title: Resveratrol promotes expression of SIRT1 and StAR in rat ovarian granulosa cells: an implicative role of SIRT1 in the ovary.
abstract: BACKGROUND
  Resveratrol is a natural polyphenolic compound known for its beneficial effects on energy homeostasis, and it also has multiple properties, including anti-oxidant, anti-inflammatory, and anti-tumor activities. Recently, silent information regulator genes (Sirtuins) have been identified as targets of resveratrol. Sirtuin 1 (SIRT1), originally found as an NAD+-dependent histone deacetylase, is a principal modulator of pathways downstream of calorie restriction, and the activation of SIRT1 ameliorates glucose homeostasis and insulin sensitivity. To date, the presence and physiological role of SIRT1 in the ovary are not known. Here we found that SIRT1 was localized in granulosa cells of the human ovary.
  
  
  METHODS
  The physiological roles of resveratrol and SIRT1 in the ovary were analyzed. Immunohistochemistry was performed to localize the SIRT1 expression. SIRT1 protein expression of cultured cells and luteinized human granulosa cells was investigated by Western blot. Rat granulosa cells were obtained from diethylstilbestrol treated rats. The cells were treated with increasing doses of resveratrol, and subsequently harvested to determine mRNA levels and protein levels. Cell viability was tested by MTS assay. Cellular apoptosis was analyzed by caspase 3/7 activity test and Hoechst 33342 staining.
  
  
  RESULTS
  SIRT1 protein was expressed in the human ovarian tissues and human luteinized granulosa cells. We demonstrated that resveratrol exhibited a potent concentration-dependent inhibition of rat granulosa cells viability. However, resveratrol-induced inhibition of rat granulosa cells viability is independent of apoptosis signal. Resveratrol increased mRNA levels of SIRT1, LH receptor, StAR, and P450 aromatase, while mRNA levels of FSH receptor remained unchanged. Western blot analysis was consistent with the results of quantitative real-time RT-PCR assay. In addition, progesterone secretion was induced by the treatment of resveratrol.
  
  
  CONCLUSIONS
  These results suggest a novel mechanism that resveratrol could enhance progesterone secretion and expression of luteinization-related genes in the ovary, and thus provide important implications to understand the mechanism of luteal phase deficiency.
authors.affiliation: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Morita
authors.forename: Osamu
authors.initials: O
authors.lastname: Wada-Hiraike
authors.forename: Tetsu
authors.initials: T
authors.lastname: Yano
authors.forename: Akira
authors.initials: A
authors.lastname: Shirane
authors.forename: Mana
authors.initials: M
authors.lastname: Hirano
authors.forename: Haruko
authors.initials: H
authors.lastname: Hiraike
authors.forename: Satoshi
authors.initials: S
authors.lastname: Koyama
authors.forename: Hajime
authors.initials: H
authors.lastname: Oishi
authors.forename: Osamu
authors.initials: O
authors.lastname: Yoshino
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Kenbun
authors.initials: K
authors.lastname: Sone
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Oda
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Tsutsui
authors.forename: Yuji
authors.initials: Y
authors.lastname: Taketani
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D005260:Female; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008875:Middle Aged; D010750:Phosphoproteins / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000096:biosynthesis* / Q000502:physiology*; D013267:Stilbenes / Q000494:pharmacology*; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D010750:Phosphoproteins; D013267:Stilbenes; D000098682:Steroidogenic Acute Regulatory Protein; C447939:SIRT1 protein, human; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D000077185:Resveratrol