Identification of a novel prostaglandin reductase reveals the involvement of prostaglandin E2 catabolism in regulation of peroxisome proliferator-activated receptor γ activation

This report identifies a novel gene encoding 15-oxoprostaglandin-Delta(13)-reductase (PGR-2), which catalyzes the reaction converting 15-keto-PGE(2) to 13,14-dihydro-15-keto-PGE(2). The expression of PGR-2 is up-regulated in the late phase of 3T3-L1 adipocyte differentiation and predominantly distributed in adipose tissue. Overexpression of PGR-2 in cells decreases peroxisome proliferator-activated receptor gamma ( PPAR gamma)-dependent transcription and prohibits 3T3-L1 adipocyte differentiation without affecting expression of PPAR gamma. Interestingly, we found that 15-keto-PGE(2) can act as a ligand of PPAR gamma to increase coactivator recruitment, thus activating PPAR gamma-mediated transcription and enhancing adipogenesis of 3T3-L1 cells. Overexpression of 15-hydroxyprostaglandin dehydrogenase, which catalyzes the oxidation reaction of PGE(2) to form 15-keto-PGE(2), significantly increased PPAR gamma-mediated transcription in a PGE(2)-dependent manner. Reciprocally, overexpression of wild-type PGR-2, but not the catalytically defective mutant, abolished the effect of 15-keto-PGE(2) on PPAR gamma activation. These results demonstrate a novel link between catabolism of PGE(2) and regulation of ligand-induced PPAR gamma activation.