The prevalence of metabolic syndrome and its hepatic manifestation, non-alcoholic fatty liver disease (NAFLD), continues to escalate. Glucocorticoids (GCs) and bile acids (BAs) are established regulators of metabolic phenotype. 5β-reductase (AKR1D1) is highly expressed in human and rodent liver, where it inactivates steroid hormones and catalyses a fundamental step in BA synthesis. We have previously demonstrated that AKR1D1 modulates hepatic GC availability and GC receptor (GR) activation in human hepatocytes, in addition to alterations in triglyceride accumulation, fatty acid oxidation, insulin sensitivity and intracellular inflammation. However, the potential role of GCs to regulate AKR1D1 expression and activity is completely unknown. In vitro, human liver HepG2 and Huh7 cells were treated with 500 nM dexamethasone for 24h and expression changes of key enzymes involved in steroid metabolism and BA synthesis were measured by qPCR and western blotting. As expected, dexamethasone induced the mRNA and protein expression of the GR-dependent genes DUSP1 and GILZ. In both cell lines, dexamethasone down-regulated AKR1D1 mRNA and protein expression (vehicle: 0.82±0.08 vs. dex: 0.64±0.06, P<0.01), with a parallel decrease in cortisone clearance (vehicle: 41.52±5.26 vs. dex: 52.78±4.69 nmol/g protein, P<0.01). CYP7A1, CYP8B1 and HSD3B7 mRNA expression were significantly increased. Pharmacological antagonism of the GR with RU-486, reversed all the dexamethasone-induced changes in gene expression. In contrast to our cellular observations, hepatic AKR1D1 mRNA and protein expression were increased in C57BL6/J mice following corticosterone treatment (vehicle: 0.54±0.08 vs. cort: 0.94±0.07, P<0.01). CYP7A1 and CYP8B1 mRNA and protein expression were also increased. However, in healthy male volunteers (n=14), dexamethasone significantly decreased urinary 5β-tetrahydrocortisol (5β-THF) excretion (pre: 329.8±23.15 vs. post: 155.8±18.22ug/8h, P<0.001) without alteration in 5α-THF excretion, consistent with decreased AKR1D1 activity. In conclusion, GCs differentially regulate AKR1D1 expression and activity in humans and rodents. In human models, down regulation of AKR1D1 activity, may act as a feed-forward mechanism, augmenting glucocorticoid action with the potential to drive adverse effects.
18 - 21 May 2019
European Society of Endocrinology