5α-Reductase Type 2 Regulates Glucocorticoid Action and Metabolic Phenotype in Human Hepatocytes

Abstract

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 5α-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 5α-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 5α-reductase inhibitors, in particular augmenting the actions of glucocorticoids to modulate hepatic lipid flux.

A 5α‐reductase (SRD5A2) polymorphism is associated with serum testosterone and sex hormone–binding globulin in men, while aromatase (CYP19A1) polymorphisms are associated with oestradiol and luteinizing hormone reciprocally

“…Our findings identify SRD5A2 rs9282858 GA vs. GG as a distinct predictor of higher SHBG concentrations, not previously identified in genomewide association studies (GWAS) of serum SHBG . This may be driven by the correlation of serum T with SHBG, or possibly reflect altered action of 5α‐reductase within the liver where synthesis of SHBG occurs . By contrast, SRD5A2 rs523349 was not associated with any differences in sex hormones, SHBG or LH.…”

“…30 This may be driven by the correlation of serum T with SHBG, or possibly reflect altered action of 5α-reductase within the liver where synthesis of SHBG occurs. 31 By contrast, SRD5A2 rs523349 was not associated with any differences in sex hormones, SHBG or LH. This V89L variant exhibits modestly reduced enzyme activity in vitro.…”

Molecular Actions of Glucocorticoids in Cartilage and Bone During Health, Disease, and Steroid Therapy

“…The ineffective inactivation and high affinity of dexamethasone to the GR could lead to a prolonged activity of the GR. In addition, A-ring reductases, in particular 5␣-reductase in hepatocytes, can inactivate GCs (246), and their reduced activity leads to nonalcoholic fatty liver disease, presumably by augmenting cortisol action.…”

Changes in Physiological Parameters, Lipid Metabolism, and Expression of MicroRNAs in Genetically Improved Farmed Tilapia (Oreochromis niloticus) With Fatty Liver Induced by a High-Fat Diet

“…ELOVL6 plays a crucial role in elongating saturated fatty acids (SFA) and MUFA with 12, 14, and 16 carbons to form 18-carbon fatty acids ( Moon et al, 2001 ). SRD5A2 was shown to suppress lipogenesis by inhibiting the effects of cortisol ( Nasiri et al, 2015 ). Because these three enzymes are important regulators in lipid metabolism, we selected their encoding genes as potential miRNA targets that warranted further analysis.…”