Vitamin D receptor (VDR) mediates the quiescence of activated hepatic stellate cells (aHSCs) by regulating M2 macrophage exosomal smooth muscle cell-associated protein 5 (SMAP-5)  

作　　者：Xuwentai LIU Yue WU Yanyi LI Kaiming LI Siyuan HOU Ming DING Jingmin TAN Zijing ZHU Yingqi TANG Yuming LIU Qianhui SUN Cong WANG Can ZHANG 

机构地区：[1]State Key Laboratory of Natural Medicines/Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases/Center of Advanced Pharmaceuticals and Biomaterials,China Pharmaceutical University,Nanjing 210009,China

出　　处：《Journal of Zhejiang University-Science B(Biomedicine & Biotechnology)》2023年第3期248-261,共14页浙江大学学报（英文版）B辑（生物医学与生物技术）

基　　金：supported by the National Natural Science Foundation of China(Nos.81930099,81773664,82130102,92159304,81703585,and 81903651);the Natural Science Foundation of Jiangsu Province(Nos.BK20212011 and BK20180565);the Technology Innovation Project of Nucleic Acid Drug from National Center of Technology Innovation for Biopharmaceuticals(No.NCTIB2022HS01014);the“Double First-Class”University Project(No.CPU2022QZ05);the 111 Project from the Ministry of Education of China and the State Administration of Foreign Expert Affairs of China(Nos.111-2-07 and B17047);the Fundamental Research Funds for the Central Universities of China(No.2632022ZD11);the Open Project of State Key Laboratory of Natural Medicines(No.SKLNMZZ202017),China.

摘　　要：An effective therapeutic regimen for hepatic fibrosis requires a deep understanding of the pathogenesis mechanism.Hepatic fibrosis is characterized by activated hepatic stellate cells(aHSCs)with an excessive production of extracellular matrix.Although promoted activation of HSCs by M2 macrophages has been demonstrated,the molecular mechanism involved remains ambiguous.Herein,we propose that the vitamin D receptor(VDR)involved in macrophage polarization may regulate the communication between macrophages and HSCs by changing the functions of exosomes.We confirm that activating the VDR can inhibit the effect of M2 macrophages on HSC activation.The exosomes derived from M2 macrophages can promote HSC activation,while stimulating VDR alters the protein profiles and reverses their roles in M2 macrophage exosomes.Smooth muscle cell-associated protein 5(SMAP-5)was found to be the key effector protein in promoting HSC activation by regulating autophagy flux.Building on these results,we show that a combined treatment of a VDR agonist and a macrophage-targeted exosomal secretion inhibitor achieves an excellent anti-hepatic fibrosis effect.In this study,we aim to elucidate the association between VDR and macrophages in HSC activation.The results contribute to our understanding of the pathogenesis mechanism of hepatic fibrosis,and provide potential therapeutic targets for its treatment.

关 键 词：Hepatic fibrosis Hepatic stellate cell(HSC) MACROPHAGE EXOSOME Vitamin D receptor(VDR) Smooth muscle cell-associated protein 5(SMAP-5) 

分 类 号：R575.2[医药卫生—消化系统]