Insulin-like growth factor 1 enhances bile-duct proliferation and fibrosis in Abcb4−/− mice

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.

► Effect of IGF1 on biliary fibrosis was tested in a model of chronic cholangiopathies. ► IGF1 overexpression increased fibrogenesis and lowered fibrolysis in Abcb4−/− mice. ► IGF1 overexpression stimulated inflammation and recruitment of macrophages. ► The enhanced IGF1 signaling stimulated cholangiocyte and bile duct proliferation. ► IGF1 is not an option for treating fibrosis caused by chronic cholangiopathies.