TY - JOUR
TI - 5 alpha-Reductase Type 2 Regulates Glucocorticoid Action and Metabolic
Phenotype in Human Hepatocytes
AU - Nasiri, Maryam
AU - Nikolaou, Nikolaos
AU - Parajes, Silvia
AU - Krone,
AU - Nils P.
AU - Valsamakis, George
AU - Mastorakos, George
AU - Hughes,
AU - Beverly
AU - Taylor, Angela
AU - Bujalska, Iwona J.
AU - Gathercole, Laura
AU - L.
AU - Tomlinson, Jeremy W.
JO - US Endocrinology
PY - 2015
VL - 156
TODO - 8
SP - 2863-2871
PB - ENDOCRINE SOC
SN - null
TODO - 10.1210/en.2015-1149
TODO - null
TODO - Glucocorticoids and androgens have both been implicated in the
pathogenesis of nonalcoholic 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 prereceptor level by the enzyme 5
alpha-reductase type 2 (SRD5A2), which inactivates glucocorticoids to
their dihydrometabolites and converts T to 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. Whereas
androgen treatment (T 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 5
alpha-reductase inhibitors finasteride and dutasteride augmented
cortisol action. We have demonstrated that manipulation of SRD5A2
activity can regulate lipogenesis in human hepatocytes in vitro. This
may have significant clinical implications for those patients prescribed
5 alpha-reductase inhibitors, in particular augmenting the actions of
glucocorticoids to modulate hepatic lipid flux.
ER -