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.

Impairment of GH/IGF-1 Axis in the Liver of Patients with HCV-Related Chronic Hepatitis

“…Interestingly, the reduction of hepatic IGF-1 expression was correlated directly with hepatocellular damage (AST, ALT) and with cholestatic indices (ggt and bilirubin). These findings underlined the importance of IGF-1 as protective factor against the deleterious effect of TNF, IL1-and cholestasis that lead to hepatocyte necrosis and fibrosis [16,17,25,32]. We also found a direct correlation between the hepatic expression of IGF-1 and the weight of the patients; this finding and the reduction of albumin in advanced stage of fibrosis confirm the role of the liver as the primary IGF-1 manufacturer with systemic anabolic effects [33].…”

Retracted:Promoting the Recovery of Injured Liver with Poly (3-Hydroxybutyrate-Co-3-Hydroxyvalerate-Co-3-Hydroxyhexanoate) Scaffolds Loaded with Umbilical Cord-Derived Mesenchymal Stem Cells

“…[44][45][46] In this study, real-time RT-PCR showed that the expression of CK-19 was detected at a low level in normal mouse liver (Control) and significantly increased on day 30 after CCl 4 injection (Fig. 4B), suggesting that increased bile duct epithelial cells may be a marker of CCl 4 -induced liver injury.…”

The role of TIMPs in regulation of extracellular matrix proteolysis

“…For instance, correlative data supports a role for TIMP2 in protecting the ECM from proteolysis in fracture healing [30], keloids [31], liver [32,33], kidneys [34,35], Dupuytren's contracture [36,37], and in heart tissues [38][39][40][41][42]. As a specific example, patients suffering from Dupuytren's contracture, a disease caused by excessive ECM deposition leading to fixed flexion of joints in the hand, have a disruption in the balance between TIMP2 and MMP2 in favor of TIMP2, which suggests that increased TIMP2 is associated with pathophysiological ECM accumulation [36,37].…”