非酒精性脂肪性肝炎 (NASH) 是一种由非酒精性脂肪肝病 (NAFLD) 进展而来的疾病，其特征是肝脏脂肪堆积、炎症和纤维化。它有可能导致肝硬化和肝癌，目前尚无有效的药物治疗方法。在这项研究中，我们研究了靶向铜蓝蛋白 (Cp)（一种主要由肝细胞分泌的含铜蛋白）治疗 NASH 的治疗潜力。我们的结果表明，NASH 个体和小鼠 NASH 模型中肝脏 Cp 显着上调。肝细胞特异性 Cp 消融通过减少脂质积累、抑制炎症、减轻纤维化和改善肝损伤，有效减轻饮食引起的 NASH 的发生。通过转录组学和代谢组学方法，我们发现肝脏Cp缺失通过深刻影响胆汁酸代谢而显着恢复NASH。肝脏删除 Cp 可通过上调 Cyp7a1 和 Cyp8b1 有效重塑胆汁酸代谢，从而导致胆汁酸合成增强和胆汁酸谱显着改变。总之，我们的研究阐明了 Cp 在 NASH 中的重要作用，强调了其作为治疗这种疾病的有前景的治疗靶点的重要性。© 作者 2023。由牛津大学出版社代表生物化学与细胞研究所出版中国科学院上海生命科学研究院生物学。

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.© The Author(s) 2023. Published by Oxford University Press on behalf of Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.