title: Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma.
abstract: Members of the platelet-derived growth factor (PDGF) ligand family are known to play important roles in wound healing and fibrotic disease. We show that both transient and stable expression of PDGF-C results in the development of liver fibrosis consisting of the deposition of collagen in a pericellular and perivenular pattern that resembles human alcoholic and nonalcoholic fatty liver disease. Fibrosis in PDGF-C transgenic mice, as demonstrated by staining and hydroxyproline content, is preceded by activation and proliferation of hepatic stellate cells, as shown by collagen, alpha-smooth muscle actin and glial fibrillary acidic protein staining and between 8 and 12 months of age is followed by the development of liver adenomas and hepatocellular carcinomas. The hepatic expression of a number of known profibrotic genes, including type beta1 TGF, PDGF receptors alpha and beta, and tissue inhibitors of matrix metalloproteinases-1 and -2, increased by 4 weeks of age. Increased PDGF receptor alpha and beta protein levels were associated with activation of extracellular regulated kinase-1 and -2 and protein kinase B. At 9 months of age, PDGF-C transgenic mice had enlarged livers associated with increased fibrosis, steatosis, cell dysplasia, and hepatocellular carcinomas. These studies indicate that hepatic expression of PDGF-C induces a number of profibrotic pathways, suggesting that this growth factor may act as an initiator of fibrosis. Moreover, PDGF-C transgenic mice represent a unique model for the study of hepatic fibrosis progressing to tumorigenesis.
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98115, USA. campjs@u.washington.edu
authors.forename: Jean S
authors.initials: JS
authors.lastname: Campbell
authors.forename: Steven D
authors.initials: SD
authors.lastname: Hughes
authors.forename: Debra G
authors.initials: DG
authors.lastname: Gilbertson
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Palmer
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Holdren
authors.forename: Aaron C
authors.initials: AC
authors.lastname: Haran
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Odell
authors.forename: Renay L
authors.initials: RL
authors.lastname: Bauer
authors.forename: Hong-Ping
authors.initials: HP
authors.lastname: Ren
authors.forename: Harald S
authors.initials: HS
authors.lastname: Haugen
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Yeh
authors.forename: Nelson
authors.initials: N
authors.lastname: Fausto
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000473:pathology; D005234:Fatty Liver / Q000209:etiology* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology* / Q000473:pathology; D008222:Lymphokines; D051379:Mice; D008822:Mice, Transgenic; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000502:physiology*
chemical_list: D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; C411423:platelet-derived growth factor C
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