Reproductive and Developmental Sciences Program, Department of Animal Science, Michigan State University, East Lansing, MI, USA.
Department of Biomedical Engineering, Michigan State University, East Lansing, MI, USA.
Endocrinology. 2022 Oct 1;163(10). doi: 10.1210/endocr/bqac127.
In women, excess androgen causes polycystic ovary syndrome (PCOS), a common fertility disorder with comorbid metabolic dysfunctions including diabetes, obesity, and nonalcoholic fatty liver disease. Using a PCOS mouse model, this study shows that chronic high androgen levels cause hepatic steatosis while hepatocyte-specific androgen receptor (AR)-knockout rescues this phenotype. Moreover, through RNA-sequencing and metabolomic studies, we have identified key metabolic genes and pathways affected by hyperandrogenism. Our studies reveal that a large number of metabolic genes are directly regulated by androgens through AR binding to androgen response element sequences on the promoter region of these genes. Interestingly, a number of circadian genes are also differentially regulated by androgens. In vivo and in vitro studies using a circadian reporter [Period2::Luciferase (Per2::LUC)] mouse model demonstrate that androgens can directly disrupt the hepatic timing system, which is a key regulator of liver metabolism. Consequently, studies show that androgens decrease H3K27me3, a gene silencing mark on the promoter of core clock genes, by inhibiting the expression of histone methyltransferase, Ezh2, while inducing the expression of the histone demethylase, JMJD3, which is responsible for adding and removing the H3K27me3 mark, respectively. Finally, we report that under hyperandrogenic conditions, some of the same circadian/metabolic genes that are upregulated in the mouse liver are also elevated in nonhuman primate livers. In summary, these studies not only provide an overall understanding of how hyperandrogenism associated with PCOS affects liver gene expression and metabolism but also offer insight into the underlying mechanisms leading to hepatic steatosis in PCOS.
在女性中，过多的雄激素会导致多囊卵巢综合征（PCOS），这是一种常见的生育障碍，伴有合并代谢功能障碍，包括糖尿病、肥胖症和非酒精性脂肪肝疾病。本研究使用 PCOS 小鼠模型表明，慢性高雄激素水平会导致肝脂肪变性，而肝细胞特异性雄激素受体（AR）敲除可挽救这种表型。此外，通过 RNA 测序和代谢组学研究，我们已经确定了受雄激素过度作用影响的关键代谢基因和途径。我们的研究表明，大量代谢基因可通过 AR 与这些基因启动子区域上的雄激素反应元件序列结合而直接受到雄激素的调控。有趣的是，许多昼夜节律基因也受到雄激素的差异调控。使用昼夜节律报告基因 [Period2::Luciferase (Per2::LUC)] 小鼠模型进行的体内和体外研究表明，雄激素可直接破坏肝脏的时间系统，这是肝脏代谢的关键调节剂。因此，研究表明雄激素通过抑制组蛋白甲基转移酶 Ezh2 的表达，同时诱导组蛋白去甲基酶 JMJD3 的表达，从而直接破坏核心时钟基因启动子上的 H3K27me3 基因沉默标记，进而降低 H3K27me3。JMJD3 负责添加和去除 H3K27me3 标记。最后，我们报告称，在高雄激素条件下，在小鼠肝脏中上调的一些昼夜节律/代谢基因在非人类灵长类动物肝脏中也升高。总之，这些研究不仅提供了对与 PCOS 相关的雄激素过多如何影响肝脏基因表达和代谢的全面理解，还深入了解了导致 PCOS 中肝脂肪变性的潜在机制。
