Lack of Fas antagonism by Met in human fatty liver disease.
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.
Zou
Chunbin
C
Department of Pathology, School of Medicine, University of Pittsburgh, S411A Biomedical Science Tower, 200 Lothrop Street, Pittsburgh, Pennsylvania 15261, USA.
Ma
Jihong
J
Wang
Xue
X
Guo
Lida
L
Zhu
Zhenqi
Z
Stoops
John
J
Eaker
Amanda E
AE
Johnson
Carla J
CJ
Strom
Stephen
S
Michalopoulos
George K
GK
DeFrances
Marie C
MC
Zarnegar
Reza
R
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*
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