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Campbell, J.S. et al.

Campbell, Hughes, Gilbertson, Palmer, Holdren, Haran, Odell, Bauer, Ren, Haugen, Yeh, Fausto,

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.[1]

References

Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. Campbell, J.S., Hughes, S.D., Gilbertson, D.G., Palmer, T.E., Holdren, M.S., Haran, A.C., Odell, M.M., Bauer, R.L., Ren, H.P., Haugen, H.S., Yeh, M.M., Fausto, N. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]

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