Category: receptor_pharmacology
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors that heterodimerize with RXR and bind PPRE (peroxisome proliferator response elements) to drive lipid + glucose metabolic gene expression. Three isoforms with distinct tissue distribution and pharmacology: PPARα (liver, BAT, muscle, kidney) — fatty acid β-oxidation, ketogenesis, lipoprotein metabolism (apoA-I/A-II, LPL); fibrates (fenofibrate, gemfibrozil) are PPARα agonists → ↑HDL, ↓TG. PPARγ (adipose, macrophage, colon) — adipogenesis, insulin sensitization, anti-inflammatory; thiazolidinediones (pioglitazone, rosiglitazone) are PPARγ agonists → insulin sensitization in T2D, but ↑edema/HF/bone-fracture risk. PPARδ/β (ubiquitous) — fatty acid oxidation in muscle, exercise mimetic; agonists (cardarine/GW501516 — banned in sport) and now seladelpar in PBC. Endogenous ligands: PUFAs (DHA, EPA, ALA — partial PPARα/γ agonists), oxidized lipids (15d-PGJ2 → PPARγ), nitro-fatty acids. Coactivator recruitment: PGC-1α (mitochondrial biogenesis), p300, SRC-1. Cross-talk: anti-inflammatory via NF-κB transrepression (PPARγ — pioglitazone benefit in atherosclerosis); ARB telmisartan is a partial PPARγ agonist (likely explains favorable metabolic profile). Cross-links: [[beta_oxidation]] (PPARα target genes), [[insulin_glucose_homeostasis]] (PPARγ adipocyte action), [[fatty_acid_biosynthesis]].