Lack of Fas antagonism by Met in human fatty liver disease

作者：Zou Chunbin; Ma Jihong; Wang Xue; Guo Lida; Zhu Zhenqi; Stoops John; Eaker Amanda E; Johnson Carla J; Strom Stephen; Michalopoulos George K; DeFrances Marie C; Zarnegar Reza^*

来源：Nature Medicine, 2007, 13(9): 1078-1085.

DOI：10.1038/nm1625

Hepatocytes in fatty livers are hypersensitive to apoptosis and undergo escalated apoptotic activity via death receptor-mediated pathways, particularly that of Fas-FasL, causing hepatic injury that can eventually proceed to cirrhosis and end-stage liver disease. Here we report that the hepatocyte growth factor receptor, Met, plays an important part in preventing Fas-mediated apoptosis of hepatocytes by sequestering Fas. We also show that Fas antagonism by Met is abrogated in human fatty liver disease (FLD). Through structure-function studies, we found that a YLGA amino-acid motif located near the extracellular N terminus of the Met alpha-subunit is necessary and sufficient to specifically bind the extracellular portion of Fas and to act as a potent FasL antagonist and inhibitor of Fas trimerization. Using mouse models of FLD, we show that synthetic YLGA peptide tempers hepatocyte apoptosis and liver damage and therefore has therapeutic potential.

• 出版日期2007-9