Boya Zhang¹, Sandra Calvo Blanco¹, Bart Wouters¹, Oriana Nobus¹, Karolien De Bosscher², Vanessa Dubois¹

¹ Basic and Translational Endocrinology (BaTE) Laboratory, Ghent University, Ghent, Belgium

² Translational Nuclear Receptor Research lab, VIB-Center for Medical Biotechnology, Ghent, Belgium

Androgens, that primarily act through the androgen receptor (AR), have anti-steatosic effects in male liver, while in female liver they promote lipid accumulation. This project aims to understand how one transcription factor can exert opposing actions on the same tissue depending on the sex. Unraveling these molecular underpinnings is clinically relevant in the context of hormonal replacement for hypogonadism in men, and polycystic ovarian syndrome in women.

First, we will unravel AR contribution to the sex-dependent hepatic androgen action. Hereto, adult mice of both sexes will be injected with degarelix to suppress endogenous hormone production, and treated for two weeks with vehicle, testosterone or dihydrotestosterone, a non-aromatizable androgen enabling to distinguish androgenic from estrogenic effects, while being fed a western diet. Biochemical, histological, and molecular readouts will quantify hepatic steatosis. A follow-up experiment will confirm AR involvement by co-treatment with the AR antagonist enzalutamide. Next, we will investigate the molecular determinants of the sex-dependent hepatic response to androgens. We hypothesize that the opposing actions of the AR in male versus female liver partly rely on differential chromatin binding and/or distinct interactions with transcriptional regulators. Livers from above-described mice will be subjected to integrative ATAC-seq profiling, transcriptomics, and proteomics. Finally, functional relevance will be assessed in vivo. Candidate regulators will be perturbed pharmacologically or through tail-vein siRNA delivery in the mouse models described above, followed by phenotypic and transcriptomic assessment.

Altogether, this work will uncover the molecular basis of sex-dependent hepatic androgen action, advancing precision approaches to hormone-related metabolic diseases.