Glucose directly links to lipid metabolism through high affinity interaction with peroxisome proliferator-activated receptor α

The pathophysiology of diabetes is characterized not only by elevated glucose but also elevated long chain fatty acid levels. We show for the first time that the peroxisome proliferator-activated receptor-alpha(PPAR alpha) binds glucose and glucose metabolites with high affinity, resulting in significantly altered PPAR alpha secondary structure. Glucose decreased PPAR alpha interaction with fatty acid metabolites and steroid receptor coactivator-1 while increasing PPAR alpha interaction with DNA. Concomitantly, glucose increased PPAR alpha interaction with steroid receptor coactivator-1, DNA binding, and transactivation of beta-oxidation pathways in the presence of activating ligands. Heterodimerization of PPAR alpha to the retinoid X receptor-alpha resulted in even larger increases in transactivation with the addition of glucose. These data suggest that PPAR alpha is responsible for maintaining energy homeostasis through a concentration- dependent regulation of both lipids and sugars and that hyperglycemic injury mediated by PPAR alpha occurs not only indirectly through elevated long chain fatty acid levels but also through direct action of glucose on PPAR alpha.