Prostaglandin reductase-3 negatively modulates adipogenesis through regulation of PPARγ activity

• Published in: Journal of lipid research Vol. 54; no. 9; pp. 2391 - 2399
• Main Authors: Yu, Yu-Hsiang, Chang, Yi-Cheng, Su, Tseng-Hsiung, Nong, Jiun-Yi, Li, Chao-Chin, Chuang, Lee-Ming
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2013; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: adipocyte differentiation; Adipocytes - cytology; Adipocytes - enzymology; Adipocytes - pathology; Adipogenesis; Adipose Tissue, White - cytology; Adipose Tissue, White - enzymology; Adipose Tissue, White - pathology; Adiposity; Animals; Cell Line; Dinoprostone - analogs & derivatives; Dinoprostone - metabolism; eicosanoid; ligand; Mice; nuclear receptor; Obesity - enzymology; Obesity - pathology; Oxidoreductases Acting on CH-CH Group Donors - metabolism; PPAR gamma - metabolism; eicosanoid; nuclear receptor; adipocyte differentiation; ligand
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M037556

Adipocyte differentiation is a multistep program under regulation by several factors. Peroxisome proliferator-activated receptor γ (PPARγ) serves as a master regulator of adipogenesis. However, the endogenous ligand for PPARγ remained elusive until 15-keto-PGE2 was identified recently as an endogenous PPARγ ligand. In this study, we demonstrate that zinc-containing alcohol dehydrogenase 2 (ZADH2; here termed prostaglandin reductase-3, PTGR-3) is a new member of prostaglandin reductase family that converts 15-keto-PGE2 to 13,14-dihydro-15-keto-PGE2. Adipogenesis is accelerated when endogenous PTGR-3 is silenced in 3T3-L1 preadipocytes, whereas forced expression of PTGR-3 significantly decreases adipogenesis. PTGR-3 expression decreased during adipocyte differentiation, accompanied by an increased level of 15-keto-PGE2. 15-keto-PGE2 exerts a potent proadipogenic effect by enhancing PPARγ activity, whereas overexpression of PTGR-3 in 3T3-L1 preadipocytes markedly suppressed the proadipogenic effect of 15-keto-PGE2 by repressing PPARγ activity. Taken together, these findings demonstrate for the first time that PTGR-3 is a novel 15-oxoprostaglandin-Δ13-reductase and plays a critical role in modulation of normal adipocyte differentiation via regulation of PPARγ activity. Thus, modulation of PTGR-3 might provide a novel avenue for treating obesity and related metabolic disorders.