title: The pro-fibrotic role of dipeptidyl peptidase 4 in carbon tetrachloride-induced experimental liver injury.
abstract: Liver fibrosis is a progressive pathological process involving inflammation and extracellular matrix deposition. Dipeptidyl peptidase 4 (DPP4), also known as CD26, is a cell surface glycoprotein and serine protease. DPP4 binds to fibronectin, can inactivate specific chemokines, incretin hormone and neuropeptides, and influences cell adhesion and migration. Such properties suggest a pro-fibrotic role for this peptidase but this hypothesis needs in vivo examination. Experimental liver injury was induced with carbon tetrachloride (CCl4) in DPP4 gene knockout (gko) mice. DPP4 gko had less liver fibrosis and inflammation and fewer B cell clusters than wild type mice in the fibrosis model. DPP4 inhibitor-treated mice also developed less liver fibrosis. DNA microarray and PCR showed that many immunoglobulin (Ig) genes and some metabolism-associated transcripts were differentially expressed in the gko strain compared with wild type. CCl4-treated DPP4 gko livers had more IgM+and IgG+intrahepatic lymphocytes, and fewer CD4+, IgD+and CD21+intrahepatic lymphocytes. These data suggest that DPP4 is pro-fibrotic in CCl4-induced liver fibrosis and that the mechanisms of DPP4 pro-fibrotic action include energy metabolism, B cells, NK cells and CD4+cells.
authors.affiliation: Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.|A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors.forename: Xin M
authors.initials: XM
authors.lastname: Wang
authors.affiliation: Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Lauren E
authors.initials: LE
authors.lastname: Holz
authors.affiliation: Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Sumaiya
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Shaun P
authors.initials: SP
authors.lastname: Cordoba
authors.affiliation: Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Evans
authors.affiliation: Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Margaret G
authors.initials: MG
authors.lastname: Gall
authors.affiliation: Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Ana Júlia
authors.initials: AJ
authors.lastname: Vieira de Ribeiro
authors.affiliation: Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Yuan Zhou
authors.initials: YZ
authors.lastname: Zheng
authors.affiliation: Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.|A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors.forename: Miriam T
authors.initials: MT
authors.lastname: Levy
authors.affiliation: Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Denise Mt
authors.initials: DM
authors.lastname: Yu
authors.affiliation: Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Tsun-Wen
authors.initials: TW
authors.lastname: Yao
authors.affiliation: Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Natasa
authors.initials: N
authors.lastname: Polak
authors.affiliation: Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Jolly
authors.affiliation: Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Patrick
authors.identifier: 0000-0001-8244-7057
authors.initials: P
authors.lastname: Bertolino
authors.affiliation: Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.|A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors.forename: Geoffrey W
authors.initials: GW
authors.lastname: McCaughan
authors.affiliation: Centenary Institute and Sydney Medical School, The University of Sydney, Sydney, New South Wales, Australia.|A.W. Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia.
authors.forename: Mark D
authors.identifier: 0000-0002-0528-2604
authors.initials: MD
authors.lastname: Gorrell
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride; D002460:Cell Line; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000201:enzymology* / Q000293:injuries* / Q000473:pathology; D008103:Liver Cirrhosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D013154:Spleen / Q000473:pathology; D015854:Up-Regulation
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D002251:Carbon Tetrachloride; D018819:Dipeptidyl Peptidase 4