PPARagonister

PPAR agonists are compounds that activate peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptors that regulate gene expression related to lipid metabolism, glucose homeostasis, and inflammation. When bound by a ligand, PPARs form a heterodimer with retinoid X receptors and bind to PPAR response elements in DNA to modulate transcription, influencing metabolic pathways and cellular energy use.

There are three main PPAR subtypes: alpha, gamma, and delta (beta). PPAR-alpha is highly expressed in liver, heart, and muscle and promotes fatty acid oxidation. PPAR-gamma is abundant in adipose tissue and governs adipogenesis and insulin sensitivity. PPAR-delta is widely distributed and affects energy expenditure and lipid metabolism, with ongoing research into therapeutic applications.

Clinically used PPAR agonists fall into different groups. PPAR-alpha agonists, known as fibrates (for example, gemfibrozil and fenofibrate), primarily lower triglycerides and raise HDL cholesterol. PPAR-gamma agonists, the thiazolidinediones (such as pioglitazone and previously rosiglitazone), act as insulin sensitizers for type 2 diabetes. Dual or pan-PPAR agonists have been developed to target multiple pathways, but several have faced safety concerns and limited or withdrawn clinical use.

Safety and adverse effects vary by agent. Fibrates can interact with statins and increase the risk of myopathy and gallbladder issues. Thiazolidinediones carry risks including weight gain, edema, heart failure in predisposed individuals, and potential liver effects; troglitazone was withdrawn due to liver toxicity. Ongoing research explores PPAR agonists for conditions such as nonalcoholic fatty liver disease, dyslipidemia, and obesity, with emphasis on improving safety profiles and targeting specific patient populations.