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.