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Endocrine Abstracts (2015) 37 GP04.04 | DOI: 10.1530/endoabs.37.GP.04.04

1University of Oxford, Oxford, UK; 2University of Birmingham, Birmingham, UK; 3University of Athens, Athens, Greece.

Non-alcoholic fatty liver disease (NAFLD) is rapidly becoming the commonest cause of liver cirrhosis and leading indication for liver transplant worldwide. It is tightly associated with obesity and type 2 diabetes, yet the precise mechanisms that drive its aetiology are not fully defined. Dysregulation of both glucocorticoid and androgen metabolism has been implicated in its pathogenesis. The availability of these hormones to bind and activate their receptors is mainly regulated by 5α-reductase type 2 (5αR2) that inactivates glucocorticoids and converts testosterone to dihydrotestosterone (DHT). We have therefore explored the role of androgens and glucocorticoids and their metabolism by 5αR2 upon lipid homeostasis in human hepatocytes. In human hepatoma cell lines, androgen treatment (testosterone and DHT) increased de novo lipogenesis (DNL) (7001.8±258.58 (ctrl) vs 8747.76±433.39 (testosterone) and 8970.03±330.17 (DHT), P<0.05). Furthermore, androgen receptor (AR) over expression, even in the absence of androgens, increased lipogenesis (7001.8±258.58 (ctrl) vs 14 193.2±755.17 (AR), P<0.05). Changes in lipid accumulation were paralleled by changes in lipogenic gene expression including fatty acid synthase (FASN) and acetyl CoA carboxylase (ACC1) (FASN: ctrl 13.90±1.99 vs AR 66.78±6.22 and ACC1: ctrl 1.06±0.26 vs AR 3.52±0.29, P<0.05). Similar observations were made in primary human hepatocytes from female, but not male donors. Glucocorticoids decreased DNL, an effect that was abrogated by over expression of 5αR2 and augmented by pharmacological inhibition of 5αR2 activity. In conclusion, we have demonstrated the ability of androgens and glucocorticoids to regulate lipogenesis in human hepatocytes. In addition, we have identified the potential for ligand independent activation of the androgen receptor to alter lipid flux. Finally, modulation of 5αR2 activity has the ability to regulate local steroid hormone availability that can impact upon metabolic phenotype within hepatocytes that may have implications for those patients currently taking 5αR inhibitors.

Disclosure: This work was supported by the Medical Research Council (MRC) (grant number G0802765).

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