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

雄激素对患有 NAFLD 的年轻女性组织特异性脂质代谢和肝损伤的影响

• 批准号: 10355174
• 负责人: Monika Sarkar
• 金额: $ 12.11万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10355174
• 关键词: Address; Adipose tissue; Age; Androgen Receptor; Androgens; Biopsy; Blood; Blood Circulation; Central obesity; Ceramides; Clinical Data; Collection; Data; Disease Progression; Enrollment; Evaluation; Fatty Acids; Fatty acid glycerol esters; Female; Fibrosis; Funding; Future; Glycerophospholipids; Goals; Grant; Histologic; Histology; Hyperandrogenism; Image; Institution; Insulin Resistance; Lipids; Liver; Liver diseases; Measurement; Measures; Metabolic; Metabolic Diseases; Obesity; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phospholipids; Polycystic Ovary Syndrome; Population; Populations at Risk; Production; Progressive Disease; Protocols documentation; Public Health; Research Infrastructure; Risk; Risk Factors; Role; Serum; Severities; Sphingomyelins; Testosterone; Therapeutic; Tissues; Travel; Visceral; Visceral fat; Woman; Work; abdominal fat; aged; androgen excess; antagonist; bariatric surgery; lipidomics; liver injury; liver transplantation; men; modifiable risk; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; precision medicine; receptor expression; reproductive; sexual dimorphism; subcutaneous; therapeutic target; transcriptome sequencing; young adult; young woman

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.

抽象的 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 由于缺乏批准的药物疗法，需要确定可改变的风险因素并量身定制 年轻女性的治疗目标。正如我们 K23 资助的数据显示的那样，雄激素可能提供这样的目标 高雄激素女性具有更严重的 NASH 组织学特征，并且睾酮水平更高 增加 NASH 和 NASH 纤维化的风险，包括没有雄激素过多的年轻女性。然而， 循环睾酮水平与肝组织中雄激素受体（AR）表达的关联尚未发现 进行了评估，这与未来评估年轻女性 NASH 的 AR 拮抗作用的研究相关。 年轻女性从雄激素到 NASH 的机制途径还需要进一步研究 阐明，内脏脂肪可能是一个关键因素。我们已经证明睾酮与 患有 NAFLD 的年轻女性腹部肥胖，与我们之前的数据一致，显示内脏肥胖 解释了睾酮与影像学证实的女性 NAFLD 之间存在很大程度的关联。 这些发现与临床数据一致，其中接受外源睾酮治疗的女性重新分配脂肪 从皮下储存到内脏储存，并观察到高雄激素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多种途径导致 NASH 途径，包括产生一些脂毒性脂质及其脂肪酸前体。在雄激素过多症中 女性，外源性雄激素的使用会增加甘油磷脂的血清水平，甘油磷脂是一种脂质，可能具有 肝脏中的脂毒性潜力，因为此类脂质的血清水平已与活检证实相关 女性 NASH。先前没有研究评估雄激素是否与这种组织水平相关， 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 相关。 利用我们机构现有的研究基础设施，我们将进行横截面血清 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 在 35 名患有一系列 NAFLD 并接受减肥手术的育龄妇女中获得。这些 测量将用于评估循环睾酮与组织水平 AR 表达的关联 肝脏和内脏脂肪，以及 AR 表达是否与 NASH 组织学相关（目标 1）。我们也会 评估雄激素与肝脏和内脏脂肪组织的脂质代谢物的关联 与 NASH 的存在和/或严重程度相关（目标 2）。研究结果的影响：这些数据将告知 后续R01全面评估雄激素、内脏脂肪、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 的潜在可改变危险因素和治疗靶点，作为 精准医疗方法可减轻不断增长的高危年轻女性群体中 NASH 的进展。