Abstract
Steroid 5β-reductase (AKR1D1) is highly expressed in human liver where it inactivates endogenous glucocorticoids and catalyses an important step in bile acid synthesis. Endogenous and synthetic glucocorticoids are potent regulators of metabolic phenotype and play a crucial role in hepatic glucose metabolism. However, the potential of synthetic glucocorticoids to be metabolised by AKR1D1 as well as to regulate its expression and activity has not been investigated. The impact of glucocorticoids on AKR1D1 activity was assessed in human liver HepG2 and Huh7 cells; AKR1D1 expression was assessed by qPCR and Western blotting. Genetic manipulation of AKR1D1 expression was conducted in HepG2 and Huh7 cells and metabolic assessments were made using qPCR. Urinary steroid metabolite profiling in healthy volunteers was performed pre- and post-dexamethasone treatment, using gas chromatography-mass spectrometry. AKR1D1 metabolised endogenous cortisol, but cleared prednisolone and dexamethasone less efficiently. In vitro and in vivo, dexamethasone decreased AKR1D1 expression and activity, further limiting glucocorticoid clearance and augmenting action. Dexamethasone enhanced gluconeogenic and glycogen synthesis gene expression in liver cell models and these changes were mirrored by genetic knockdown of AKR1D1 expression. The effects of AKR1D1 knockdown were mediated through multiple nuclear hormone receptors, including the glucocorticoid, pregnane X and farnesoid X receptors. Glucocorticoids down-regulate AKR1D1 expression and activity and thereby reduce glucocorticoid clearance. In addition, AKR1D1 down-regulation alters the activation of multiple nuclear hormone receptors to drive changes in gluconeogenic and glycogen synthesis gene expression profiles, which may exacerbate the adverse impact of exogenous glucocorticoids.
Highlights
Glucocorticoids (GCs) are steroid hormones that are released in response to stress and play a crucial role in inflammation and in carbohydrate, lipid and protein metabolism
In addition to governing GC availability (Kondo et al 1994, Chen et al 2011, Nikolaou et al 2019a), we have shown that AKR1D1 has an important role in regulating lipid metabolism in human hepatocytes, largely, not exclusively, through its role to limit the generation of bile acids (BAs) that can activate the farnesoid X receptor (FXR) (Nikolaou et al 2019b)
HEK293 cells were transfected with either empty pCMV6-XL4 vector (EV) or AKR1D1 containing vector (Origene Technologies) for 48 h
Summary
Glucocorticoids (GCs) are steroid hormones that are released in response to stress and play a crucial role in inflammation and in carbohydrate, lipid and protein metabolism. We have recently shown that 5β-reductase (AKR1D1) is a potent regulator of GC availability and GR activation in human hepatocytes (Nikolaou et al 2019a). In addition to governing GC availability (as well as the availability of other steroid hormones including progesterone and androgens) (Kondo et al 1994, Chen et al 2011, Nikolaou et al 2019a), we have shown that AKR1D1 has an important role in regulating lipid metabolism in human hepatocytes, largely, not exclusively, through its role to limit the generation of bile acids (BAs) that can activate the farnesoid X receptor (FXR) (Nikolaou et al 2019b)
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