Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma
Open Access
- 22 February 2005
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 102 (9), 3389-3394
- https://doi.org/10.1073/pnas.0409722102
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.Keywords
This publication has 56 references indexed in Scilit:
- Liver extracellular matrix in health and diseaseThe Journal of Pathology, 2003
- PDGF Receptor-α Deficiency in Glomerular Mesangial Cells of Tenascin-C Knockout MiceBiochemical and Biophysical Research Communications, 2002
- Development of Hepatocellular Adenomas and Carcinomas Associated with Fibrosis in C57BL/6J Male Mice Given a Choline‐deficient, L‐Amino Acid‐defined DietJapanese Journal of Cancer Research, 2002
- Hepatic Stellate Cells as a Target for the Treatment of Liver FibrosisSeminars in Liver Disease, 2001
- Transforming growth factor-β gene expression in normal and fibrotic rat liverJournal of Hepatology, 1997
- Transforming growth factor-?1 regulates platelet-derived growth factor receptor ? subunit in human liver fat-storing cells*1, *2Hepatology, 1995
- Transforming growth factor-β1 regulates platelet-derived growth factor receptor β subunit in human liver fat-storing cellsHepatology, 1995
- Actions of platelet-derived growth factor isoforms in mesangial cellsJournal of Cellular Physiology, 1994
- Immunohistochemical detection of transforming growth factor-β1 in fibrotic liver diseasesHepatology, 1991