5α-reductase type 2 regulates glucocorticoid action and metabolic phenotype in human hepatocytes.

Endocrinology. 2015 May 14:en20151149. [Epub ahead of print]

Nasiri M, Nikolaou N, Parajes S, Krone NP, Valsamakis G, Mastorakos G, Hughes B, Taylor A, Bujalska IJ, Gathercole LL, Tomlinson JW.

Abstract

Glucocorticoids and androgens have both been implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD); androgen deficiency in males, androgen excess in females and glucocorticoid excess in both sexes are associated with NAFLD. Glucocorticoid and androgen action are regulated at a pre-receptor level by the enzyme 5|ga-reductase type 2 (SRD5A2) that inactivates glucocorticoids to their dihydrometabolites and converts testosterone to dihydrotestosterone (DHT). We have therefore explored the role of androgens and glucocorticoids and their metabolism by SRD5A2 upon lipid homeostasis in human hepatocytes. In both primary human hepatocytes and human hepatoma cell lines, glucocorticoids decreased de novo lipogenesis in a dose-dependent manner. Whilst androgen treatment (testosterone and DHT) increased lipogenesis in cell lines and in primary cultures of human hepatocytes from female donors, it was without effect in primary hepatocyte cultures from men. SRD5A2 over-expression reduced the effects of cortisol to suppress lipogenesis and this effect was lost following transfection with an inactive mutant construct. Conversely, pharmacological inhibition using the 5α-reductase inhibitors finasteride and dutasteride, augmented cortisol action. We have demonstrated that manipulation of 5α-reductase type 2 activity can regulate lipogenesis in human hepatocytes in vitro. This may have significant clinical implications for those patients prescribed 5α-reductase inhibitors, in particular augmenting the actions of glucocorticoids to modulate hepatic lipid flux.

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