5α-Reductase Type 2 Regulates Glucocorticoid Action and Metabolic Phenotype in Human Hepatocytes
Open accessAbstract
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.
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Both T and DHT increase lipogenesis in human hepatocytes of female but not male donors.
“Both T and DHT have recently been shown to increase lipogenesis in human hepatocytes of female (but not male) donors (Nasiri et al., 2015)”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Nasiri et al., 2015
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Intracrine androgen biosynthesis, metabolism and action revisited
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“Both T and DHT have recently been shown to increase lipogenesis in human hepatocytes of female (but not male) donors (Nasiri et al., 2015) and androgens have been shown to play a crucial role in the development of hepatocellular carcinoma (Kalra et al., 2008; Kanda et al., 2014).”
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- Authors
- Nasiri, M., Nikolaou, N., Parajes, S., Krone, N. P., Valsamakis, G., Mastorakos, G., Hughes, B., Taylor, A., Bujalska, I. J., Gathercole, L. L., & Tomlinson, J. W.
- Affiliations
- Churchill Hospital (GB)
- Corresponding author
- Tomlinson, Jeremy W.
- ORCID
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2015-08
- Volume
- 156
- Issue
- 8
- Pages
- 2863-2871
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC4511138
- OpenAlex
- W1845645347
- Cited by
- 50
- References
- 32
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 4 · 2023: 1 · 2022: 14 · 2021: 9 · 2020: 3 · 2019: 3 · 2018: 5 · 2017: 3 · 2016: 3 · 2015: 1
- FWCI
- 3.14
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Endocrinology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- 5α-reductase type 2, SRD5A2, glucocorticoid activity, androgens, dihydrotestosterone, cortisol, de novo lipogenesis, hepatic lipid metabolism, non-alcoholic fatty liver disease, 5-alpha reductase inhibitors, finasteride, dutasteride, sex differences, human hepatocytes
- MeSH terms
- Adult, Aged, Androgens, Biological Transport, Cells, Cultured, Female, Glucocorticoids, Humans, Insulin, Male, Membrane Proteins, Middle Aged, Phenotype, 3-Oxo-5-alpha-Steroid 4-Dehydrogenase, Finasteride, Hepatocytes, Lipogenesis, 5-alpha Reductase Inhibitors
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