Lack of Fas antagonism by Met in human fatty liver disease |
| |
Authors: | 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 |
| |
Affiliation: | Department of Pathology, School of Medicine, University of Pittsburgh, S411A Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, Pennsylvania 15261, USA. |
| |
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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|