title: Insulin-like growth factor 1 enhances bile-duct proliferation and fibrosis in Abcb4(-/-) mice.
abstract: Adamant progression of chronic cholangiopathies towards cirrhosis and limited therapeutic options leave a liver transplantation the only effective treatment. Insulin-like growth factor 1 (IGF1) effectively blocks fibrosis in acute models of liver damage in mice, and a phase I clinical trial suggested an improved liver function. IGF1 targets the biliary epithelium, but its potential benefit in chronic cholangiopathies has not been studied. To investigate the possible therapeutic effect of increased IGF1 expression, we crossed Abcb4(-/-) mice (a model for chronic cholangiopathy), with transgenic animals that overexpress IGF1. The effect on disease progression was studied in the resulting IGF1-overexpressing Abcb4(-/-) mice, and compared to that of Abcb4(-/-) littermates. The specificity of this effect was further studied in an acute model of fibrosis. The overexpression of IGF1 in transgenic Abcb4(-/-) mice resulted in stimulation of fibrogenic processes - as shown by increased expression of Tgfß, and collagens 1, 3 and 4, and confirmed by Sirius red staining and hydroxyproline measurements. Excessive extracellular matrix deposition was favored by raise in Timp1 and Timp2, while a reduction of tPA expression indicated lower tissue remodeling. These effects were accompanied by an increase in expression of inflammation markers like Tnfα, and higher presence of infiltrating macrophages. Finally, increased number of Ck19-expressing cells indicated proliferation of biliary epithelium. In contrast to liver fibrosis associated with hepatocellular damage, IGF1 overexpression does not inhibit liver fibrogenesis in chronic cholangiopathy.
authors: Tytgat Institute for Liver and Intestinal Research, Academic Medical Center, University of Amsterdam, The Netherlands. a.sokolovic@gmail.com
authors: Aleksandar
authors: A
authors: Sokolović
authors: Carlos M
authors: CM
authors: Rodriguez-Ortigosa
authors: Lysbeth Ten
authors: LT
authors: Bloemendaal
authors: Ronald P J
authors: RP
authors: Oude Elferink
authors: Jesús
authors: J
authors: Prieto
authors: Piter J
authors: PJ
authors: Bosma
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002779:Cholestasis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002908:Chronic Disease; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D004848:Epithelium / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis*; D051379:Mice; D018345:Mice, Knockout; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis / Q000235:genetics; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D003094:Collagen; D007334:Insulin-Like Growth Factor I; D019715:Tissue Inhibitor of Metalloproteinase-1; D010959:Tissue Plasminogen Activator; D016212:Transforming Growth Factor beta; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C560825:Timp1 protein, mouse; C519530:insulin-like growth factor-1, mouse