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Upregulation of GLT25D1 in Hepatic Stellate Cells Promotes Liver Fibrosis via the TGF-β1/SMAD3 Pathway In Vivo and In vitro

查看全文 作　　者：Shiwei [1]Wang;Lingling [1]He;Fan [2]Xiao;Meixin [1]Gao;Herui [1]Wei;Junru [1]Yang;Yang [1]Shu;Fuyang [1]Zhang;Xiaohui [3]Ye;Ping [1]Li;Xiaohua [4]Hao;Xingang [5]Zhou;Hongshan [1,6]Wei 高影响力作者 机构地区：[1]Department of Gastroenterology,Beijing Ditan Hospital,Capital Medical University,Beijing,China;[2]Institute of Infectious Diseases,Beijing Ditan Hospital,Capital Medical University,Beijing,China;[3]Department of Gastroenterology,Beijing Huaxin Hospital,the First Affiliated Hospital of Tsinghua University,Beijing,China;[4]Beijing Ditan Hospital,Capital Medical University,Beijing,China;[5]Department of Pathology,Beijing Ditan Hospital,Capital Medical University,Beijing,China;[6]Department of Gastroenterology,Peking University Ditan Teaching Hospital,Beijing,China高影响力机构 出　　处：《Journal of Clinical and Translational Hepatology》索引2023年第11卷第1期,共14页高影响力期刊 基　　金：funded by the National Science Foundation of China [No.82170541];National Science Foundation of China [No.81900549];Natural Science Foundation of Beijing Municipality [No.7202071];The Capital Foundation for Clinical Characteristic Applied Research Projects [No.Z181100001718084];The Digestive Medical Coordinated Development Center of Beijing Municipal Administration of Hospitals [No.XXZ0404];The Study on Modernization of Traditional Chinese Medicine [No.2018YFC1705700];Capital Medical University Research Development Fund [No.PYZ20031]. 摘　　要：Background and Aims:Collagenβ(1-O)galactosyltransferase 25 domain 1(GLT25D1)is associated with collagen production and glycosylation,and its knockout in mice results in embryonic death.However,its role in liver fibrosis remains elusive,particularly in hepatic stellate cells(HSCs),the primary collagen-producing cells associated with liver fibrogenesis.Herein,we aimed to elucidate the role of GLT25D1 in HSCs.Methods:Bile duct ligation(BDL)-induced mouse liver fibrosis models,primary mouse HSCs(mHSCs),and transforming growth factor beta 1(TGF-β1)-stimulated LX-2 human hepatic stellate cells were used in in vivo and in vitro studies.Stable LX-2 cell lines with either GLT25D1 overexpression or knockdown were established using lentiviral transfection.RNA-seq was performed to investigate the genomic differences.HPLCMS/MS were used to identify glycosylation sites.Scanning electronic microscopy(SEM)and second-harmonic generation/two-photon excited fluorescence(SHG/TPEF)were used to image collagen fibril morphology.Results:GLT25D1 expression was upregulated in nonparenchymal cells in human cirrhotic liver tissues.Meanwhile,its knockdown attenuated collagen deposition in BDL-induced mouse liver fibrosis and inhibited mHSC activation.GLT25D1 was overexpressed in activated versus quiescence LX-2 cells and regulated in vitro LX-2 cell activation,including proliferation,contraction,and migration.GLT25D1 also significantly increased liver fibrogenic gene and protein expression.GLT25D1 upregulation promoted HSC activation and enhanced collagen expression through the TGF-β1/SMAD signaling pathway.Mass spectrometry showed that GLT25D1 regulated the glycosylation of collagen in HSCs,affecting the diameter of collagen fibers.Conclusions:Collectively,the upregulation of GLT25D1 in HSCs promoted the progression of liver fibrosis by affecting HSCs activation and collagen stability. 关 键 词：COLLAGEN GLYCOSYLATION Hepatic stellate cells Liver fibrosis TGF-Β1
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