Peroxisome proliferator-activated receptor gamma and Peroxisome proliferator-activated receptor alpha (PPARγ/PPARα)

Peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms (alpha, gamma, and delta) that function as ligand-activated transcription factors to regulate energy homeostasis [1, 10, 11]. PPARalpha is predominantly expressed in the liver, heart, and skeletal muscle, where it orchestrates the expression of genes involved in fatty acid uptake and beta-oxidation, thereby lowering plasma triglycerides and increasing HDL cholesterol [1, 10, 13]. PPARgamma is the master regulator of adipogenesis and is highly expressed in adipose tissue, where it enhances insulin sensitivity and glucose uptake [5, 13, 14]. Dual PPARgamma/PPARalpha agonists, collectively known as glitazars, were designed to provide a comprehensive treatment for type 2 diabetes and metabolic syndrome by combining the insulin-sensitizing effects of PPARgamma with the lipid-modifying benefits of PPARalpha [3, 8, 19]. Despite their potent metabolic efficacy, the clinical development of many glitazars has been terminated due to significant safety concerns, including peripheral edema, weight gain, increased risk of congestive heart failure, and potential carcinogenicity [2, 4, 9, 12]. Currently, saroglitazar and chiglitazar are among the few dual agonists that have achieved regulatory approval in specific markets like India and China, respectively [2, 17].

Other names

PPAR-gamma/alphaPPARG/PPARANR1C3/NR1C1Glitazar targetPeroxisome proliferator-activated receptor gamma and alpha

Dual agonism of PPARalpha and PPARgamma [1, 3, 10]. PPARalpha activation increases fatty acid oxidation and improves lipid profiles by lowering triglycerides and increasing HDL-C [1, 10, 13]. PPARgamma activation improves insulin sensitivity and glucose metabolism by regulating gene expression in adipose tissue [1, 5, 13, 14].