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).

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

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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).

Author: Xuwentai LIU ¹ ; Yue WU ¹ ; Yanyi LI ¹ ; Kaiming LI ¹ ; Siyuan HOU ¹ ; Ming DING ¹ ; Jingmin TAN ¹ ; Zijing ZHU ¹ ; Yingqi TANG ¹ ; Yuming LIU ¹ ; Qianhui SUN ¹ ; Cong WANG ² ; Can ZHANG ³
Author Information

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.
2. 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. zhangcan@cpu.edu.cn, wangcong@cpu.edu.cn.
3. 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. zhangcan@cpu.edu.cn.
Publication Type:Journal Article
Keywords: Exosome; Hepatic fibrosis; Hepatic stellate cell (HSC); Macrophage; Smooth muscle cell-associated protein 5 (SMAP-5); Vitamin D receptor (VDR)
MeSH: Humans; Hepatic Stellate Cells/pathology*; Receptors, Calcitriol; Liver Cirrhosis/pathology*; Macrophages/metabolism*
From: Journal of Zhejiang University. Science. B 2023;24(3):248-261
CountryChina
Language:English
Abstract: 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.