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卫生影响是 由于缺乏经批准的药物治疗，需要确定可改变的风险因素， 年轻女性的治疗目标。雄激素可能提供这样的目标，因为我们的K23资助的数据显示， 雄激素过多的女性有更严重的NASH组织学特征，睾酮水平更高， NASH和NASH纤维化风险增加，包括没有雄激素过多的年轻女性。然而，在这方面， 循环睾酮水平和肝组织中雄激素受体（AR）表达的相关性尚未被证实， 这与未来评估年轻女性NASH的AR拮抗作用的研究相关。 在年轻女性中，从雄激素到NASH的机制途径还需要进一步研究。 说明，内脏脂肪可能是一个关键因素。我们已经证明睾丸激素与 NAFLD年轻女性的腹部肥胖，与我们先前的数据一致，表明内脏肥胖 解释了睾丸激素与女性影像学证实的NAFLD之间的显著相关性。 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一致 从皮下到内脏储存，并观察到高雄激素血症患者内脏脂肪体积减少， 接受AR拮抗剂治疗的女性。内脏脂肪被认为通过几种途径促成NASH。 途径，包括产生一些脂毒性脂质及其脂肪酸前体。在高雄激素 在女性中，外源性雄激素的使用增加了血清甘油磷脂的水平，这是一种脂质类， 肝脏中的脂毒性潜力，因为这类脂质的血清水平与活检证实的 女性NASH以前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，或这些组织水平的代谢物是否与NASH相关。 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 雄激素，全面的脂质组学，以及利用血液，内脏脂肪和肝脏组织的AR RNA测序 在35名接受减肥手术的患有NAFLD的育龄妇女中获得。这些 将使用测量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组织学相关（目的1）。我们还将 评估雄激素与来自肝脏和内脏脂肪组织的脂质代谢物的相关性， 与NASH的存在和/或严重程度相关（目的2）。调查结果的影响：这些数据将为 随后的R 01，以全面评估雄激素、内脏脂肪和NASH的关系 年轻女性的进展，包括有针对性的脂质组学评估。这项工作符合我更广泛的目标 研究雄激素作为NASH潜在的可改变的风险因素和治疗靶点，作为一项 精准医学方法，以缓解日益增长的高危年轻女性人群中的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.