Identification of a novel prostaglandin reductase reveals the involvement of prostaglandin E2 catabolism in regulation of peroxisome proliferator-activated receptor gamma activation.
This report identifies a novel gene encoding 15-oxoprostaglandin-Delta13-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 gamma (PPARgamma)-dependent transcription and prohibits 3T3-L1 adipocyte differentiation without affecting expression of PPARgamma. Interestingly, we found that 15-keto-PGE2 can act as a ligand of PPARgamma to increase co-activator recruitment, thus activating PPARgamma-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 PPARgamma-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 PPARgamma activation. These results demonstrate a novel link between catabolism of PGE2 and regulation of ligand-induced PPARgamma activation.
Chou
Wen-Ling
WL
Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Chuang
Lee-Ming
LM
Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan.
Chou
Chi-Chi
CC
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; National Core Facilities for Proteomics Research, Taipei 115, Taiwan.
Wang
Andrew H-J
AH
Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan; National Core Facilities for Proteomics Research, Taipei 115, Taiwan.
Lawson
John A
JA
Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
FitzGerald
Garret A
GA
Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104.
Chang
Zee-Fen
ZF
Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 100, Taiwan. Electronic address: ZFCHANG@ha.mc.ntu.edu.tw.
D011452:15-Oxoprostaglandin 13-Reductase / Q000235:genetics* / Q000502:physiology*; D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002454:Cell Differentiation; D015232:Dinoprostone / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D010100:Oxygen / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
D047495:PPAR gamma; D011452:15-Oxoprostaglandin 13-Reductase; D015232:Dinoprostone; D010100:Oxygen