Peroxisome proliferators such as clofibric acid, nafenopin, and WY-14,643 have been shown to activate PPAR (peroxisome proliferator-activated receptor), a member of the steroid nuclear receptor superfamily. We have cloned the cDNA from the rat that is homologous to that from the mouse [Issemann, I. & Green, S. (1990) Unsaturated fatty acids induce peroxisomal proliferation and lower blood triglyceride levels (1-3). Similar effects are evoked by a number of man-made compounds which are either considered for therapy of hyperlipidemia-e.g., clofibric acid, nafenopin, WY-14,643, or sulfur-substituted fatty acids-or are in use as industrial plasticizers (4-6). The steroid dehydroepiandrosterone (DHEA) also induces peroxisomal proliferation but increases blood triglyceride and cholesterol levels (7,8). Two main hypotheses have been developed to explain the complex response of peroxisomal proliferation to this wide variety of inducers. According to one theory the intracellular accumulation of fatty acids is the key stimulus for triggering peroxisomal proliferation (4, 9). The other theory postulates the involvement of a receptor protein (4, 10) and an as-yet-unknown intracellular messenger-e.g., the ligand for this receptor.The latter idea gained substantial support from the discovery of mouse peroxisome proliferator-activated receptor (mPPAR), a member of the steroid nuclear receptor superfamily (11,12). The gene encoding PPAR belongs to a number of genes cloned in the last few years by means of their homology with steroid receptors. In general, ligands or physiologically occurring activators have been identified for only a few of these so-called orphan receptors (13-15). In the case of mPPAR, transactivation studies using chimeric proteins composed of the putative ligand-binding domain of the novel receptor and DNA-binding domains of known steroid receptors showed that mPPAR could be activated by peroxisome proliferators (11). However, the identity ofthe ultimate ligand of the receptor protein, the nature of physiological activators, and how the receptor might relate to the concept of fatty acids as inducers of peroxisomal proliferation remain unclear.We now describe the cloning from rat liver of a gene homologous to that encoding mPPAR.