Targeting hepatic ceruloplasmin mitigates nonalcoholic steatohepatitis by modulating bile acid metabolism  

作　　者：Quanxin Jiang Ning Wang Sijia Lu Jie Xiong Yanmei Yuan Junli Liu Suzhen Chen 

机构地区：[1]Shanghai Diabetes Institute,Department of Endocrinology and Metabolism,Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,Shanghai 200233,China

出　　处：《Journal of Molecular Cell Biology》2023年第9期53-68,共16页分子细胞生物学报（英文版）

基　　金：supported by grants to S.C.from the National Natural Science Foundation of China(82170863);Shanghai Rising-Star Program(21QA1407000),the Lingang Laboratory Grant(LG-QS-202205-06);the Innovative Research Team of High-level Local Universities in Shanghai(SHSMU-ZDCX20212501);Shanghai Sixth People’s Hospital(ynyq202103);supported by grants to J.L.from the National Key R&D Program of China(2021YFA0804800 and 2018YFA0800600);Shanghai Municipal Commission of Science and Technology(20410713200 and 21S11909000);the National Facility for Translational Medicine(TMSK-2020-102);the‘Shuguang Program’supported by Shanghai Education Development Foundation and Shanghai Municipal Education Commission(20SG10),and Shanghai Sixth People’s Hospital(ynjq202102).

摘　　要：Nonalcoholic steatohepatitis(NASH)is a condition that progresses from nonalcoholic fatty liver disease(NAFLD)and is characterized by hepatic fat accumulation,inflammation,and fibrosis.It has the potential to develop into cirrhosis and liver cancer,and currently no effective pharmacological treatment is 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 is 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 remarkable restoration of bile acid(BA)metabolism during NASH.Hepatic deletion of Cp effectively remodels BA metabolism by upregulating Cyp7a1 and Cyp8b1,which subsequently leads to enhanced BA synthesis and notable alterations in BA 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.

关 键 词：CERULOPLASMIN nonalcoholic steatohepatitis bile acid INFLAMMATION FIBROSIS 

分 类 号：R575.1[医药卫生—消化系统]