Inhibition of CBP/β-catenin signaling ameliorated fibrosis in cholestatic liver disease.

Abstract

Chronic cholestatic liver diseases are characterized by injury of the bile ducts and hepatocytes caused by accumulated bile acids (BAs) and inflammation. Wnt/β-catenin signaling is implicated in organ fibrosis; however, its role in cholestatic liver fibrosis remains unclear. Therefore, we explored the effect of a selective cAMP response element-binding protein-binding protein (CBP)/β-catenin inhibitor, PRI-724, on murine cholestatic liver fibrosis. PRI-724 suppressed liver fibrosis induced by multidrug resistance protein 2 knockout (KO), bile duct ligation, or a 3.5-diethoxycarbonyl-1.4-dihydrocollidine (DDC) diet; it also suppressed BA synthesis and macrophage infiltration. The expression of early growth response-1 (Egr-1), which plays a key role in BA synthesis, was increased in the hepatocytes of patients with cholestatic liver disease. PRI-724 inhibited Egr-1 expression induced by cholestasis, and adenoviral shEgr-1-mediated Egr-1 knockdown suppressed BA synthesis and fibrosis in DDC diet-fed mice, suggesting that PRI-724 exerts its effects, at least in part, by suppressing Egr-1 expression in hepatocytes. Hepatocyte-specific CBP KO in mice suppressed BA synthesis, liver injury, and fibrosis, whereas hepatocyte-specific KO of P300, a CBP homolog, exacerbated DDC-induced fibrosis. Intrahepatic Egr-1 expression was also decreased in hepatocyte-specific CBP-KO mice and increased in P300-KO mice, indicating that Egr-1 is located downstream of CBP/β-catenin signaling. Conclusion: PRI-724 inhibits cholestatic liver injury and fibrosis by inhibiting BA synthesis in hepatocytes. These results highlight the therapeutic effect of CBP/β-catenin inhibition in cholestatic liver diseases.

• Authors: Masamichi Kimura, Koji Nishikawa, Yosuke Osawa, Jun Imamura, Kenzaburo Yamaji, Kenichi Harada, Hiroshi Yatsuhashi, Kazumoto Murata, Kouichi Miura, Atsushi Tanaka, Tatsuya Kanto, Michinori Kohara, Terumi Kamisawa, Kiminori Kimura
• Journal: Hepatology communications (Hepatol Commun) Vol. 6 Issue 10 Pg. 2732-2747 (10 2022) ISSN: 2471-254X [Electronic] United States
• PMID: 35855613 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

Chemical References

• Bile Acids and Salts
• Cyclic AMP Response Element-Binding Protein
• beta Catenin

Topics

• Animals
• Bile Acids and Salts
• Cholestasis (complications)
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Liver Cirrhosis (metabolism)
• Mice
• Mice, Knockout
• Wnt Signaling Pathway
• beta Catenin (metabolism)