Anti-inflammatory and antifibrotic effects of CBP/β-catenin inhibitor for hepatocytes: small molecular inhibitor, OP-724 possibly improves liver function.

Abstract

Wnt/β-catenin signals are associated with several functions, including organ fibrosis. A synthetic small molecule, OP-724 (prodrug of C-82), an inhibitor of cyclic AMP response element-binding protein (CREB)-binding protein (CBP)/β-catenin, has demonstrated antifibrotic activity in mouse models of hepatic fibrosis. OP-724 is mediated by profibrotic and antifibrotic cells, such as hepatic stellate cells, macrophages, and neutrophils. In this study, the direct effects of C-82 on hepatocytes in hepatic inflammation were investigated. Immortalized human hepatocytes were pretreated with inflammatory cytokines. Moreover, the alteration of mRNA and protein expressions of cytokines and chemokines associated with hepatic inflammation and fibrosis, and of mitochondria-related molecules after C-82 treatment were analyzed in this study. The mRNA expression of several proinflammatory and profibrotic chemokines was upregulated by the stimulation of these inflammatory cytokines. In addition, this increase was prevented by C-82. In particular, the protein secretion of CCL2, CCL5, CXCL1, CXCL9, and CXCL10 was noticeably upregulated by TNFα and prevented by additional C-82. Moreover, C-82 increased the VEGF-A and FGF-2 proteins, categorized as anti-inflammatory and antifibrotic molecules, respectively. It also increased the expression of mitochondrial components and mitochondrial membrane potential. In conclusion, C-82 inhibits hepatocyte-mediated proinflammation and fibrogenesis. It also directly activates the mitochondrial function, thus improving liver dysfunction.