Endocrine Abstracts (2019) 65 P186 | DOI: 10.1530/endoabs.65.P186

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

Shelley Harris1, Nikolaos Nikolaou1, Anastasia Arvaniti1,2, Roger Cox3, Laura Gathercole2 & Jeremy Tomlinson1


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.

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