Androgen-mediated Perturbation of the Hepatic Circadian System Through Epigenetic Modulation Promotes NAFLD in PCOS Mice
Androgen-mediated Perturbation of the Hepatic Circadian System Through Epigenetic Modulation Promotes NAFLD in PCOS Mice
复制标题
DOI：
10.1210/endocr/bqac127
复制
发表时间：
2022-10-01
期刊：
影响因子：
4.8
通讯作者：
Sen, Aritro
中科院分区：
文献类型：
--
作者：
Roy, Sambit;Abudu, Aierken;Sen, Aritro
在女性中，雄激素过多会导致多囊卵巢综合征（PCOS），这是一种常见的生育障碍，同时伴有代谢功能障碍，包括糖尿病、肥胖和非酒精性脂肪性肝病。通过PCOS小鼠模型，本研究表明，慢性高雄激素水平导致肝脂肪变性，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，我们已经确定了受高雄激素症影响的关键代谢基因和途径。我们的研究表明，大量代谢基因通过AR结合这些基因启动子区域上的雄激素反应元件序列，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不同调节。使用昼夜节律报告因子[Period2::Luciferase (Per2::LUC)]小鼠模型进行的体内和体外研究表明，雄激素可以直接破坏肝脏定时系统，而肝脏定时系统是肝脏代谢的关键调节因子。因此，研究表明雄激素通过抑制组蛋白甲基转移酶Ezh2的表达来降低核心时钟基因启动子上的基因沉默标记H3K27me3，同时诱导组蛋白去甲基化酶JMJD3的表达，JMJD3分别负责添加和去除H3K27me3标记。最后，我们报告说，在高雄激素条件下，一些在小鼠肝脏中上调的昼夜节律/代谢基因在非人灵长类动物肝脏中也升高。综上所述，这些研究不仅全面了解了多囊卵巢综合征相关的高雄激素血症如何影响肝脏基因表达和代谢，而且还深入了解了多囊卵巢综合征导致肝脏脂肪变性的潜在机制。
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.