Salvianolic acid B suppresses hepatic fibrosis by inhibiting ceramide glucosyltransferase in hepatic stellate cells  

作　　者：Zi-bo Li Lin Jiang Jia-dong Ni Yuan-hang Xu Fang Liu Wen-ming Liu Shao-gui Wang Zhong-qiu Liu Cai-yan Wang 

机构地区：[1]Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines,Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines,International Institute for Translational Chinese Medicine,Guangzhou University of Chinese Medicine,Guangzhou 510006,China [2]School of Pharmaceutical Sciences,Guangzhou University of Chinese Medicine,Guangzhou 510006,China

出　　处：《Acta Pharmacologica Sinica》2023年第6期1191-1205,共15页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(Grant No.81930114);Key-Area Research and Development Program of Guangdong Province(Grant No.2020B1111100004);the 2020 Guangdong Provincial Science and Technology Innovation Strategy Special Fund(Guangdong-Hong Kong-Macao Joint Laboratory,Grant No.2020B1212030006).

摘　　要：UDP-glucose ceramide glucosyltransferase(UGCG)is the first key enzyme in glycosphingolipid(GSL)metabolism that produces glucosylceramide(GlcCer).Increased UGCG synthesis is associated with cell proliferation,invasion and multidrug resistance in human cancers.In this study we investigated the role of UGCG in the pathogenesis of hepatic fibrosis.We first found that UGCG was over-expressed in fibrotic livers and activated hepatic stellate cells(HSCs).In human HSC-LX2 cells,inhibition of UGCG with PDMP or knockdown of UGCG suppressed the expression of the biomarkers of HSC activation(α-SMA and collagen I).Furthermore,pretreatment with PDMP(40μM)impaired lysosomal homeostasis and blocked the process of autophagy,leading to activation of retinoic acid signaling pathway and accumulation of lipid droplets.After exploring the structure and key catalytic residues of UGCG in the activation of HSCs,we conducted virtual screening,molecular interaction and molecular docking experiments,and demonstrated salvianolic acid B(SAB)from the traditional Chinese medicine Salvia miltiorrhiza as an UGCG inhibitor with an IC_(50)value of 159μM.In CCl_(4)-induced mouse liver fibrosis,intraperitoneal administration of SAB(30 mg·kg^(−1)·d^(−1),for 4 weeks)significantly alleviated hepatic fibrogenesis by inhibiting the activation of HSCs and collagen deposition.In addition,SAB displayed better anti-inflammatory effects in CCl4-induced liver fibrosis.These results suggest that UGCG may represent a therapeutic target for liver fibrosis;SAB could act as an inhibitor of UGCG,which is expected to be a candidate drug for the treatment of liver fibrosis.

关 键 词：liver fibrosis hepatic stellate cells UGCG autophagy PDMP salvianolic acid B 

分 类 号：R965[医药卫生—药理学]