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- Title
Lack of Fas antagonism by Met in human fatty liver disease.
- Authors
Chunbin Zou; Jihong Ma; Xue Wang; Lida Guo; Zhenqi Zhu; Stoops, John J.; Eaker, Amanda E.; Johnson, Carla J.; Strom, Stephen; Michalopoulos, George K.; DeFrances, Marie C.; Zarnegar, Reza
- 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 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.
- Subjects
LIVER diseases; FATTY liver; LIVER cells; PEPTIDES; APOPTOSIS; THERAPEUTICS
- Publication
Nature Medicine, 2007, Vol 13, Issue 9, p1078
- ISSN
1078-8956
- Publication type
Article
- DOI
10.1038/nm1625