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

English version

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
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0225332

Souhrn

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.

Methods

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.

Results

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).

Conclusions

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:

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

Zdroje

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