Abstract
Background and aimNon-alcoholic steatohepatitis (NASH) is predicted to become the most common cause of cirrhosis and liver failure. Risk factors include obesity, insulin resistance and diabetes. Macrophages and other myeloid cells play crucial roles in initiating and driving inflammation. Aryl hydrocarbon Receptor Nuclear Translocator (ARNT) is a transcription factor which binds to a range of partners to mediate responses to environmental signals, including the diet. In people with diabetes it is decreased in liver. We hypothesised that myeloid cell ARNT activity may contribute to the development of liver pathology.MethodsFloxed-ARNT mice were bred with LysM-Cre mice to generate mice with reduced ARNT in myeloid cells. Animals were fed a high fat diet (HFD) and liver pathology was assessed. Histology, mRNA, fat accumulation and metabolism were studied.ResultsAnimals with reduced myeloid ARNT developed steatohepatitis on a HFD, with additional alterations of metabolism and fat deposition. Steatohepatitis was accompanied by hepatic macrophage infiltration and expression of both M1 and M2 markers. Expression of mRNAs for Cxcl1, Mcp-1, Tnf-α and Tgf-β1 were increased. Human livers from controls and people with NASH were tested; ARNT mRNA was decreased by 80% (p = 0.0004).ConclusionsDecreased myeloid ARNT may play a role in the conversion from non-alcoholic fatty liver to steatohepatitis. Increasing ARNT may be a therapeutic strategy to reduce NASH.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is defined as the accumulation of excess, microscopically visible lipid in hepatocytes in the absence of excessive alcohol consumption and is the most common chronic liver disease in developed countries [1, 2]
Human livers from controls and people with non-alcoholic steatohepatitis (NASH) were tested; Aryl hydrocarbon Receptor Nuclear Translocator (ARNT) mRNA was decreased by 80% (p = 0.0004)
Decreased myeloid ARNT may play a role in the conversion from non-alcoholic fatty liver to steatohepatitis
Summary
Non-alcoholic fatty liver disease (NAFLD) is defined as the accumulation of excess, microscopically visible lipid in hepatocytes in the absence of excessive alcohol consumption and is the most common chronic liver disease in developed countries [1, 2]. The risk of NAFLD is increased with obesity, insulin resistance and type 2 diabetes mellitus (T2DM); the incidence of these risk factors has been increasing in recent years [3]. ~20% of patients with NAFLD progress to develop non-alcoholic steatohepatitis (NASH), which in addition to steatosis is characterised by lobular inflammation, hepatocyte ballooning and fibrosis [4]. Factors known to influence the progression from NAFLD to NASH include greater hepatocyte lipid accumulation, insulin resistance, oxidative stress leading to lipid peroxidation, production of pro-inflammatory cytokines, and mitochondrial dysfunction [7,8,9]. Non-alcoholic steatohepatitis (NASH) is predicted to become the most common cause of cirrhosis and liver failure. We hypothesised that myeloid cell ARNT activity may contribute to the development of liver pathology
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