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

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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.