Fatty acids and their thioester derivatives as ligands for human PPARα

Abstract

<p>Peroxisome proliferator activated receptor alpha (PPARa) belongs to the family of the ligand dependant nuclear transcription factors that play key roles in regulating lipid homeostasis. Previous studies have suggested binding of mouse and xenopus recombinant PPARa to fatty acids (FA) and their thioester derivatives (fatty acyl coenzyme A; FA-CoA) however, no such studies have been done with full length human PPARa (hPPARa). Owing to differences in the physiological effects of PPARa activation across species (i.e. peroxisome proliferation seen in rodents but not in humans), it is possible that binding affinities and specificities for such ligands may differ. Dysregulation of FA and FA-CoA may alter the transcriptional activity of PPARa and may contribute significantly to the pathogenesis of the metabolic syndrome. In the current study, we test the binding of various FA and FA-CoA to hPPARa. Data from both spectrofluorometry and circular dichroism spectroscopy suggest binding of both saturated and unsaturated FA and FA- CoA to the hPPARa at physiologically relevant concentrations found inside the cell. This is in contrast to murine PPARa which bound to only unsaturated FA but not saturated ones. Our data helps determine various endogenous ligands for hPPARa which will further help delineate the role of PPARa as a nutrient sensor in regulating energy homeostasis. This work is supported by USPHS NIH grant DK77573.</p>