title: Peroxisome proliferator-activated receptor gamma, coactivator 1α enhances local estrogen biosynthesis by stimulating aromatase activity in endometriosis.
abstract: BACKGROUND
  Endometriosis is an estrogen-dependent disease, and estrogen is overproduced by abnormally elevated aromatase in endometriotic tissues. Peroxisome proliferator-activated receptor gamma, coactivator 1α (PGC-1α) is a transcriptional coactivator-modulating steroid hormone.
  
  
  OBJECTIVE
  To investigate the effect of PGC-1α on aromatase activity in endometriosis.
  
  
  METHODS
  Specimens from ovarian endometrioma (OE), endometrium with endometriosis (EE), and normal endometrium (NE) were analyzed for PGC-1α and aromatase expression. PGC-1α-dependent changes in aromatase expression in primary cultured stromal cells (SCs) were identified using luciferase and enzymatic assays, exon I-specific RT-PCR, and real-time PCR. Environmental stimulus-induced changes in PGC-1α were also examined.
  
  
  RESULTS
  PGC-1α was more highly expressed in OE than in EE and NE (P < .01). In OE, PGC-1α was coexpressed with aromatase, and their mRNA expressions were also correlated (r = 0.56, P = .02). PGC-1α was recruited to the nuclear receptor half-site between PI.3 and PII in the aromatase promoter. PGC-1α overexpression enhanced aromatase promoter activity (P < .01), mRNA expression (P < .05), and enzymatic activity (P < .01) in SCs from OE, but not in SCs from EE or NE. The levels of PI.3, PII, and exon II mRNA increased and transcriptional enhancement was abolished by mutation of the PGC-1α-interacting site. PGC-1α expression was enhanced in SCs from OE by tumor necrosis factor (TNF)-α (P < .05) but not by hypoxia or 17β-estradiol.
  
  
  CONCLUSIONS
  PGC-1α stimulated by TNF-α regulates aromatase expression and activity to promote local estrogen biosynthesis in OE, suggesting that PGC-1α is a promising candidate for novel targeted therapies in endometriosis treatment.
authors.affiliation: Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto 602-8566, Japan.
authors.forename: Izumi
authors.initials: I
authors.lastname: Suganuma
authors.forename: Taisuke
authors.initials: T
authors.lastname: Mori
authors.forename: Fumitake
authors.initials: F
authors.lastname: Ito
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Aya
authors.initials: A
authors.lastname: Sasaki
authors.forename: Seiki
authors.initials: S
authors.lastname: Matsuo
authors.forename: Izumi
authors.initials: I
authors.lastname: Kusuki
authors.forename: Jo
authors.initials: J
authors.lastname: Kitawaki
mesh_terms: D000328:Adult; D001141:Aromatase / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004715:Endometriosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000378:metabolism / Q000473:pathology; D004958:Estradiol / Q000096:biosynthesis*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008875:Middle Aged; D010049:Ovarian Diseases / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000502:physiology*; D015854:Up-Regulation
chemical_list: C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D004958:Estradiol; D001141:Aromatase