Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2019) 65 P186 | DOI: 10.1530/endoabs.65.P186

SFEBES2019 POSTER PRESENTATIONS Metabolism and Obesity (104 abstracts)

AKR1D1 (5β-reductase) deletion drives hepatic inflammation, fibrosis and tumour development in vivo

Shelley Harris 1 , Nikolaos Nikolaou 1 , Anastasia Arvaniti 1, , Roger Cox 3 , Laura Gathercole 2 & Jeremy Tomlinson 1

1University of Oxford, Oxford, UK; 2Oxford Brookes University, Oxford, UK; 3MRC Harwell Institute, Didcot, UK

The enzyme 5β-reductase (AKR1D1) catalyses an essential step in bile acid synthesis. In addition, it controls intra-cellular steroid hormone availability through hormone clearance. As disturbances in steroid hormones and bile acid metabolism have potent effects on metabolic health, we hypothesize that AKR1D1 may play a role hepatic lipid accumulation. We generated global AKR1D1 knockout mice (KO) alongside wild-type controls (WT). Mice were fed either normal chow (NC) or the American lifestyle induced obesity syndrome diet (ALIOS; 45% fat, 55% fructose: 45% glucose in H2O), which replicates the clinical features of non-alcoholic fatty liver disease (NAFLD), for 52 weeks. AKR1D1 KO mice fed ALIOS had increased hepatic steatosis in comparison with WT mice (WT: 16.7±3.3, KO: 21.7±3.6 mg/g, P<0.005). In addition, there was evidence of increased hepatic inflammation scores in male AKR1D1 KO mice on NC (1.6 vs. 1.1, P<0.01), but not ALIOS. However, liver biochemistry was significantly elevated in AKR1D1 KO mice fed ALIOS in comparison with WT mice (ALT; WT: 140.7±51.9, KO: 404.7±171.4 U/l, P<0.05. AST; WT: 136.7±39.0, KO: 360.7±121.7 U/l, P<0.05). Endorsing observations in our rodent model, AKR1D1 knockdown experiments in human hepatoma cells increased mRNA expression and secretion of pro-inflammatory cytokines (IL1β, IL-6 and IL-8). Hepatic inflammation is a key driver of fibrosis. AKR1D1 KO mice fed ALIOS had increased hepatic fibrosis as quantified by sirius red staining (WT: 5.4±2.6%, KO: 10.0±4.9%, P<0.01). Furthermore, it is well-established that advanced fibrotic metabolic liver disease increases the risk for the development of hepatocellular carcinoma (HCC) and AKR1D1 KO mice were more prone to tumour development (WT: 11.5%, KO: 42.1%, P<0.05). Deletion of AKR1D1 in combination with dietary stress evokes increased hepatic triacylglycerol content and fibrosis, which could exacerbate the progression of NAFLD to NASH and potentially fuel development of HCC.

Volume 65

Society for Endocrinology BES 2019

Brighton, United Kingdom
11 Nov 2019 - 13 Nov 2019

Society for Endocrinology 

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