Endocrine Abstracts

Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders affecting 6-15% of women of reproductive age. The syndrome is characterised by a variety of reproductive and metabolic features, including hyperandrogenism, chronic anovulation and hirsutism as well as insulin resistance, dyslipidaemia, and non-alcoholic fatty liver disease (NAFLD). Specifically regarding NAFLD, androgen excess is hypothesised to have a direct effect on hepatic lipid storage, thus making patients with PCOS more prone to develop fatty liver. Bile acids (BAs) have been shown to play a central role in the pathogenesis of NAFLD, and elevated serum primary BA levels have been recently observed in patients with PCOS. However, the cellular processes that drive alterations in BA profiles in PCOS are unknown. We hypothesised that androgen excess modulates BA synthesis in the liver. C57BL/6J female mice were treated with either dihydro-testosterone (DHT) or placebo for 90-120 days, and liver samples were collected for downstream analyses. Primary human hepatocytes were treated with either testosterone (50nM) or dihydrotestosterone (10nM) for 24 h. mRNA and protein expression of BA-synthesising and BA-regulated enzymes were measured by qPCR and western blotting, respectively. In C57BL/6J female mice, DHT treatment significantly increased sterol 12α-hydroxylase (CYP8B1) expression at both mRNA and protein level. However, no significant differences in the expression of other BA-synthesising and BA-regulated enzymes were observed (Cyp7a1, Cyp27a1, Akr1d1, Nr0b2, Nr5a2). Supporting these data, both testosterone and DHT treatment significantly increased CYP8B1 protein levels in primary human hepatocytes compared to vehicle-treated cells. In conclusion, these data suggest an as yet unknown role of androgens in the regulation of BA synthesis. More experiments are now required to elucidate the importance of these findings on hepatic metabolic phenotype both in vivo and in vitro.