Influence of Androgens on Tissue-Specific Lipid Metabolites and Liver Injury in Young Women with NAFLD

摘要 非酒精性脂肪性肝炎(NASH)对女性和年轻人的公共健康影响是 由于缺乏已获批准的药物疗法，因此有必要确定可改变的风险因素并量身定做 年轻女性的治疗靶点。正如我们K23资助的数据显示的那样，雄激素可能会提供这样的靶点 高雄激素性女性NASH的组织学特征更严重，睾酮水平更高 增加NASH和NASH纤维化的风险，包括在没有雄激素过剩的年轻女性中。然而， 循环睾酮水平与肝组织雄激素受体(AR)表达的相关性尚未见报道 这与未来评估年轻女性对NASH的AR拮抗作用有关。 年轻女性从雄激素到NASH的机制途径也需要进一步的 阐明，内脏脂肪可能是一个关键因素。我们已经证明，睾丸激素与 患有NAFLD的年轻女性中的腹型肥胖，与我们之前的数据显示内脏肥胖是一致的 在很大程度上解释了睾丸激素与影像证实的女性NAFLD之间的关联。 这些发现与接受外源性睾酮治疗的女性重新分配脂肪的临床数据相一致。 从皮下到内脏储存，观察到高雄激素者内脏脂肪体积的减少 接受AR拮抗剂治疗的女性。内脏脂肪被认为是通过以下几种途径导致NASH的 途径，包括一些脂毒性脂质及其脂肪酸前体的产生。在高雄激素水平上 女性，使用外源性雄激素会增加血清甘油磷脂的水平，这是一种可能具有 肝脏中的脂毒性潜力，因为血清中这类脂类的水平与活检证实有关 女人中的纳什。之前还没有研究评估雄激素是否与组织水平有关， 或肝脏或内脏脂肪中的其他脂质代谢物，或者这些组织水平的代谢物是否与NASH有关。 利用我们机构现有的研究基础设施，我们将进行横断面血清检测 利用血液、内脏脂肪和肝组织进行雄激素、综合脂质组学和AR RNA测序 35名患有NAFLD谱系的育龄妇女在接受减肥手术时获得。这些 这些措施将被用来评估循环睾酮与组织水平AR表达的相关性 肝脏和内脏脂肪，以及AR表达是否与NASH组织学有关(目标1)。我们还将 评估雄激素与来自肝脏和内脏脂肪组织的脂代谢产物的相关性 与NASH的存在和/或严重程度有关(目标2)。调查结果的影响：这些数据将向 随后的R01综合评价雄激素、内脏脂肪和NASH的关系 年轻女性的进展，包括有针对性的脂类评估。这项工作与我更广泛的目标一致 将雄激素作为NASH潜在的可改变的危险因素和治疗靶点进行研究，作为 在不断增长的高危年轻女性人口中，采用精准医学方法缓解NASH进展。

ABSTRACT The public health implications of nonalcoholic steatohepatitis (NASH) in women and young adults is vast, and given lack of approved drug therapies, there is need to identify modifiable risk factors and tailored therapeutic targets in young women. Androgens may provide such target as our K23-funded data show hyperandrogenic women to have more severe histologic features of NASH, and that higher testosterone levels increase risk for NASH and NASH fibrosis, including among young women without androgen excess. However, the association of circulating testosterone levels and androgen receptor (AR) expression in liver tissue has not been evaluated, which is relevant to future studies evaluating AR antagonism for NASH in young women. The mechanistic pathway leading from androgens to NASH in young women also requires further elucidation, and visceral fat may be a key contributor. We have shown that testosterone is associated with abdominal obesity in young women with NAFLD, consistent with our prior data showing that visceral adiposity explained a substantial degree of the association of testosterone with imaging-confirmed NAFLD in women. These findings align with clinical data in which females treated with exogenous testosterone redistribute fat from subcutaneous to visceral stores, and observed reductions in visceral fat volume among hyperandrogenic women treated with an AR antagonist. Visceral fat is proposed to contribute to NASH through several pathways, including production of some lipotoxic lipids and their fatty acid precursors. In hyperandrogenic women, exogenous androgen use increases serum levels of glycerophospholipids, a lipid class that may have lipotoxic potential in the liver, as serum levels of this lipid class have been associated with biopsy-confirmed NASH in women. No prior studies have evaluated whether androgens are associated with tissue levels of this, or other lipid metabolites in liver or visceral fat, or whether these tissue-level metabolites associate with NASH. Leveraging an existing research infrastructure at our institution, we will perform cross sectional serum androgens, comprehensive lipidomics, and AR RNA sequencing utilizing blood, visceral fat, and liver tissue obtained in 35 reproductive-aged women with a spectrum of NAFLD undergoing bariatric surgery. These measures will be used to evaluate the association of circulating testosterone with tissue-level AR expression in liver and visceral fat, and whether AR expression associates with NASH histology (Aim 1). We will also evaluate the association of androgens with lipid metabolites from liver and visceral fat tissue that are associated with presence and/or severity of NASH (Aim 2). Impact of findings: These data will inform a subsequent R01 to comprehensively evaluate the relationship of androgens, visceral fat, and NASH progression in young women, including a targeted lipidomic evaluation. This work aligns with my broader goal of studying androgens as a potential modifiable risk factor and therapeutic target for NASH, as part of a precision medicine approach to mitigate NASH progression in the growing population of at-risk young women.