Peroxisome proliferator-activated receptor-alpha regulates the expression of pancreatic/duodenal homeobox-1 in rat insulinoma (INS-1) cells and ameliorates glucose-induced insulin secretion impaired by palmitate

Abstract

Both peroxisome proliferator-activated receptor-alpha (PPARalpha) and pancreatic/duodenal homeobox-1 (PDX-1) have been reported to be associated with glucose-stimulated insulin secretion (GSIS), but the relationship between PPARalpha and PDX-1 is not yet fully understood. In the present study, we tested the hypothesis that PPARalpha regulates the expression of PDX-1 in beta-cells. Isolated pancreatic islets from Wistar rats and rat pancreatic insulinoma (INS-1) beta-cells were cultured in media supplemented with and without 0.2 or 0.4 mm palmitate, and treated with and without a PPARalpha agonist (fenofibrate) or PPARalpha antagonist (MK886). Results indicated that treatment with fenofibrate significantly enhanced PPARalpha 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 PPARalpha, blocking PPARalpha-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 PPARalpha and PDX-1 in INS-1 cells. Furthermore, PPARalpha activation potentiates GSIS under elevated palmitate conditions possibly via up-regulation of PDX-1. Our findings have potential clinical implications for the use of PPARalpha agonists in the treatment of type 2 diabetes.