Hepatic Vps33b deficiency aggravates cholic acid-induced cholestatic liver injury in male mice  

作　　者：Kai-li Fu Pan Chen Yan-ying Zhou Yi-ming Jiang Yue Gao Hui-zhen Zhang Li-huan Guan Cong-hui Wang Jun-ling Liu Min Huang Hui-chang Bi 

机构地区：[1]Guangdong Provincial Key Laboratory of New Drug Design and Evaluation,Sun Yat-sen University,Guangzhou,510006,China [2]Department of Pharmacy,the First Affiliated Hospital,Sun Yat-sen University,Guangzhou,510080,China [3]Department of Pathophysiology,Shanghai Jiao Tong University School of Medicine,Shanghai,200025,China

出　　处：《Acta Pharmacologica Sinica》2022年第4期933-940,共8页中国药理学报（英文版）

基　　金：The work was supported by the National Natural Science Foundation of China(Grants:82025034,81973392,81320108027);the National Key Research and Development Program(Grant:2017YFE0109900);the Shenzhen Science and Technology Program(KQTD20190929174023858);the Key Laboratory Foundation of Guangdong Province(Grant:2017B030314030);the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program(2017BT01Y093);the National Engineering and Technology Research Center for New Drug Druggability Evaluation(Seed Program of Guangdong Province,2017B090903004).

摘　　要：Vacuolar protein sorting 33B (VPS33B) is important for intracellular vesicular trafficking process and protein interactions, which is closely associated with the arthrogryposis, renal dysfunction, and cholestasis syndrome. Our previous study has shown a crucial role of Vps33b in regulating metabolisms of bile acids and lipids in hepatic Vps33b deficiency mice with normal chow, but it remains unknown whether VPS33B could contribute to cholestatic liver injury. In this study we investigated the effects of hepatic Vps33b deficiency on bile acid metabolism and liver function in intrahepatic cholestatic mice. Cholestasis was induced in Vps33b hepatic knockout and wild-type male mice by feeding 1% CA chow diet for 5 consecutive days. We showed that compared with the wild-type mice, hepatic Vps33b deficiency greatly exacerbated CA-induced cholestatic liver injury as shown in markedly increased serum ALT, AST, and ALP activities, serum levels of total bilirubin, and total bile acid, as well as severe hepatocytes necrosis and inflammatory infiltration. Target metabolomics analysis revealed that hepatic Vps33b deficiency caused abnormal profiles of bile acids in cholestasis mice, evidenced by the upregulation of conjugated bile acids in serum, liver, and bile. We further demonstrated that the metabolomics alternation was accompanied by gene expression changes in bile acid metabolizing enzymes and transporters including Cyp3a11, Ugt1a1, Ntcp, Oatp1b1, Bsep, and Mrp2. Overall, these results suggest a crucial role of hepatic Vps33b deficiency in exacerbating cholestasis and liver injury, which is associated with the altered metabolism of bile acids.

关 键 词：CHOLESTASIS liver injury Vps33b bile acids METABONOMICS 

分 类 号：R57[医药卫生—消化系统]