Nonalcoholic Fatty Liver Disease (NAFLD) in Polycystic Ovary Syndrome: The Role of Androgens on Liver Injury and NAFLD Progression

摘要 非酒精性脂肪性肝炎（NASH）引起的肝硬化的发病率在年轻人中迅速上升， 治疗和受影响的个体的异质性，迫切需要和未满足的需要，以确定量身定制的 针对高危年轻人群的治疗目标。雄激素可能反映这样的目标为10- 15%，或接近 多囊卵巢综合征（PCOS）是一种常见的妇科疾病。PCOS的典型特征是 雄激素升高，超过50%的女性患有NAFLD。我们已经证明多囊卵巢综合征会增加 普遍的NASH和晚期NASH纤维化，发生在比非PCOS对照更年轻的年龄。 高雄激素可以解释他们观察到的疾病严重程度的“领先优势”，因为我们的横断面数据来自 没有PCOS的年轻女性发现较高的睾酮水平（尽管在正常范围内）与PCOS相关。 NASH纤维化。雄激素升高是否是PCOS患者肝损伤风险的基础， 发生这种情况的机械途径尚不清楚。我们的发现支持雄激素受体 拮抗作用作为一个潜在的治疗目标，为广大人口的妇女多囊卵巢综合征和肝病。 我们的中心假设是雄激素促进PCOS患者的肝损伤和NASH进展， 通过异常的脂质活性（包括脂毒性和失调的从头脂肪生成），部分来自 对内脏脂肪的雄激素作用。女性使用外源性雄激素确实会增加内脏脂肪， 通过几种途径促进NASH，包括产生脂毒性脂质物质。雄激素也是 与PCOS中支链氨基酸代谢失调有关，这与共同研究者有关。 我们的团队发现了一种酶失衡，导致肝脏新生脂肪生成失调 和NASH，并且通过支链氨基酸和酮酸的血清水平反映。 在这些数据的基础上，我们提出了一项双中心（UCSF和杜克）纵向研究，包括150例生殖系统疾病患者， 老年NASH女性（125例PCOS和25例非PCOS对照），以确定雄激素对 多囊卵巢综合征的肝损伤和进展以及内脏肥胖的机制作用（目的1）， 脂质代谢异常（目的2）。目的3是50例PCOS的机制概念验证试验 参与者确定24周的雄激素受体阻断是否改善了脂质代谢， 分别反映肝脏脂毒性和新生脂肪生成失调，以及成像定量 肝脏和内脏脂肪以及NASH组织学。利用我们现有的UCSF PCOS队列和已建立的 UCSF和杜克在NAFLD、PCOS、肥胖和脂质代谢方面的基础设施和合作， 我们已作好准备，可以达到建议的目标。调查结果的影响：确定 雄激素对PCOS肝损伤的作用及其潜在机制将支持疗效研究 评估NASH的雄激素受体拮抗作用，或需要靶向脂质特异性途径作为定制的治疗方案。 这是一种阻止NASH进展的方法，在这个独特的代谢高风险人群中。

ABSTRACT Rates of cirrhosis from nonalcoholic steatohepatitis (NASH) are rapidly rising in young adults, and given limited therapies and the heterogeneity of affected individuals, there is an urgent and unmet need to identify tailored therapeutic targets for at-risk young populations. Androgens may reflect such target for the 10-15%, or nearly 10 million reproductive-aged women with Polycystic Ovary Syndrome (PCOS). PCOS is typically marked by elevated androgens, and over 50% of these women have NAFLD. We have shown PCOS to increase the risk of prevalent NASH and advanced NASH fibrosis, which occurs at a younger age than in non-PCOS controls. High androgens may explain their observed “head start” in disease severity, as our cross-sectional data from young women without PCOS found higher (though normal range) testosterone levels to be associated with NASH fibrosis. Whether elevated androgens underlie the risk of liver injury in PCOS, and the potential mechanistic pathways by which this occurs, are not known. Our findings would support androgen receptor antagonism as a potential therapeutic target for the large population of women with PCOS and liver disease. Our central hypothesis is that androgens promote liver injury and NASH progression in PCOS, which occurs through aberrant lipid activity (including lipotoxicity and dysregulated de novo lipogenesis), in part from androgenic effects on visceral fat. Exogenous androgen use in women does increase visceral fat, which in turn promotes NASH through several pathways, including production of lipotoxic lipid species. Androgens are also linked to dysregulated branched-chain amino acid metabolism in PCOS, which is relevant as co-investigators on our team have discovered an enzymatic imbalance that leads to dysregulated hepatic de novo lipogenesis and NASH, and is reflected by serum levels of branched-chain amino and ketoacids. Building upon these data, we propose a 2-center (UCSF and Duke) longitudinal study of 150 reproductive- aged women with NASH (125 PCOS and 25 non-PCOS controls) to determine the influence of androgens on liver injury and progression in PCOS and the mechanistic contributions of visceral adiposity (Aim 1) and aberrant lipid metabolism (Aim 2) to this process. Aim 3 is a mechanistic proof-of-concept trial of 50 PCOS participants to determine whether 24 weeks of androgen receptor blockade improves lipid metabolites that reflect hepatic lipotoxicity and dysregulated de novo lipogenesis, respectively, as well as imaging-quantified hepatic and visceral fat, and NASH histology. Leveraging our existing UCSF PCOS cohort and the established infrastructures and collaborations between UCSF and Duke in NAFLD, PCOS, obesity, and lipid metabolism, we are well positioned to accomplish the proposed aims. Impact of findings: Determining the contribution of androgens to liver injury in PCOS and the underlying mechanistic pathways will support efficacy studies evaluating androgen receptor antagonism for NASH, or the need to target lipid-specific pathways as a tailored approach to halt NASH progression in this hormonally-distinct and metabolically high-risk population.