Targeting hepatic ceruloplasmin mitigates nonalcoholic steatohepatitis by modulating bile acid metabolism

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.

Examining the Pathogenesis of MAFLD and the Medicinal Properties of Natural Products from a Metabolic Perspective

“…Mechanistically, copper deficiency inhibits AMPK and thus leads to impaired mitochondrial biogenesis and fatty acid oxidation, in turn resulting in MAFLD (Figure 1) [227]. Cp is a protein containing copper that is secreted by hepatocytes, and hepatocyte-specific ablation of Cp reduces lipid accumulation, inhibits inflammation, attenuates fibrosis, and ameliorates liver injury, which may be associated with the remodeling of bile acid metabolism [228]. Furthermore, copper overload leads to lipogenesis, oxidative stress, and mitochondrial dysfunction, which induce hepatic steatosis and lipotoxicity [229,230].…”

The Role of Oxidative Stress and Inflammatory Parameters in Heart Failure

“…Clinical studies have linked elevated Cp levels with metabolic disorders, including metabolic syndrome, diabetes and cardiovascular diseases. Cp is an acute-phase reactant protein whose plasma concentration increases in response to inflammation, trauma or infection [106].…”