Regulation of the metabolic phenotype of human hepatocytes by glucocorticoids and androgens

Nasiri, Maryam (2016). Regulation of the metabolic phenotype of human hepatocytes by glucocorticoids and androgens. University of Birmingham. Ph.D.

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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 5αR2 (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 overexpression 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 5αR inhibitors finasteride and dutasteride, augmented cortisol action.
We have demonstrated that manipulation of 5αR2 activity can regulate lipogenesis in human hepatocytes in vitro. This may have significant clinical implications for those patients prescribed 5αR inhibitors, in particular augmenting the actions of glucocorticoids to modulate hepatic lipid flux.

Type of Work: Thesis (Doctorates > Ph.D.)
Award Type: Doctorates > Ph.D.
College/Faculty: Colleges (2008 onwards) > College of Medical & Dental Sciences
School or Department: School of Clinical and Experimental Medicine
Funders: Medical Research Council, Other
Other Funders: The University of Birmingham
Subjects: R Medicine > RC Internal medicine


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