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Lack of Fas antagonism by Met in human fatty liver disease
- Source :
- Nature Medicine. 13:1078-1085
- Publication Year :
- 2007
- Publisher :
- Springer Science and Business Media LLC, 2007.
-
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.
- 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
Subjects
Details
- ISSN :
- 1546170X and 10788956
- Volume :
- 13
- Database :
- OpenAIRE
- Journal :
- Nature Medicine
- Accession number :
- edsair.doi.dedup.....562ed5af05c0f31574f2c8859698ee8d