In women, polycystic ovarian syndrome (PCOS) is a common fertility disorder that is associated with metabolic dysfunction such as, non-alcoholic fatty liver disease (NAFLD), obesity, and insulin resistance. Androgen excess, the main feature of PCOS, significantly contributes to the development of NAFLD in women with PCOS. Recently, clinical reports establish that independent of insulin resistance and obesity, hyperandrogenism by itself causes NAFLD. Here, using a liver-specific androgen receptor knockout (AR-KO) mouse and well-characterized mouse PCOS model, we determine the role of androgens in NAFLD development in hyper-androgenic conditions. We show that hyperandrogenism causes fat accumulation, increases triglyceride levels and dysregulates metabolic gene expression in the liver. Interestingly, we found that KO of the AR in the liver rescues the NALFD phenotype and metabolic gene expression in PCOS conditions. Mechanistically, androgens modulate gene expression indirectly by regulating the trimethylation of lysine 27 of histone H3 (H3K27me3) repressive mark in downstream gene promotors both in mouse and human hepatocytes. This study shows that androgen actions, through the AR, are necessary for the development of NAFLD and liver dysfunction. However, in the female liver, androgens regulate gene expression indirectly rather than direct. This study demonstrates that the AR can be used as a therapeutic target to prevent NALFD in PCOS. Moreover, the novel in vivo and in vitro models created in this study, can be used to specifically differentiate the effects of nuclear vs extranuclear androgen actions both at a physiological and cellular level in the liver.
Read
