Peroxisome proliferator-activated receptors: From genes to physiology

The peroxisome proliferator-activated receptors (PPAR alpha, gamma, delta) are members of the nuclear receptor superfamily of ligand-activated transcr iption factors that have central roles in the storage and catabolism of fat ty acids. Although the three PPAR subtypes are closely related and bind to similar DNA response elements as heterodimers with the 9-cis retinoic acid receptor RXR, each subserves a distinct physiology. PPAR alpha (NR1CI) is t he receptor for the fibrate drugs, which are widely used to lower triglycer ides and raise high-density lipoprotein cholesterol levels in the treatment and prevention of coronary artery disease. In rodents, PPAR alpha agonists induce hepatomegaly and stimulate a dramatic proliferation of peroxisomes as part of a coordinated physiological response to lipid overload. PPAR gam ma (NRIC3) plays a critical role in adipocyte differentiation and serves as the receptor for the glitazone class of insulin-sensitizing drugs used in the treatment of type 2 diabetes. In contrast to PPAR alpha and PPAR gamma, relatively little is known about the biology of PPARG (NRIC2), although re cent findings suggest that this subtype also has a role in lipid homeostasi s. All three PPARs are activated by naturally occurring fatty acids and fat ty acid metabolites, indicating that they function as the body's fatty acid sensors. Three-dimensional crystal structures reveal that the ligand-bindi ng pockets of the PPARs are much larger and more accessible than those of o ther nuclear receptors, providing a molecular basis for the promiscuous lig and-binding properties of these receptors. Given the fundamental roles that the PPARs play in energy balance, drugs that modulate PPAR activity are li kely to be useful for treating a wide range of metabolic disorders, includi ng atherosclerosis, dyslipidemia, obesity, and type 2 diabetes.