PEROXISOME PROLIFERATORS AND PEROXISOME PROLIFERATOR ACTIVATED RECEPTORS (PPARS) AS REGULATORS OF LIPID-METABOLISM

Peroxisome proliferation (PP) in mammalian cells, first described 30 y ears ago, represents a fascinating field of modern research. Major imp rovements made in its understanding were obtained through basic advanc es that have opened up new areas in cell biology, biochemistry and gen etics. A decade after the first report on PP, a new metabolic pathway (peroxisomal beta-oxidation) and its inducibility by peroxisome prolif erators were discovered. More recently, a new type of nuclear receptor , the peroxisome proliferator-activated receptor (PPAR), has been desc ribed. The first PPAR was discovered in 1990. Since then, many other P PARs have been characterized. This original class of nuclear receptors belongs to the superfamily of steroid receptors. With activation of c ell signal transduction pathways, the occurrence of PPARs provides, fo r the first time, a coherent explanation of mechanisms by which PP is triggered. Nevertheless, although many compounds or metabolites are ca pable of activating PPARs, the natural direct ligands of these recepto rs have not been, up to now, clearly identified, with, however, the ex ception of 15-deoxy-12,14-prostaglandin J2 which is the ligand of PPAR gamma 2 while leukotrien LTB4 binds PPAR alpha. At this stage, the hy pothesis of some orphan PPARs (ie receptors without known ligand) can not be ruled out. Despite these relatively restrictive aspects, the me chanisms by which activation of PPARs leads to PP become clear; also, coherent hypotheses among which a scenario involving receptor phosphor ylation or a heat shock protein (ie HSP 72) can be proposed to explain how PPARs would be activated. The aim of this note is to review recen t developments on PPARs, to present members up to now recognized to be long to the PPAR family, their characterization, functions, regulation and mechanisms of activation as well as their involvement in lipid me tabolism regulation such as control of beta-oxidation, ketogenesis, fa tty acid synthesis and lipoprotein metabolism. As an introducing secti on, a brief review of the major events between the first report of PP in mammals and the discovery of the first PPAR is given. Another secti on is devoted to current hypotheses on mechanisms responsible for PPAR activation and PP induction. Rather than an exhaustive presentation o f cellular alterations accompanying PP induction, a dynamic overview o f the lipid metabolism is provided. By assessing the biological signif icance of this organellar proliferative process, the reader will be le d to conclude that the discovery of PPARs and related gene activation through peroxisome proliferator responsive element (PPRE) makes PP ind uction one of the most illustrative examples of control that occurs in lipid metabolism.