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Minireview: Lipid Metabolism, Metabolic Diseases, and Peroxisome Proliferator-Activated Receptors

Howard Hughes Medical Institute, Gene Expression Laboratory (C.-H.L., P.O., R.M.E.), The Salk Institute for Biological Studies, La Jolla, California 92037; and Department of Biology (P.O.), University of California, San Diego, La Jolla, California 92037

Address all correspondence and requests for reprints to: Ronald M. Evans, Ph.D., Howard Hughes Medical Institute, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037. E-mail: evans{at}salk.edu.

Lipid and carbohydrate homeostasis in higher organisms is under the control of an integrated system that has the capacity to rapidly respond to metabolic changes. The peroxisome proliferator-activated receptors (PPARs) are nuclear fatty acid receptors that have been implicated to play an important role in obesity-related metabolic diseases such as hyperlipidemia, insulin resistance, and coronary artery disease. The three PPAR subtypes, , , and , have distinct expression patterns and evolved to sense components of different lipoproteins and regulate lipid homeostasis based on the need of a specific tissue. Recent advances in identifying selective ligands in conjunction with microarray analyses and gene targeting studies have helped delineate the subtype-specific functions and the therapeutic potential of these receptors. PPAR potentiates fatty acid catabolism in the liver and is the molecular target of the lipid-lowering fibrates (e.g. fenofibrate and gemfibrozil), whereas PPAR is essential for adipocyte differentiation and mediates the activity of the insulin-sensitizing thiazolidinediones (e.g. rosiglitazone and pioglitazone). Recent evidence suggests that PPAR may be important in controlling triglyceride levels by sensing very low-density lipoprotein. Thus, uncovering the regulatory mechanisms and transcriptional targets of the PPARs will continue to provide insight into the pathogenesis of metabolic diseases and, at the same time, offer valuable information for rational drug design.

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