ChREBP Mediates Glucose Repression of Peroxisome Proliferator-activated Receptor α Expression in Pancreatic β-Cells

Chronic exposure to elevated levels of glucose and fatty acids leads to dysfunction of pancreatic beta-cells by mechanisms that are only partly understood. The transcription factor peroxisome proliferator-activated receptor alpha (PPAR alpha) is an important regulator of genes involved in fatty acid metabolism and has been shown to protect against lipid-induced beta-cell dysfunction. We and others have previously shown that expression of the PPAR alpha gene in beta-cells is rapidly repressed by glucose. Here we show that the PPAR alpha gene is transcribed from five alternative transcription start sites, resulting in three alternative first exons that are spliced to exon 2. Expression of all PPAR alpha transcripts is repressed by glucose both in insulinoma cells and in isolated pancreatic islets. The observation that the dynamics of glucose repression of PPAR alpha transcription are very similar to those of glucose activation of target genes by the carbohydrate response element-binding protein (ChREBP) prompted us to investigate the potential role of ChREBP in the regulation of PPAR alpha expression. We show that a constitutively active ChREBP lacking the N-terminal domain efficiently represses PPAR alpha expression in insulinoma cells and in rodent and human islets. In addition, we demonstrate that siRNA-mediated knockdown of ChREBP abrogates glucose repression of PPAR alpha expression as well as induction of well established ChREBP target genes in insulinoma cells. In conclusion, this work shows that ChREBP is a critical and direct mediator of glucose repression of PPAR alpha gene expression in pancreatic beta-cells, suggesting that ChREBP may be important for glucose suppression of the fatty acid oxidation capacity of beta-cells.