1. Lack of Fas antagonism by Met in human fatty liver disease
- Author
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Chunbin Zou, George K. Michalopoulos, John Stoops, Zhenqi Zhu, Carla Johnson, Lida Guo, Jihong Ma, Marie C. DeFrances, Amanda E. Eaker, Reza Zarnegar, Stephen C. Strom, and Xue Wang
- Subjects
Carcinoma, Hepatocellular ,Cirrhosis ,Molecular Sequence Data ,Apoptosis ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Fas ligand ,Jurkat Cells ,Liver disease ,Cell Line, Tumor ,Proto-Oncogene Proteins ,medicine ,Extracellular ,Humans ,Receptors, Growth Factor ,Amino Acid Sequence ,fas Receptor ,Liver Neoplasms ,Fatty liver ,General Medicine ,Proto-Oncogene Proteins c-met ,medicine.disease ,Fas receptor ,Immunohistochemistry ,Peptide Fragments ,Fatty Liver ,Kinetics ,Protein Subunits ,Biochemistry ,Hepatocyte Growth Factor Receptor ,Hepatocytes ,Cancer research ,Collagen - Abstract
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.
- Published
- 2007