EYES2019 7th ESE Young Endocrinologists and Scientists (EYES) Meeting Oral Presentations (67 abstracts)
AKR1D1 is a novel regulator of metabolic phenotype in human hepatocytes and is dysregulated in non-alcoholic fatty liver disease
Nikolaos Nikolaou 1 , Laura L Gathercole 1, , Lea Marchand 1 , Sara Althari 1 , Niall J Dempster 1 , Charlotte J Green 1 , Martijn van de Bunt 1 , Catriona McNeil 1 , Anastasia Arvaniti 1, , Beverly A Hughes 4 , Bruno Sgromo 5 , Richard S Gillies 5 , John Ryan 3 , Wiebke Arlt 4 , Leanne Hodson 1 & Jeremy W Tomlinson 1
1Oxford Centre for Diabetes, Endocrinology and Metabolism, NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Oxford, UK, OX3 7LE, UK; 2Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, OX3 0BP, UK; 3Translational Gastroenterology Unit, University of Oxford, Oxford, UK; 4Institute of Metabolism and Systems Research, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK; 5Department of Upper GI Surgery, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Objective: Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome. Steroid hormones and bile acids are potent regulators of hepatic carbohydrate and lipid metabolism. Steroid 5β-reductase (AKR1D1) is highly expressed in human liver where it inactivates steroid hormones and catalyzes a fundamental step in bile acid synthesis.
Methods: Human liver biopsies were obtained from 34 obese patients and AKR1D1 mRNA expression levels were measured using qPCR. Genetic manipulation of AKR1D1 was performed in human HepG2 and Huh7 liver cells. Metabolic assessments were made using transcriptome analysis, western blotting, mass spectrometry, clinical biochemistry, and enzyme immunoassays.
Results: In human liver biopsies, AKR1D1 expression decreased with advancing steatosis, fibrosis and inflammation. Expression was decreased in patients with type 2 diabetes. In human liver cells, AKR1D1 knockdown decreased bile acid biosynthesis and steroid hormone clearance. RNA sequencing identified disruption of key metabolic pathways, including insulin action and fatty acid metabolism. AKR1D1 knockdown increased hepatocyte triglyceride accumulation, insulin sensitivity, and glycogen synthesis, through increased de novo lipogenesis and decreased β-oxidation, fueling hepatocyte inflammation. Pharmacological manipulation of bile acid receptor activation prevented the induction of lipogenic and carbohydrate genes, suggesting that the observed metabolic phenotype is driven through bile acid rather than steroid hormone availability.
Conclusions: Genetic manipulation of AKR1D1 regulates the metabolic phenotype of human liver cells, driving steatosis and inflammation. Taken together, with the observation that AKR1D1 mRNA expression is down-regulated with advancing NAFLD, suggests that it may have a crucial role in the pathogenesis and progression of the disease.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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