Scientists from the Helmholtz Zentrum München made this discovery 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 renowned medical journal Cancer Cell.
Human hepatozytes filled with lipids representing macro-vesicular steatosis in hepatocytes (arrows) and inflamed cells (arrow head) caused by chronic fat diet | Source: Prof. Dr. Achim Weber, Universitätsspital Zürich
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 excercise 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 alteratons 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 appr. 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, Prof. Matthias Tschöp, Dr. Kerstin Stemmer, Dr. Kristian Unger and Prof. Ulrike Protzer from the Helmholtz Zentrum München together with a team headed by Prof. Percy Knolle of the Technische Universität München (TUM), Prof. Achim Weber from Zurich University Hospital and Dr. Monika Wolf, Institute of Surgical Pathology, University Hospital Zurich. 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.
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 now want to develop new, preventive and therapeutic strategies to combat these diseases.” The initial studies are already under way in the preclinical model.
*Metabolic syndrome: a combination of obesity / abdominal adiposity, insulin resistance, raise levels of lipids in the blood and raised blood pressure.
The hepatozyte in the center of the image is in contact with NKT-cells and “forced” to take up more lipids (under the condition of a high fat diet). At the same time the NKT cell inhibit the hepatozyte to metabolize the lipids – leading to macrovesicular steatosis. Moreover, cytotoxic CD8 T –cells attack hepatoyztes and damage the latter. This leads – if chronically present in the liver (due to chronic high fat, high sugar diet and due to a sedentary life style) to NASH and liver cancer | Source: Peter von Walter
Wolf, M. et al. (2014), Metabolic activation of intrahepatic CD8+ and NKT-cells causes nonalcoholic steatohepatitis and hepatocellular carcinoma via cross-talk with hepatocytes. Cancer Cell, doi: 10.1016/j.ccell.2014.09.003
The Helmholtz Zentrum München, as the German Research Center for Environmental Health, pursues the objective of developing personalized medicine for the diagnosis, therapy and prevention of wide-spread diseases such as diabetes mellitus and lung diseases. To this end, it investigates the interactions of genetics, environmental factors and lifestyle. The Zentrum’s headquarters is located in Neuherberg in the north of Munich. The Helmholtz Zentrum München employs around 2,200 people and is a member of the Helmholtz Association, which has 18 scientific-technical and biological-medical research centres with around 34,000 employees. www.helmholtz-muenchen.de
The Institute of Virology (VIRO) investigates viruses that chronically infect humans and can cause life-threatening diseases. The research activities of the institute focus mainly on the HI virus which causes AIDS, on endogenous retroviruses, which are integrated into our germline, and hepatitis B and C viruses, which cause liver cirrhosis and hepatocellular carcinoma. Molecular studies identify new diagnostic and therapeutic concepts to prevent and treat these viral diseases or to prevent the formation of virus-induced tumors.
The Research Unit Radiation Cytogenetics (ZYTO) investigates radiation-induced chromosome and DNA damage in cell systems and human tumours. The focus is on clarifying the mechanisms associated with radiation-induced carcinogenesis and radiation sensitivity of tumour cells. The aim of this research is to find biomarkers associated with radiation-induced tumours in order to develop personalized radiation therapy for the stratification of patients. ZYTO is a part of the Department of Radiation Sciences (DRS).
The Institute of Diabetes and Obesity (IDO) studies the diseases of the metabolic syndrome by means of systems biological and translational approaches on the basis of cellular systems, genetically modified mouse models and clinical intervention studies. It seeks to discover new signaling pathways in order to develop innovative therapeutic approaches for the personalized prevention and treatment of obesity, diabetes and their concomitant diseases. IDO is part of the Helmholtz Diabetes Center (HDC).
Prof. Mathias Heikenwälder, Helmholtz Zentrum München – Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Institute of Virology, Ingolstaedter Landstr. 1, 85764 Neuherberg, Germany – Tel.: +49 89-4140-7440 – E-Mail