TGF-beta 1 suppresses de novo cholesterol biosynthesis in granulosa-lutein cells by down-regulating DHCR24 expression via the GSK-3 beta/EZH2/H3K27me3 signaling pathway

文献类型： 外文期刊

第一作者： Li, Hui

作者： Li, Hui;Zhao, Fang;Zhao, Weimin;Chen, Fang;Fu, Yanfeng;Li, Bixia;Cheng, Jinhua;Shen, Jie;Deng, Yanfei;Ma, Shinan

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关键词： TGF-01; DHCR24; De novo cholesterol biosynthesis

期刊名称：INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES （ 影响因子：8.2； 五年影响因子：7.8 ）

ISSN： 0141-8130

年卷期： 2023 年 224 卷

页码：

收录情况： SCI

摘要： Cholesterol is a precursor to steroid hormones and can be obtained from serum LDL or de novo synthesis in steroidogenic cells. Before luteinizing hormone (LH) surge-induced ovulation, follicles remain avascular, and cholesterol required for progesterone production in granulosa cells (GCs) is derived from de novo biosynthesis. Previous studies have verified that the intrafollicular TGF-01 plays inhibitory roles in GCs luteinization, vascularization, and progesterone production. Nevertheless, the regulatory function of TGF-01 on de novo cholesterol synthesis in granulosa-lutein (GL) cells remains largely unknown. We aim to investigate this aspect in this study using in vivo cultured human GL cells. Our results suggested that TGF-01 significantly suppresses intracellular cholesterol levels and down-regulates the expression of the final step enzyme, DHCR24, that cat-alyzes de novo cholesterol synthesis. We used specific inhibitors and siRNA-mediated knockdown approaches demonstrate that TGF-01 suppression of DHCR24 expression in GL cells is mediated by the GSK-30/EZH2/ H3K27me3 signaling pathway. Further ChIP assays revealed that elevated H3K27me3 levels in the promoter region of DHCR24 play a vital role in TGF-01-induced DHCR24 down-regulation, and RNA-sequencing results confirmed these findings. Notably, our study provides a novel insight into the molecular mechanisms by which TGF-01 suppresses de novo cholesterol biosynthesis in GL cells.

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