2. Academic Validation
  3. SFRP4 contributes to insulin resistance-induced polycystic ovary syndrome by triggering ovarian granulosa cell hyperandrogenism and apoptosis through the nuclear β-catenin/IL-6 signaling axis

SFRP4 contributes to insulin resistance-induced polycystic ovary syndrome by triggering ovarian granulosa cell hyperandrogenism and apoptosis through the nuclear β-catenin/IL-6 signaling axis

  • Biochim Biophys Acta Mol Cell Res. 2024 Oct;1871(7):119822. doi: 10.1016/j.bbamcr.2024.119822.
Jiangxia Wang 1,  Runlin Gui 1,  Yang Li 2,  Zhuozhuo Li 2,  Zi Li 2,  Shanshan Liu 3,  Miao Zhang 3,  Lu Qian 4,  Xiaobin Fan 5,  Yuyan Xiong 6
Affiliations

Affiliations

  • 1 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, Shaanxi 710069, PR China; Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi 710018, PR China.
  • 2 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, Shaanxi 710069, PR China.
  • 3 Department of Obstetrics and Gynecology, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi 710018, PR China.
  • 4 Xi'an Mental Health Center, Xi'an, Shaanxi 710100, PR China.
  • 5 Department of Obstetrics and Gynecology, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi 710018, PR China. Electronic address: xbfan@126.com.
  • 6 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, College of Life Sciences, Northwest University, Xi'an, Shaanxi 710069, PR China; Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi 710018, PR China. Electronic address: yuyan.xiong@nwu.edu.cn.
PMID: 39159685 DOI: 10.1016/j.bbamcr.2024.119822
Abstract

Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by chronic ovulation dysfunction and overproduction of androgens. Women with PCOS are commonly accompanied by Insulin resistance (IR), which can impair Insulin sensitivity and elevate blood glucose levels. IR promotes ovarian cysts, ovulatory dysfunction, and menstrual irregularities in women patients, leading to the pathogenesis of PCOS. Secreted frizzled-related protein 4 (SFRP4), a secreted glycoprotein, exhibits significantly elevated expression levels in obese individuals with IR and PCOS. Whereas, whether it plays a role in regulating IR-induced PCOS still has yet to be understood. In this study, we respectively established in vitro IR-induced hyperandrogenism in human ovarian granular cells and in vivo IR-induced PCOS models in mice to investigate the action mechanisms of SFRP4 in modulating IR-induced PCOS. Here, we revealed that SFRP4 expression levels in both mRNA and protein were remarkably upregulated in the IR-induced hyperandrogenism with elevated testosterone in the human ovarian granulosa cell line KGN. Under normal conditions without hyperandrogenism, overexpressing SFRP4 triggered the remarkable elevation of testosterone along with the increased nuclear translocation of β-catenin, cell Apoptosis and proinflammatory cytokine IL-6. Furthermore, we found that phytopharmaceutical disruption of SFRP4 by genistein ameliorated IR-induced increase in testosterone in ovarian granular cells, and IR-induced PCOS in high-fat diet obese mice. Our study reveals that SFRP4 contributes to IR-induced PCOS by triggering ovarian granulosa cell hyperandrogenism and Apoptosis through the nuclear β-catenin/IL-6 signaling axis. Elucidating the role of SFRP4 in PCOS may provide a novel therapeutic strategy for IR-related PCOS therapy.

Keywords

Cell apoptosis; Insulin resistance; Polycystic ovary syndrome; Secreted frizzled-related protein 4; β-Catenin.

Figures
Products