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Steroid hormones and BAs are established regulators of metabolic phenotype. 5β-reductase (AKR1D1) is highly expressed in the liver where it inactivates steroid hormones and catalyses a fundamental step in bile acid (BA) synthesis. We have hypothesised that AKR1D1 plays a crucial regulatory role in hepatic metabolic homeostasis. Genetic manipulation of AKR1D1 was performed in human liver HepG2 and Huh7 cells. Expression changes were confirmed by qPCR and western blotting, with parallel alterations in cortisone clearance, tetrahydrocortisone generation and BA production, measured using GC-MS technology. RNA sequencing analysis following AKR1D1 knockdown identified discrete dysregulated metabolic pathways, notably those impacting upon insulin action and fatty acid (FA) storage and utilization. Insulin sensitivity was enhanced with increased insulin-stimulated phosphorylation of AKT and mTOR, following AKR1D1 knockdown. Endorsing our cellular observations, hepatic AKT, mTOR and INSRβ protein levels were higher in AKR1D1 knockout (KO) male mice than in wild type (WT) controls. In vitro, AKR1D1 knockdown increased glucose transporter mRNA expression with an associated decrease in extracellular glucose concentrations (P<0.05) and increased intracellular glycogen accumulation (P<0.05). In addition, FASN and ACC1 expression were increased, resulting in enhanced ACC phosphorylation and increased intracellular triglyceride accumulation (P<0.01). Consistent with our in vitro findings, we also observed a significant increase in total ACC levels in KO male mice. Mass spectrometry analysis of lipid composition demonstrated increased palmitic and palmitoleic acid synthesis, indicative of increased de novo lipogenesis and fatty acid saturation. Cell media 3-hydroxybutyrate levels were reduced (P<0.01). Pharmacological manipulation of BA receptor activation prevented the induction of lipogenic genes, suggesting that the observed metabolic phenotype is likely to be driven through BA rather than steroid hormone availability. In conclusion, AKR1D1 is able to regulate hepatocyte insulin sensitivity, carbohydrate and lipid metabolism, and may therefore have an as yet unexplored role in metabolic disease.

Original publication




Journal article


Endocrine Abstracts



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