This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sun, Y. Articles by Gao, L. Search for Related Content PubMed PubMed Citation Articles by Sun, Y. Articles by Gao, L.

Peroxisome Proliferator-Activated Receptor- Regulates the Expression of Pancreatic/Duodenal Homeobox-1 in Rat Insulinoma (INS-1) Cells and Ameliorates Glucose-Induced Insulin Secretion Impaired by Palmitate

Departments of Endocrinology (Y.S., L.Z., W.H., M.R., J.Z.) and Central Laboratory (L.W., H.G., W.X., L.G.), Shandong Provincial Hospital, Shandong University, Jinan, Shandong Province, China 250021; Rolf Luft Center for Diabetes Research (H.F.G.), Department of Molecular Medicine and Surgery, Karolinska Institute, Karolinska University Hospital (Solna), SE-141 86 Stockholm, Sweden; Department of Neurology (B.G.), Case Western Reserve University, Cleveland, Ohio 44106; and Department of Pharmacology (F.W.), Shandong University of Traditional Chinese Medicine, Shandong, China 250021

Address all correspondence and requests for reprints to: Jiajun Zhao and Ling Gao, 324 Jing 5 Road, Department of Endocrinology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong Province, China 250021. E-mail: jjzhao{at}medmail.comcn and lxg52{at}cwru.edu, respectively.

Both peroxisome proliferator-activated receptor- (PPAR) and pancreatic/duodenal homeobox-1 (PDX-1) have been reported to be associated with glucose-stimulated insulin secretion (GSIS), but the relationship between PPAR and PDX-1 is not yet fully understood. In the present study, we tested the hypothesis that PPAR regulates the expression of PDX-1 in β-cells. Isolated pancreatic islets from Wistar rats and rat pancreatic insulinoma (INS-1) β-cells were cultured in media supplemented with and without 0.2 or 0.4 mM palmitate, and treated with and without a PPAR agonist (fenofibrate) or PPAR antagonist (MK886). Results indicated that treatment with fenofibrate significantly enhanced PPAR mRNA and protein expression in cells cultured with elevated palmitate concentrations compared with cells that did not receive fenofibrate treatment. In turn, this enhanced expression led to an increase in PDX-1 mRNA and nuclear protein, as well as DNA binding activity of PDX-1 with the insulin promoter. Accordingly, the expression of the PDX-1 downstream targets, insulin and glucose transporter-2, increased, resulting in increased intracellular insulin content and GSIS. Treatment with MK886 inhibited expression of PPAR, blocking PPAR-regulated PDX-1 expression, and the downstream transcription events of PDX-1. EMSA revealed that nuclear protein might bind with the peroxisome proliferator response element sequence located in the PDX-1 promoter. Collectively, these results demonstrate a regulatory relationship between PPAR and PDX-1 in INS-1 cells. Furthermore, PPAR activation potentiates GSIS under elevated palmitate conditions possibly via up-regulation of PDX-1. Our findings have potential clinical implications for the use of PPAR agonists in the treatment of type 2 diabetes.