Hyperglycemic concentrations of glucose directly affect PPARα

Abstract

The pathophysiology of diabetes exhibits elevated glucose and long chain fatty acids (LCFA). Since LCFA are high affinity ligands for the peroxisome proliferator‐activated receptor alpha (PPARα), which regulates transcription of multiple genes in fatty acid and glucose metabolism, it was hypothesized that glucose might also serve in this role. Indeed, PPARα also functions as a high affinity glucose sensor, exhibiting high glucose sensitivity prior to any physical manifestation, such as autoglycation, seen much later in chronic exposure to high glucose. Circular dichroism, co‐immunoprecipitation, binding assays, and transactivation assays were utilized to examine the effects of hyperglycemic concentrations of glucose on PPARα. High glucose altered: (i) conformational of PPARα; (ii) lipid binding to PPARα; (iii) interaction of co‐factors, such as the liver fatty acid binding protein (L‐FABP), with PPARα; (iv) altered the nuclear distribution of a fluorescent LCFA—ligands bound and transported by L‐FABP; (v) increased PPARα transactivation, and (vi) hyperactivated PPARα in the presence of peroxisome proliferators. These data suggest that PPARα is an endogenous sensor not only of LCFA, but also glucose, and may be a drug target for glucose as well as LCFA regulated complications in diabetes. Supported in part by the NIH DK41402 (FS, ABK); DK066732 & DK77573 (HAH).