NASH or fatty liver disease, a treatment path thanks to the immune system

Two Lille research teams led by David Dombrowicz and Bart Staels within the “Nuclear receptors, cardiovascular diseases and diabetes” unit (UMR 1011 -EGID, Inserm, Institut Pasteur de Lille, University of Lille, CHU de Lille) come from ” identify specific immune cell populations in non-alcoholic steatohepatitis – also called NASH – the most common liver disease in industrialized countries. Published in Nature Metabolism, this study brings together specialists in immunology and metabolism from Lille with hepatologists from the University Hospital of Antwerp (Belgium). This discovery suggests that the immune system could represent a real therapeutic target in the treatment of NASH.

Non-alcoholic steatohepatitis, or NASH, is a chronic liver disease that affects millions of people with epidemic proportions in industrialized countries and for which there is currently no approved treatment. “Fatty liver disease”, as it is also known, caused by an overload of fats in liver cells, causes liver abnormalities, ranging from benign and reversible steatosis which can progress to non-alcoholic steatohepatitis or NASH, associated or no to fibrosis. NASH can lead to cirrhosis in about one in five cases and may require a liver transplant. It is currently the leading cause of liver transplantation in industrialized countries and the therapeutic arsenal is still booming. Obesity and type 2 diabetes are major factors favoring the development of NASH.

Continuing their work in the field of immuno-metabolism aimed at understanding the interactions between metabolism and the immune system and in the field of NASH, the research teams led by David Dombrowicz and Bart Staels, associated with Antwerp hepatologists, were able to demonstrate an association between NASH and specific populations of immune cells: a subpopulation of dendritic cells (cDC2) and cytotoxic T lymphocytes (CD8).

The progression of benign steatosis to NASH is associated with the development of intrahepatic inflammatory foci and the presence of balloon cells characteristic of hepatocyte stress. However, the underlying molecular mechanisms involved in the development of NASH are not yet well understood. Therefore, a study of the hepatic transcriptome and immune populations was performed on cohorts of NASH patients, histologically characterized, who were treated with bariatric surgery or dietary intervention. Transcriptomic analysis of one of the cohorts reveals a characteristic signature that is sensitive to NASH regression independent of body weight loss. This signature is enriched with genes associated with the immune system and linked to inflammatory responses, antigen presentation and cytotoxic cells. In an independent cohort, NASH is also associated with alterations in blood immune cell populations, including conventional dendritic cells (cDCs) type 1 and 2, and cytotoxic CD8 T cells. Intrahepatic inflammation and bloating are associated with the buildup of CD8 T cells in the liver. In addition, the progression of benign NASH steatosis in a diet-induced mouse model of NASH results in a comparable hepatic transcriptome signature linked to the immune system and the accumulation of intrahepatic cDC2 and CD8 T cells.

All of these results provide a better understanding of NASH and identify potential targets for the treatment of NASH, notably through immunomodulatory agents.

Sources: Haaset al. Transcriptional Network Analysis Implicates Altered Hepatic Immune Function in NASH development and resolution. Nature Metabolism, in press.

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