Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ

TLDR

Fatty acids and their derivatives are essential metabolites whose levels are tightly regulated, and the peroxisome proliferator‑activated receptor alpha (PPARα) senses these changes to maintain lipid homeostasis. The study seeks to explain how structurally diverse lipid‑like compounds can activate a single receptor. A novel conformation‑based assay was developed to screen activators for their ability to bind PPARα/δ and induce DNA binding. Specific fatty acids, eicosanoids, and hypolipidemic drugs were identified as ligands for PPARα or PPARδ, suggesting that PPARs act as molecular sensors linking altered fatty‑acid levels to metabolic disorders such as obesity, atherosclerosis, hypertension, and diabetes.

Abstract

Fatty acids (FAs) and their derivatives are essential cellular metabolites whose concentrations must be closely regulated. This implies that regulatory circuits exist which can sense changes in FA levels. Indeed, the peroxisome proliferator-activated receptor alpha (PPARalpha) regulates lipid homeostasis and is transcriptionally activated by a variety of lipid-like compounds. It remains unclear as to how these structurally diverse compounds can activate a single receptor. We have developed a novel conformation-based assay that screens activators for their ability to bind to PPARalpha/delta and induce DNA binding. We show here that specific FAs, eicosanoids, and hypolipidemic drugs are ligands for PPARalpha or PPARdelta. Because altered FA levels are associated with obesity, atherosclerosis, hypertension, and diabetes, PPARs may serve as molecular sensors that are central to the development and treatment of these metabolic disorders.