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Clarifying molecular mechanisms for common liver diseases

Immune cells in the liver drive fatty liver disease and liver cancer

The picture shows a histological tissue slice of a steatoheaptitis in human liver tissue. (Picture: A. Weber / Universitätsspital Zürich, explanation see below)
The picture shows a histological tissue slice of a steatoheaptitis in human liver tissue. (Picture: A. Weber / Universitätsspital Zürich, explanation see below)

Research news

Immune cells that migrate to the liver and interact there with liver tissue cells get activated by metabolic stress (e.g. through lipids of a high fat diet) and drive the development of fatty liver disease, non-alcoholic steatohepatitis and liver cancer. Scientists from the Technische Universität München (TUM), the Helmholtz Zentrum München and the Zurich University Hospital made this discovery in an animal model and in patients and thus identified the previously unknown mechanism underlying these serious and widespread diseases. The results of their research have been published as the cover story of the journal Cancer Cell.

Fatty liver disease – alongside fatty liver due to massive alcohol consumption – is mainly caused by excessive consumption of fat and sugar combined with a lack of exercise or a sedentary life style. This is referred to as non-alcoholic fatty liver disease (NAFLD). If NAFLD becomes chronic – e.g. through the constant uptake of high lipids and high sugar combined with lack of exercise a chronic inflammatory response is triggered in the liver tissue in addition. This can lead to non-alcoholic steatohepatitis (NASH) – a liver disease with clear detectable pathologic alterations of the tissue. These liver diseases (NAFLD and NASH), along with chronic viral infections, are the most common causes of liver cancer, or hepatocellular carcinoma (HCC).

In the United States, about 90 million people suffer from NAFLD. In Europe, the figure is more than 40 million, and even in threshold countries like India and China, the number of people affected is rising due to increasingly unhealthy lifestyles. More worrying, in all of the above mentioned states the numbers of NAFLD and NASH patients is constantly increasing. Consequently, the incidence of HCC resulting from NASH and NAFLD is also rising worldwide. In the United States, HCC is the fastest-growing form of cancer at the moment. No efficient causal therapy exists for HCC patients of which approximately 800.000 die every year.

T cells involved in the development of fatty liver disease, NASH and HCC

The mechanisms that cause diseases such as fatty liver disease, steatohepatitis and HCC are still not widely understood. However, immune cells, particularly CD8+ T cells and NK T cells seem to play an important role. This finding was made by a team of scientists led by Prof. Mathias Heikenwälder from the Institute of Virology, together with Prof. Percy Knolle of the Technische Universität München (TUM) and colleagues of the group of Prof. Matthias Tschöp and Dr. Kristian Unger from the Helmholtz Zentrum München together with Prof. Achim Weber and Dr. Monika Wolf from Zurich University Hospital.

The animal model which was used to examine the long-term effects of metabolic syndrome enabled the scientists to elucidate new mechanisms that cause fatty liver disease and also show how it can develop into liver cancer. It also represents human pathology. The metabolic syndrome is a combination of obesity/abdominal adiposity, insulin resistance, raise levels of lipids in the blood and raised blood pressure.

Inflammatory events offer starting point for prevention and treatment

The scientists assume that an existing metabolic imbalance results in the activation and migration of immune cells to the liver. There, the immune cells interact with liver cells and trigger an inflammatory response that damages the liver tissue and also destabilizes the metabolic activity of the liver cells.

“Initially it immune cells promote fatty liver degeneration. The inflammation, which is triggered by specific immune cells, encourages the progression of fatty liver pathology and causes NASH to develop. These processes are the basis for liver cell degeneration, which can cause HCC,” explains Prof. Heikenwälder, who led the study. “Our results provide completely new insights into the development of these serious liver diseases. Building on this knowledge, we already develop new, preventive and therapeutic strategies to combat these diseases.” The initial studies are already under way in the preclinical model.


Original publication
Wolf M. J., Adili A., Piotrowitz K., Abdullah Z., Boege Y., Stemmer K., Ringelhan M., Simonavicius N., Egger M., Wohlleber D., Lorentzen A., Einer C., Schulz S., Clavel T., Protzer U., Thiele C., Zischka H., Moch H., Tschöp M., Tumanov A. V., Haller D., Unger K., Karin M., Kopf M., Knolle P., Weber A. and Heikenwalder M., Metabolic activation of intrahepatic CD8+ and NKT-cells causes nonalcoholic steatohepatitis and hepatocellular carcinoma via cross-talk with hepatocytes, Cancer Cell, 2014.
DOI: 10.1016/j.ccell.2014.09.003

Contact
Prof. Dr. Mathias Heikenwälder
Helmholtz Zentrum München/Technische Universität München
Institute of Virology
Phone: +49 89 4140-7440
heikenwaelder@helmholtz-muenchen.de 
www.virologie.med.tu-muenchen.de/en


Further information

Human hepatozytes filled with lipids representing macro-vesicular steatosis in human hepatocytes (arrows) and inflamed cells (arrow head) caused by chronic fat diet (Picture: A. Weber / Universitätsspital Zürich)
Human hepatozytes filled with lipids representing macro-vesicular steatosis in human hepatocytes (arrows) and inflamed cells (arrow head) caused by chronic fat diet (Picture: A. Weber / Universitätsspital Zürich)