Study of the NF-kB inhibitory protein A20 in the liver and liver pathologies like hepatocellular carcinoma

01 January 2016 → 31 December 2016
Research Foundation - Flanders (FWO)
Research disciplines
  • Natural sciences
    • Other biological sciences
liver pathologies
Project description

The transcription factor NF-KB is of crucial importance for inflammatory signaling, adaptive and innate immunity, development, cell survival and cell proliferation. Because of its function in a broad range of cellular processes, NF-KB signaling pathways need to be tightly regulated. One of the proteins known to play a key role in the termination of NF-KB signaling is A20, a protein which is induced by NF-KB and will terminate the signaling cascade by changing the ubiquitination status of key signaling proteins. The specific outcome of NF-KB activation and the function of A20 is highly cell type dependent. For our studies, the role of A20 is studied in hepatocytes by using a liver parenchymal cell-specific knockout mouse line. These mice spontaneously develop a condition of chronic inflammation characterized by the presence of inflammatory foci in the liver. Hepatocytes of these mice are hypersensitive to TNF- and LPS--induced NF-KB activation and apoptosis. Since hepatocyte A20 knockout mice develop low-grade liver inflammation and are sensitized to hepatocyte apoptosis, we wondered whether these mice are also sensitized to the development of hepatocellular carcinoma (HCC) . However, ihese mice do noi develop sponianeous HCC. Therefore, mice were subjected to the chemical carcinogen diethylnitrosamine (DEN), a model of chemically-induced HCC. First analysis indicates that mice lacking A20 in the liver are indeed more sensitive to develop HCC. Mice were also challenged with a high fat diet to induce obesity and to investigate the development of obesity-associated liver pathologies like non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), type 2 diabetes and HCC. Although initial conclusions can be made, further analysis is needed to establish the importance of A20 in liver pathology. These results will provide new insights on the hepatocyte-specific functions of A20 and NF-KB, and their involvement in hepatocarcinogenesis, which may help to develop new therapeutics for the treatment of liver disease