Myeloid cell deletion of Aryl hydrocarbon Receptor Nuclear Translocator (ARNT) induces non-alcoholic steatohepatitis

Autoři: Christopher Scott aff001;  Rebecca Stokes aff001;  Kuan Minn Cha aff001;  Andrew Clouston aff004;  Mohammed Eslam aff002;  Mayda Metwally aff002;  Michael M. Swarbrick aff001;  Jacob George aff002;  Jenny E. Gunton aff001
Působiště autorů: Centre for Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia aff001;  Sydney Medical School, The University of Sydney, Sydney, NSW, Australia aff002;  Garvan Institute of Medical Research, Darlinghurst, NSW, Australia aff003;  Envoi Specialist Pathologists, Brisbane, Queensland, Australia aff004;  Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia aff005;  St. Vincent’s Clinical School, University of NSW, Sydney, NSW, Australia aff006
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article


Background and aim

Non-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.


Floxed-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.


Animals 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).


Decreased 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.

Klíčová slova:

Bone marrow cells – Fats – Fatty liver – Gene expression – Histology – Inflammation – Liver diseases – Macrophages


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