Inhibition of CBP/β-catenin signaling ameliorated fibrosis in cholestatic liver disease
Chronic cholestatic liver illnesses are characterised by injuries from the bile ducts and hepatocytes brought on by accrued bile acids (BAs) and inflammation. Wnt/ß-catenin signaling is implicated in organ fibrosis however, its role in cholestatic liver fibrosis remains unclear. Therefore, we explored the consequence of selective cAMP response element-binding protein-binding protein (CBP)/ß-catenin inhibitor, PRI-724, on murine cholestatic liver fibrosis. PRI-724 covered up liver fibrosis caused by multidrug resistance protein 2 knockout (KO), bile duct ligation, or perhaps a 3.5-diethoxycarbonyl-1.4-dihydrocollidine (DDC) diet additionally, it covered up BA synthesis and macrophage infiltration. The expression of early growth response-1 (Egr-1), which plays a vital role in BA synthesis, was elevated within the hepatocytes of patients with cholestatic liver disease. PRI-724 inhibited Egr-1 expression caused by cholestasis, and adenoviral shEgr-1-mediated Egr-1 knockdown covered up BA synthesis and fibrosis in DDC diet-given rodents, suggesting that PRI-724 exerts its effects, a minimum of partly, by suppressing Egr-1 expression in PRI-724 hepatocytes. Hepatocyte-specific CBP KO in rodents covered up BA synthesis, liver injuries, and fibrosis, whereas hepatocyte-specific KO of P300, a CBP homolog, exacerbated DDC-caused fibrosis. Intrahepatic Egr-1 expression seemed to be decreased in hepatocyte-specific CBP-KO rodents and elevated in P300-KO rodents, indicating that Egr-1 is situated downstream of CBP/ß-catenin signaling. Conclusion: PRI-724 inhibits cholestatic liver injuries and fibrosis by inhibiting BA synthesis in hepatocytes. These results highlight the therapeutic aftereffect of CBP/ß-catenin inhibition in cholestatic liver illnesses.