首页|Targeting hepatic ceruloplasmin mitigates nonalcoholic steatohepatitis by modulating bile acid metabolism

Targeting hepatic ceruloplasmin mitigates nonalcoholic steatohepatitis by modulating bile acid metabolism

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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.

ceruloplasminnonalcoholic steatohepatitisbile acidinflammationfibrosis

Quanxin Jiang、Ning Wang、S?ia Lu、Jie Xiong、Yanmei Yuan、Junli Liu、Suzhen Chen

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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

National Natural Science Foundation of ChinaShanghai Rising-Star ProgramLingang Laboratory GrantInnovative Research Team of Highlevel Local Universities in ShanghaiShanghai Sixth People's HospitalNational Key R&D Program of ChinaNational Key R&D Program of ChinaShanghai Municipal Commission of Science and TechnologyShanghai Municipal Commission of Science and TechnologyNational Facility for Translational Medicinethe'Shuguang Program'supported by Shanghai Education Development Foundation and Shanghai Municipal Education CommissionShanghai Sixth People's Hospital

8217086321QA1407000LG-QS-202205-06SHSMU-ZDCX20212501ynyq2021032021YFA08048002018YFA08006002041071320021S11909000TMSK-2020-10220SG10ynjq202102

2023

10.1093/jmcb/mjad060

分子细胞生物学报(英文版)
中国科学院上海生命科学研究院,生物化学与细胞生物学研究所,中国细胞生物学学会

分子细胞生物学报(英文版)

CSTPCDCSCD
影响因子：0.595
ISSN：1673-520X
年,卷(期)：2023.(9)
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