Targeting hepatic ceruloplasmin mitigates nonalcoholic steatohepatitis by modulating bile acid metabolism

Abstract

Abstract Non-alcoholic steatohepatitis (NASH) is a condition that progresses from non-alcoholic fatty liver disease (NAFLD) and is characterized by hepatic fat accumulation, inflammation, and fibrosis. It has the potential to lead to cirrhosis and liver cancer, with currently no effective pharmacological treatment available. In this study, we investigate the therapeutic potential of targeting ceruloplasmin (Cp), a copper-containing protein predominantly secreted by hepatocytes, for treating NASH. Our result show that hepatic Cp was remarkedly upregulated in individuals with NASH and the mouse NASH model. Hepatocyte-specific Cp ablation effectively attenuates the onset of dietary-induced NASH by decreasing lipid accumulation, curbing inflammation, mitigating fibrosis and ameliorating liver damage. By employing transcriptomics and metabolomics approaches, we have discovered that hepatic deletion of Cp brings about the remarkable restoration of NASH by profoundly influencing bile acid metabolism. Hepatic deletion of Cp effectively remodels bile acid metabolism by upregulating Cyp7a1 and Cyp8b1, which subsequently leads to enhanced bile acid synthesis and notable alterations in bile acid profiles. In conclusion, our studies elucidate the crucial involvement of Cp in NASH, highlighting its significance as a promising therapeutic target for the treatment of this disease.