdelta plays an important role in protecting pancreatic beta-cells against aberrations caused by lipotoxicity in metabolic syndrome and diabetes.
Wan
Jun
J
Department of Endocrinology, West China Hospital of Sichuan University, 37 Guoxue Lane, Chengdu, Sichuan 610041, China.
Jiang
Li
L
Lü
Qingguo
Q
Ke
Linqiu
L
Li
Xiaoyu
X
Tong
Nanwei
N
D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000235:genetics; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics; D002460:Cell Line; D006224:Cricetinae; D005227:Fatty Acids / Q000378:metabolism*; D005786:Gene Expression Regulation; D050259:Genes, Mitochondrial; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D007473:Ion Channels / Q000235:genetics; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics; D010084:Oxidation-Reduction; D047494:PPAR delta / Q000819:agonists / Q000378:metabolism*; D019308:Palmitic Acid / Q000494:pharmacology; D011494:Protein Kinases / Q000235:genetics; D013844:Thiazoles / Q000494:pharmacology; D000071246:Uncoupling Protein 2; D015854:Up-Regulation
D005227:Fatty Acids; C425931:GW 501516; D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; D047494:PPAR delta; D013844:Thiazoles; D000071246:Uncoupling Protein 2; D019308:Palmitic Acid; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D002334:Carnitine O-Palmitoyltransferase; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4