Fibroblast activation protein: a cell surface dipeptidyl peptidase and gelatinase expressed by stellate cells at the tissue remodelling interface in human cirrhosis.
Fibroblast activation protein (FAP) is a cell surface-bound protease of the prolyl oligopeptidase gene family expressed at sites of tissue remodelling. This study aimed to delineate the expression of FAP in cirrhotic human liver and examine its biochemical activities. Seventeen cirrhotic and 8 normal liver samples were examined by immunohistochemistry and reverse-transcriptase polymerase chain reaction (RT-PCR). Hepatic stellate cells (HSC) were isolated and immunostained. Recombinant FAP and immunopurified, natural FAP were analyzed for protease activities and similarities to dipeptidyl peptidase IV (DPPIV), a structurally related enzyme. FAP-specific messenger RNA and immunoreactivity were detected in cirrhotic, but not normal, livers. FAP immunoreactivity was most intense on perisinusoidal cells of the periseptal regions within regenerative nodules (15 of 15 cases); this pattern coincides with the tissue remodelling interface. In addition, human FAP was expressed by cells within the fibrous septa (10 of 15 cases). Cell morphology, location, and colocalization with glial fibrillary acidic protein (GFAP) indicated that FAP is present on HSC in vivo. Similarly, isolated HSC expressed FAP in vitro. Both natural FAP from cirrhotic liver and recombinant FAP were shown to have gelatinase and dipeptidyl peptidase activities. FAP is a cell-bound, dual-specificity dipeptidyl peptidase and gelatinase expressed by activated HSC at the tissue remodelling interface in human cirrhosis. FAP may contribute to the HSC-induced extracellular matrix (ECM) changes of cirrhosis.
Levy
M T
MT
A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Liver Immunobiology Laboratory, Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Australia.
McCaughan
G W
GW
Abbott
C A
CA
Park
J E
JE
Cunningham
A M
AM
Müller
E
E
Rettig
W J
WJ
Gorrell
M D
MD
D000199:Actins / Q000235:genetics; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D006528:Carcinoma, Hepatocellular / Q000201:enzymology; D015209:Cholangitis, Sclerosing / Q000201:enzymology; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics*; D010450:Endopeptidases; D018093:Gelatinases / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D006133:Growth Substances / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000166:cytology / Q000201:enzymology* / Q000473:pathology; D008103:Liver Cirrhosis / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008104:Liver Cirrhosis, Alcoholic / Q000201:enzymology; D008565:Membrane Proteins; D012333:RNA, Messenger / Q000235:genetics; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012697:Serine Endopeptidases / Q000096:biosynthesis / Q000235:genetics*; D014158:Transcription, Genetic; D000099167:Fibroblast Activation Protein Alpha
D000199:Actins; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; D010450:Endopeptidases; D018093:Gelatinases; D005904:Glial Fibrillary Acidic Protein; D006133:Growth Substances; D008565:Membrane Proteins; D012333:RNA, Messenger; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha