title: Activation of PPARδ up-regulates the expression of insulin gene transcription factor MafA and ameliorates glucose-induced insulin secretion impaired by palmitate.
abstract: PPARδ, a member of the peroxisome proliferator-activated receptor superfamily, plays a key role in the transcriptional regulation of genes involved in cellular lipid and energy metabolism. Therefore, PPARδ may represent a new target for the treatment of obesity, hyperlipidemia, and type 2 diabetes. MafA is a β-cell-specific and glucose-regulated transcriptional activator for insulin gene expression and plays a crucial role in pancreas development, β-cell differentiation as well as maintenance of β-cell function. However, little is known about how PPARδ regulates MafA and ameliorates glucose-stimulated insulin secretion impaired by free fatty acids (FFA). In the present study, we evaluated the basal insulin secretion (BIS), glucose-stimulated insulin secretion (GSIS), and insulin secretion index (ISI) of INS-1E cells that were cultured in media supplemented with or without 0.5 mM palmitate and treated with or without a PPARδ agonist (GW501516) or PPARδ siRNA. The expression of MafA, glucose transportor-2 (GLUT2), and insulin was found to be up-regulated in cells treated with GW501516. Finally, analysis of the level of JNK phosphorylation revealed that activated PPARδ could inhibit the activation of JNK and increase the expression of MafA. Accordingly, the insulin secretion dysfunction in lipotoxic INS-1E cells was improved. Collectively, these results demonstrate that activation of PPARδ improves insulin secretion impaired by palmitate and plays a role in the JNK-MafA-GLUT2 pathway.
authors.affiliation: Division of Endocrinology, West China Hospital of Sichuan University, 37 Guoxuexiang, Chengdu 610041, Sichuan, China.
authors.forename: Mingming
authors.initials: M
authors.lastname: Cao
authors.forename: Yang
authors.initials: Y
authors.lastname: Long
authors.forename: Yuzhen
authors.initials: Y
authors.lastname: Tong
authors.forename: Jun
authors.initials: J
authors.lastname: Wan
authors.forename: Nanwei
authors.initials: N
authors.lastname: Tong
mesh_terms: D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000502:physiology*; D051273:Glucose Transporter Type 2 / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051256:Oncogene Protein v-maf / Q000235:genetics* / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D010168:Palmitates / Q000494:pharmacology*; D010766:Phosphorylation; D034622:RNA Interference; D051381:Rats; D015854:Up-Regulation
chemical_list: D005230:Fatty Acids, Nonesterified; D051273:Glucose Transporter Type 2; D007328:Insulin; D051256:Oncogene Protein v-maf; D047495:PPAR gamma; D010168:Palmitates; C495683:Slc2a2 protein, rat; D048031:JNK Mitogen-Activated Protein Kinases; D005947:Glucose