title: Lack of Fas antagonism by Met in human fatty liver disease.
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.
authors: Department of Pathology, School of Medicine, University of Pittsburgh, S411A Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, Pennsylvania 15261, USA.
authors: Chunbin
authors: C
authors: Zou
authors: Jihong
authors: J
authors: Ma
authors: Xue
authors: X
authors: Wang
authors: Lida
authors: L
authors: Guo
authors: Zhenqi
authors: Z
authors: Zhu
authors: John
authors: J
authors: Stoops
authors: Amanda E
authors: AE
authors: Eaker
authors: Carla J
authors: CJ
authors: Johnson
authors: Stephen
authors: S
authors: Strom
authors: George K
authors: GK
authors: Michalopoulos
authors: Marie C
authors: MC
authors: DeFrances
authors: Reza
authors: R
authors: Zarnegar
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D005234:Fatty Liver / Q000473:pathology / Q000503:physiopathology*; D022781:Hepatocytes / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D019169:Jurkat Cells; D007700:Kinetics; D008113:Liver Neoplasms; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000494:pharmacology; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor / Q000502:physiology*; D019014:fas Receptor / Q000302:isolation & purification / Q000502:physiology*
chemical_list: D010446:Peptide Fragments; D021122:Protein Subunits; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D019014:fas Receptor; D003094:Collagen; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met