DIFFERENTIAL ACTIVATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS BY EICOSANOIDS

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormon e receptors that regulate gene transcription in response to peroxisome proliferators and fatty acids. PPARs also play an important role in t he regulation of adipocyte differentiation. It is unclear, however, wh at naturally occurring compounds activate each of the PPAR subtypes. T o address this issue, a screening assay was established using heterolo gous fusions of the bacterial tetracycline repressor to several member s of the peroxisome proliferator-activated receptor (PPAR) family. Thi s assay was employed to compare the activation of PPAR family members by known PPAR activators including peroxisome proliferators and fatty acids. Interestingly, the activation of PPARs by fatty acids was parti ally inhibited by the cyclooxygenase inhibitor indomethacin, which pre vents prostaglandin synthesis. Indeed, prostaglandins PGA1 and 2, PGD1 and 2, and PGJ2-activated PPARs, while a number of other prostaglandi ns had no effect. We also screened a variety of hydroxyeicosatetraenoi c acids (HETEs) for the ability to activate PPARs. 8(S)-HETE, but not other (S)-HETEs, was a strong activator of PPAR alpha. Remarkably, PPA R activation by 8(S)-HETE was stereoselective. In addition, 8(S)-HETE was able to induce differentiation of 3T3-L1 preadipocytes. These resu lts indicate that PPARs are differentially activated by naturally occu rring eicosanoids and related molecules.