IDENTIFICATION CHARACTERIZATION, AND TISSUE DISTRIBUTION OF HUMAN PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR) ISOFORMS PPAR-GAMMA-2 VERSUS PPAR-GAMMA-1 AND ACTIVATION WITH RETINOID-X RECEPTOR AGONISTS AND ANTAGONISTS

We describe the cloning, characterization, and tissue distribution of the two human peroxisome proliferator activated receptor isoforms hPPA R gamma 2 and hPPAR gamma 1. In cotransfection assays the two isoforms were activated to approximately the same extent by known PPAR gamma a ctivators, Human PPAR gamma binds to DNA as a heterodimer with the ret inoid X receptor (RXR). This heterodimer was activated by both RXR ago nists and antagonists and the addition of PPAR gamma ligands with reti noids resulted in greater than additive activation, Such heterodimer-s elective modulators may have a role in the treatment of PPAR gamma/RXR -modulated diseases like diabetes. Northern blot analysis indicated th e presence of PPAR gamma in skeletal muscle, and a sensitive RNase pro tection assay confirmed the presence of only PPAR gamma 1 in muscle th at was not solely due to fat contamination. However, both PPAR gamma 1 and PPAR gamma 2 RNA were detected in fat, and the ratio of PPAR gamm a 1 to PPAR gamma B RNA varied in different individuals. The presence of tissue-specific distribution of isoforms and the variable ratio of PPAR gamma 1 to PPAR gamma 2 raised the possibility that isoform expre ssion may be modulated in disease states like non insulin-dependent di abetes mellitus. Interestingly, a third protected band was detected wi th fat RNA indicating the possible existence of a third human PPAR gam ma isoform.