The role of prostaglandin catabolism in adipocyte differentiation.

• Main Authors: Wen-Ling Chou, 周玟伶
• Other Authors: 張智芬
• Format: Others
• Language: en_US
• Published: 2007
• Online Access: http://ndltd.ncl.edu.tw/handle/49596513204883317557

博士 === 國立臺灣大學 === 生物化學暨分子生物學研究所 === 95 === 3T3-L1 preadipocyte cell line has been used as a model for characterizing the events responsible for adipocyte differentiation. In this thesis, we used differential display to identify a novel gene, encoding prostaglandin reductase designated as PGR-2, in the beginning. Its expression pattern is abundant in adipose tissues and highly up-regulated in the late phase of 3T3-L1 adipocyte differentiation. By functional characterization, we found that PGR-2 is capable of converting 15-keto-PGE2 into 13,14-dihydro-15-keto-PGE2. PGE2, a short lived mediator, is catabolized via an oxidation reaction catalyzed by NAD+-dependent 15-hydroxyprostaglandin dehydrogenase (PGDH) for the generation of 15-keto-PGE2, which is further catabolized by a reduction reaction catalyzed by NADPH/NADH-dependent 15-oxoprostaglandin-Δ13-reductase (PGR). It has been shown that adipose tissue possesses high activity of both PGDH and PGR, indicating that PGE2 catabolism is highly active in adipocytes. Peroxisome proliferator-activated receptor γ (PPAR-γ) plays important roles in adipogenesis. PPAR-γ is a ligand-dependent transcription factor that belongs to the nuclear receptor family, activating the transcription of its target genes as heterodimers with retinoid X receptor (RXR). Upon ligand binding, PPAR-γreleases bound corepressors and recruits coactivator for transcriptional activation. Thiazolidinediones (TZDs) are high-affinity synthetic agonists which have been widely used as insulin-sensitizing agents to treat type 2 diabetes. Several natural substances have been identified as potential endogenous PPAR-γ ligands. To date, their physiological significance and role as true endogenous activators for PPAR-γ have been uncertain. Interestingly, these identified ligands are usually associated with different inflammatory stimuli, which correlate with the anti-inflammatory role of PPAR-γ. The production of prostaglandin E2 (PGE2) is elevated in many inflammatory stimuli. However, little is known about whether the catabolism of PGE2 is associated with modulation of PPAR-γactivity. In this thesis, enforced expression of PGR-2 represses transcriptional activity of PPAR-γand adipocyte differentiation of 3T3-L1 cells. Following these observations, we further found that 15-keto-PGE2, an intermediate metabolite within the PGE2 catabolic pathway, functions as a PPAR-γ ligand, by which it stimulates the differentiation of mouse fibroblasts into adipocytes. In accordance, overexpression of PGDH also increased PGE2-dependent activation of PPAR-γ. Our findings provide new insights into PGE2 catabolism in regulation of PPAR-γactivity.