CBP/β-Catenin Signaling in Hepatocytes Plays Pivotal Roles in MMP-7-Mediated Liver Fibrosis in a Metabolic Dysfunction-Associated Steatohepatitis Mouse Model.

Abstract

In this study, we focused on CBP/β-catenin signaling in hepatocytes and investigated its involvement in fibrosis in a metabolic dysfunction-associated steatohepatitis (MASH) model using a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Alb-Cre/CBPKO (CBP hep-KO ), Alb-Cre/P300KO (P300 hep-KO ), and Alb-Cre mice were fed CDAHFD for 4 months, and liver tissue was used for Sirius Red staining. After 4 months of feeding, the CDAHFD CBP hep-KO mice showed a significant decrease in the liver fibrosis area compared to the other mice. RNA was extracted from the livers and analyzed for fibrosis-related gene expression using RT-PCR, PCR array, and RNA-seq analysis. RNA-seq analysis revealed a significant difference in MMP-7 expression between the livers of CBP hep-KO and P300 hep-KO mice. Next, MMP-7KO and control mice were fed CDAHFD for 4 months. The MMP-7KO mice showed a significant decrease in the liver fibrosis area. The C57BL/6 mice were fed CDAHFD, and 4 months later, AAV8/ShMMP-7 and AAV8/control (2 × 10 12 copies/mouse) were injected twice at 2-week intervals, and fibrosis was assessed. The AAV8/ShMMP-7 treatment reduced the fibrotic area and expression of Col1A1 and Col3A1 in the livers of CDAHFD-fed mice. Thus, CBP/β-catenin signaling in hepatocytes has been implicated in MASH fibrosis via MMP-7, suggesting that MMP-7 is a potential target for new anti-fibrosis drugs.