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Nature Medicine 13, 1078-1085 (1 September 2007) | doi:10.1038/nm1625;

Lack of Fas antagonism by Met in human fatty liver disease

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

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 α-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.

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