Lack of Fas antagonism by Met in human fatty liver disease

Chunbin Zou, et al. 2007. Nature Medicine. 13, 1078-1085

Speaker: Yu Ting Kao (高毓婷)              Time: 14:00~15:00, Oct. 31, 2007

Commentator: 楊倍昌老師                 Place: Room 601

Abstract:

   The pathogenesis of nonalcoholic steatohepatitis (NASH), the most extreme form of Non-alcoholic fatty liver disease (NAFLD), was reported to have a direct connection to the Fas expression. In the previous studies, the authors found that hepatocyte apoptosis is a common mechanism of serious liver damage and related to fatty liver disease (1). Met, also known as hepatocyte growth factor receptor (HGFR), was reported to play an important role in antiapoptosis mechanism to protect hepatocyte from liver damage. Met could directly bind to and sequester the death receptor Fas to prevent Fas self-aggregation and FasL binding (2). However, the Fas-mediated apoptosis inhibited by the Met-mediated survival mechanism was abrogated in fatty liver disease. The results showed that the Met-Fas compelx formed for cell survival was dissociated in diseased liver. And the authors also found that fat accumulation in hepatocyte trigger FasL expression in hepatocytes and induce dissociation of Met-Fas complex. The extracellular regions of Met (AlphaMet) are sufficient for the interaction with Fas. After mapping the interaction region between AlphaMet and Fas, they found that Fas binds to the YLGA sequence of AlphaMet, and the synthetic peptides including YLGA region bind to Fas strongly and specifically. And these YLGA-containing peptides derived from AlphaMet could inhibit Fas-mediated and Fas-induced apoptosis. For testing the therapeutic effects of these synthesis peptides in vivo, the authors used three different models in their study. Including injection of the Fas-agonistic Jo2 monoclonal antibody to mice caused Fas aggregation resulting in hepatocyte apoptosis, using ob/ob mice as a fatty liver disease model, and feeding mice with a methionine- and choline-deficient (MCD) diet caused the systems similar to those in human NASH. The above data showed that administration of YLGA-containing peptides, especially YLGA 12-mer, tempers hepatocyte apoptosis and liver damage and therefore has therapeutic potential.

References:

1.      Canbay, A., Friedman,S.& Gores, G.J. 2004. Apoptosis: the nexus of liver injury and fibrosis. Hepatology 39, 273–278.

2.      Wang, X., et al. 2002. A mechanism of cell survival: sequestration of Fas by the HGF receptor Met. Mol. Cell 9, 411-421.

* Presentation in English