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Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model.

Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model.
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Tokunaga Y, Osawa Y, Ohtsuki T, Hayashi Y, Yamaji K, Yamane D, Hara M, Munekata K, Tsukiyama-Kohara K, Hishima T, Kojima S, Kimura K, Kohara M,


Tokunaga Y, Osawa Y, Ohtsuki T, Hayashi Y, Yamaji K, Yamane D, Hara M, Munekata K, Tsukiyama-Kohara K, Hishima T, Kojima S, Kimura K, Kohara M, (click to view)

Tokunaga Y, Osawa Y, Ohtsuki T, Hayashi Y, Yamaji K, Yamane D, Hara M, Munekata K, Tsukiyama-Kohara K, Hishima T, Kojima S, Kimura K, Kohara M,

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Scientific reports 2017 03 237(1) 325 doi 10.1038/s41598-017-00282-w
Abstract

Chronic hepatitis C virus (HCV) infection is one of the major causes of serious liver diseases, including liver cirrhosis. There are no anti-fibrotic drugs with efficacy against liver cirrhosis. Wnt/β-catenin signaling has been implicated in the pathogenesis of a variety of tissue fibrosis. In the present study, we investigated the effects of a β-catenin/CBP (cyclic AMP response element binding protein) inhibitor on liver fibrosis. The anti-fibrotic activity of PRI-724, a selective inhibitor of β-catenin/CBP, was assessed in HCV GT1b transgenic mice at 18 months after HCV genome expression. PRI-724 was injected intraperitoneally or subcutaneously in these mice for 6 weeks. PRI-724 reduced liver fibrosis, which was indicated by silver stain, Sirius Red staining, and hepatic hydroxyproline levels, in HCV mice while attenuating αSMA induction. PRI-724 led to increased levels of matrix metalloproteinase (MMP)-8 mRNA in the liver, along with elevated levels of intrahepatic neutrophils and macrophages/monocytes. The induced intrahepatic neutrophils and macrophages/monocytes were identified as the source of MMP-8. In conclusion, PRI-724 ameliorated HCV-induced liver fibrosis in mice. We hypothesize that inhibition of hepatic stellate cells activation and induction of fibrolytic cells expressing MMP-8 contribute to the anti-fibrotic effects of PRI-724. PRI-724 is a drug candidate which possesses anti-fibrotic effect.

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