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

摘要 在年轻人中，非酒精性脂肪性肝炎(NASH)所致的肝硬化率正在迅速上升，并给予有限的 治疗方法和受影响个体的异质性，迫切需要找出量身定做的 针对高危青年人群的治疗目标。雄激素可能反映了10%-15%的人的这种目标，或者接近 1000万多囊卵巢综合征(PCOS)育龄妇女。多囊卵巢综合征通常由 雄激素升高，这些妇女中超过50%患有非酒精性脂肪肝。我们已经证明了多囊卵巢综合征会增加风险 流行的NASH和晚期NASH纤维化，发生在比非PCOS对照组更年轻的年龄。 高雄激素可能解释了他们在疾病严重程度上观察到的“领先”，因为我们的横断面数据来自 没有多囊卵巢综合征的年轻女性发现较高的(尽管正常范围)睾酮水平与多囊卵巢综合征有关 纳什纤维症。雄激素升高是否是多囊卵巢综合征肝损伤风险的基础，以及潜在的 发生这种情况的机械途径尚不清楚。我们的发现将支持雄激素受体 对于患有多囊卵巢综合征和肝病的大量女性来说，拮抗是一个潜在的治疗靶点。 我们的中心假设是雄激素促进了多囊卵巢综合征的肝损伤和NASH进展，这发生在 通过异常的脂类活性(包括脂毒性和失控的新生脂肪生成)，部分来自 对内脏脂肪的促雄激素作用。女性使用外源性雄激素确实会增加内脏脂肪，进而增加内脏脂肪 通过几个途径促进NASH，包括产生脂毒性脂质物种。雄激素也是 与多囊卵巢综合征支链氨基酸代谢失调有关，这是与合作研究者相关的 发现了一种酶的失衡导致肝脏新生脂肪生成的失调 和NASH，并通过血清支链氨基酸和酮酸的水平反映出来。 在这些数据的基础上，我们建议对150名生殖健康患者进行一项双中心(加州大学旧金山分校和杜克大学)纵向研究。 老年NASH患者(125例多囊卵巢综合征和25例非多囊卵巢综合征对照)雄激素对 多囊卵巢综合征的肝脏损伤和进展以及内脏肥胖的机制贡献(目标1)和 异常的脂代谢(目标2)与这一过程有关。目标3是一项对50个多囊卵巢综合征的机械性概念验证试验 参与者确定24周的雄激素受体阻断是否改善脂代谢产物 分别反映肝脏的脂毒性和异常的新生脂肪生成，以及影像定量 肝脏和内脏脂肪，以及纳什组织学。利用我们现有的加州大学旧金山分校PCOS队列和现有的 加州大学旧金山分校和杜克大学在NAFLD、PCOS、肥胖和脂肪代谢方面的基础设施和合作， 我们处于有利地位，能够实现所提出的目标。调查结果的影响：确定 雄激素对多囊卵巢综合征肝损伤的作用及其机制将支持疗效研究 评估雄激素受体拮抗剂对NASH的作用，或作为一种量身定制的靶向脂类特异性通路的必要性 在这一荷尔蒙不同和代谢高危人群中阻止NASH进展的方法。

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.