Peroxisome Proliferators and Peroxisome Proliferator-Activated Receptor α: Biotic and Xenobiotic Sensing

The morphological phenomenon of peroxisome (microbody) proliferation, induced in hepatic parenchymal cells of rats and mice by the hypolipidemic drug clofibrate,1 fascinated me ever since I ventured into the research laboratory of the late Donald J. Svoboda at the University of Kansas Medical Center as a pathology resident more than 35 years ago. The elegant ultrastructural illustrations of liver cell cytoplasm suffocated with “microbodies” Don Svoboda displayed2 left an indelible impression that propelled me to pursue the cellular, biochemical, and molecular underpinnings of that phenomenon of peroxisome proliferation.3–8 The central effort of my research since then revolves around the analysis of causes and consequence of the induction of peroxisome proliferation by structurally diverse classes of chemicals, which we designated as peroxisome proliferators.9 This longstanding interest and avocation enabled my colleagues and me to make certain factual and conceptual advances, among which the following deserve special mention. First, the demonstration that the phenomenon of peroxisome proliferation can be induced by many structurally diverse agents led to our proposal that peroxisome proliferation is linked to lipid metabolism8,9 and this formed the impetus for the identification of the peroxisomal β-oxidation system.10 Second, the consistent observation that peroxisome proliferation induced by peroxisome proliferators is carcinogenic in rats and mice,11–14 resulted in the proposal that peroxisome proliferators form a novel class of nonmutagenic chemical carcinogens.15,16 This resulted in the dictum that all peroxisome proliferators are potentially hepatocarcinogenic and that peroxisome proliferation can serve as a biological marker or predictor of carcinogenicity of a nongenotoxic chemical.15,17–19 Third, sustained disproportionate induction of hydrogen peroxide generating- and hydrogen peroxide-degrading enzymes in livers by peroxisome proliferators resulted in the postulation that hepatocarcinogenicity of peroxisome proliferators is due to oxidative stress leading to oxidative DNA damage from metabolic perturbations.15,19–23 Fourth, the tissue/cell specificity of pleiotropic responses and the coordinated rapid transcriptional activation of peroxisomal β-oxidation system genes led to the hypothesis that peroxisome proliferators exert their action by a receptor-mediated mechanism.15,18,19,24,25 This formed the stimulus for the identification of a subfamily of nuclear receptors called peroxisome proliferator-activated receptors (PPARs).26,27 PPARs play a central role in regulating the combustion and storage of dietary lipids, essentially by serving as sensors for fatty acids and their metabolic intermediates. In addition, they sense certain classes of exogenous chemicals and, in the process, transcriptionally regulate sets of target genes that control energy (lipid) metabolism. Thus, PPARs function as sensors for both endogenous and exogenous stimuli and this sensing mechanism regulates lipid homeostasis. I summarize here some of our studies dealing with the biological effects of peroxisome proliferators, an area of research we “nurtured” with some proprietary pride for many years. I am greatly honored that this work has been recognized by the Rous-Whipple Award this year, and dedicate this to all those who were part of our efforts and others who contributed to the developments in this field. My purpose in this paper is to review our own studies with inclusion of relevant literature citations although they are in no way comprehensive.