PPARalpha

PPAR alpha (peroxisome proliferator-activated receptor alpha) is a member of the nuclear receptor family and functions as a ligand-activated transcription factor that regulates gene expression in response to lipid-derived signals. In humans, it is encoded by the PPARA gene and is highly expressed in the liver, with appreciable levels in heart, skeletal muscle, kidney, and brown adipose tissue. Its activity coordinates the uptake, transport, and oxidation of fatty acids.

Mechanistically, PPARα forms a heterodimer with retinoid X receptor (RXR) and binds to peroxisome proliferator response elements (PPREs) in target gene promoters. Upon binding endogenous ligands such as long-chain fatty acids and certain eicosanoids, or synthetic ligands, it modulates transcription by recruiting coactivators or corepressors. Endogenous and pharmacologic activators can influence genes involved in fatty acid transport and oxidation, including mitochondrial and peroxisomal beta-oxidation pathways, as well as lipoprotein metabolism.

Physiological roles of PPARα activation include increased fatty acid uptake and oxidation, reduced triglyceride levels, and modulation of lipoprotein composition. It also participates in ketogenesis during fasting and can exert anti-inflammatory effects in various tissues.

Clinically, PPARα agonists such as fibrates are used to treat hypertriglyceridemia and mixed dyslipidemia. Research areas include potential benefits in nonalcoholic fatty liver disease and metabolic syndrome, as well as inflammatory conditions. Notably, rodents show robust liver peroxisome proliferation with PPARα activation, a response that differs in humans and informs species-specific risk considerations. Genetic variations in PPARA can influence individual lipid and metabolic responses to diet and therapy.