Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma.
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.
Campbell
Jean S
JS
Department of Pathology, University of Washington, Seattle, WA 98115, USA. campjs@u.washington.edu
Hughes
Steven D
SD
Gilbertson
Debra G
DG
Palmer
Thomas E
TE
Holdren
Matthew S
MS
Haran
Aaron C
AC
Odell
Melissa M
MM
Bauer
Renay L
RL
Ren
Hong-Ping
HP
Haugen
Harald S
HS
Yeh
Matthew M
MM
Fausto
Nelson
N
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*
D008222:Lymphokines; D010982:Platelet-Derived Growth Factor; C411423:platelet-derived growth factor C
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