Anchoring hepatic gene expression with development of fibrosis and neoplasia in a toxicant-induced fish model of liver injury.
Published
Journal Article
Fish have been used as laboratory models to study hepatic development and carcinogenesis but not for pathogenesis of hepatic fibrosis. In this study, a dimethylnitrosamine-induced fish model of hepatic injury was developed in Japanese medaka (Oryzias latipes) and gene expression was anchored with the development of hepatic fibrosis and neoplasia. Exposed livers exhibited mild hepatocellular degenerative changes 2 weeks' postexposure. Within 6 weeks, hepatic fibrosis/cirrhosis was evident with development of neoplasia by 10 weeks. Stellate cell activation and development of fibrosis was associated with upregulation of transforming growth factor beta 1 (tgfb1), tgfb receptor 2, mothers against decapentaplegic homolog 3 (smad3a), smad3b, beta-catenin (ctnnb1), myc, matrix metalloproteinase (mmp2), mmp14a, mmp14b, tissue inhibitors of metalloproteinase (timp) 2a, timp2b, timp3, collagen type I alpha 1a (col1a1a), and col1a1b and a less pronounced increase in mmp13 and col4a1 expression. Tgfb receptor I expression was unchanged. Immunohistochemistry suggested that biliary epithelial cells and stellate cells were the main producers of TGF-β1. This study identified a group of candidate genes likely to be involved in the development of hepatic fibrosis and demonstrated that the TGF-β pathway likely plays a major role in the pathogenesis. These results support the medaka as a viable fish model of hepatic fibrosis.
Full Text
Duke Authors
Cited Authors
- Van Wettere, AJ; Law, JM; Hinton, DE; Kullman, SW
Published Date
- July 2013
Published In
Volume / Issue
- 41 / 5
Start / End Page
- 744 - 760
PubMed ID
- 23197195
Pubmed Central ID
- 23197195
Electronic International Standard Serial Number (EISSN)
- 1533-1601
International Standard Serial Number (ISSN)
- 0192-6233
Digital Object Identifier (DOI)
- 10.1177/0192623312464308
Language
- eng