PPAR

The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family of ligand-activated transcription factors that heterodimerize with retinoid X receptor (RXR) isoforms to regulate gene expression. Three subtypes of PPAR have been identified and cloned: α, δ (also known as β) and γ. Many endogenous ligands have been isolated for PPARs; these include prostacyclin, fatty acids, lysophosphatidic acid and leukotriene B4. PPARs play many important roles in the cell, including lipid homeostasis, cell proliferation, differentiation, adipogenesis and immune functions and are useful in the treatment of metabolic disease. The table below summarizes the pharmacological properties of these receptors.

Receptor Subtype	PPARα	PPARδ	PPARγ

Primary Distribution	Liver, adipose tissue, kidney, heart, skeletal muscle, large intestine	Ubiquitous	Adipose tissue, lymphoid tissue, colon, liver, heart
Tissue Function	Fatty acid synthesis and oxidation, gluconeogenesis, ketogenesis, lipoprotein assembly	Placental and gut development, fatty acid oxidation, adaptive thermogenesis, control of cell proliferation and differentiation, tissue repair	Adipocyte differentiation, glucose homeostasis
Human Disease Relevance	Atherosclerosis	Atherosclerosis	Obesity and insulin resistance, type II diabetes mellitus, hypertension, atherosclerosis, cancer

Key Compounds	K_i Values (nM)

Agonists	Ciglitazone (1307) Clofibrate (0824) GW 0742 (2229) GW 7647 (1677) GW 1929 (1664) L-165,041 (1856) WY 14643 (1312)	> 1000* 50 1.1 0.006 > 10 10 5	> 1000* > 100 0.001 6.2 > 10 0.53 60	3* ~ 500 2 1.1 0.0062 5.5 35
Antagonists	BADGE (1326) GW 9662 (1508)	>> 100 0.032	> 100 2	~ 100 0.0033