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- Δ¹³-reductase (PGR-2), which catalyzes the reaction converting 15-keto-PGE₂ to 13,14-dihydro-15-keto-PGE2. 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 γ (PPARγ)-dependent transcription and prohibits 3T3-L1 adipocyte differentiation without affecting expression of PPARγ. Interestingly, we found that 15-keto-PGE₂ can act as a ligand of PPARγ to increase coactivator recruitment, thus activating PPARγ-mediated transcription and enhancing adipogenesis of 3T3-L1 cells. Overexpression of 15-hydroxyprostaglandin dehydrogenase, which catalyzes the oxidation reaction of PGE₂ to form 15-keto-PGE₂, significantly increased PPARγ-mediated transcription in a PGE₂-dependent manner. Reciprocally, overexpression of wild-type PGR-2, but not the catalytically defective mutant, abolished the effect of 15-keto-PGE₂ on PPARγ activation. These results demonstrate a novel link between catabolism of PGE₂ and regulation of ligand-induced PPARγ activation.