Hepatic small extracellular vesicles promote microvascular endothelial hyperpermeability during NAFLD via novel-miRNA-7

Abstract Background A recent study has reported that patients with nonalcoholic fatty liver disease (NAFLD) are more susceptible to coronary microvascular dysfunction (CMD), which may predict major adverse cardiac events. However, little is known regarding the causes of CMD during NAFLD. In this stu...

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Autores principales:	Rui Zuo, Li-Feng Ye, Yi Huang, Zi-Qing Song, Lei Wang, Hui Zhi, Min-Yi Zhang, Jie-Yi Li, Li Zhu, Wen-Jing Xiao, Hong-Cai Shang, Yang Zhang, Rong-Rong He, Yang Chen
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Liver inflammation Microvascular endothelial dysfunction Inter-organ communication Tight junction NLRP3 inflammasome Biotechnology TP248.13-248.65 Medical technology R855-855.5
Acceso en línea:	https://doaj.org/article/bc64632446ca46b9b30060575477167b
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spelling	oai:doaj.org-article:bc64632446ca46b9b30060575477167b2021-11-28T12:26:38ZHepatic small extracellular vesicles promote microvascular endothelial hyperpermeability during NAFLD via novel-miRNA-710.1186/s12951-021-01137-31477-3155https://doaj.org/article/bc64632446ca46b9b30060575477167b2021-11-01T00:00:00Zhttps://doi.org/10.1186/s12951-021-01137-3https://doaj.org/toc/1477-3155Abstract Background A recent study has reported that patients with nonalcoholic fatty liver disease (NAFLD) are more susceptible to coronary microvascular dysfunction (CMD), which may predict major adverse cardiac events. However, little is known regarding the causes of CMD during NAFLD. In this study, we aimed to explore the role of hepatic small extracellular vesicles (sEVs) in regulating the endothelial dysfunction of coronary microvessels during NAFLD. Results We established two murine NAFLD models by feeding mice a methionine-choline-deficient (MCD) diet for 4 weeks or a high-fat diet (HFD) for 16 weeks. We found that the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-dependent endothelial hyperpermeability occurred in coronary microvessels during both MCD diet and HFD-induced NAFLD. The in vivo and in vitro experiments proved that novel-microRNA(miR)-7-abundant hepatic sEVs were responsible for NLRP3 inflammasome-dependent endothelial barrier dysfunction. Mechanistically, novel-miR-7 directly targeted lysosomal associated membrane protein 1 (LAMP1) and promotes lysosomal membrane permeability (LMP), which in turn induced Cathepsin B-dependent NLRP3 inflammasome activation and microvascular endothelial hyperpermeability. Conversely, a specific novel-miR-7 inhibitor markedly improved endothelial barrier integrity. Finally, we proved that steatotic hepatocyte was a significant source of novel-miR-7-contained hepatic sEVs, and steatotic hepatocyte-derived sEVs were able to promote NLRP3 inflammasome-dependent microvascular endothelial hyperpermeability through novel-miR-7. Conclusions Hepatic sEVs contribute to endothelial hyperpermeability in coronary microvessels by delivering novel-miR-7 and targeting the LAMP1/Cathepsin B/NLRP3 inflammasome axis during NAFLD. Our study brings new insights into the liver-to-microvessel cross-talk and may provide a new diagnostic biomarker and treatment target for microvascular complications of NAFLD. Graphical AbstractRui ZuoLi-Feng YeYi HuangZi-Qing SongLei WangHui ZhiMin-Yi ZhangJie-Yi LiLi ZhuWen-Jing XiaoHong-Cai ShangYang ZhangRong-Rong HeYang ChenBMCarticleLiver inflammationMicrovascular endothelial dysfunctionInter-organ communicationTight junctionNLRP3 inflammasomeBiotechnologyTP248.13-248.65Medical technologyR855-855.5ENJournal of Nanobiotechnology, Vol 19, Iss 1, Pp 1-19 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Liver inflammation Microvascular endothelial dysfunction Inter-organ communication Tight junction NLRP3 inflammasome Biotechnology TP248.13-248.65 Medical technology R855-855.5
spellingShingle	Liver inflammation Microvascular endothelial dysfunction Inter-organ communication Tight junction NLRP3 inflammasome Biotechnology TP248.13-248.65 Medical technology R855-855.5 Rui Zuo Li-Feng Ye Yi Huang Zi-Qing Song Lei Wang Hui Zhi Min-Yi Zhang Jie-Yi Li Li Zhu Wen-Jing Xiao Hong-Cai Shang Yang Zhang Rong-Rong He Yang Chen Hepatic small extracellular vesicles promote microvascular endothelial hyperpermeability during NAFLD via novel-miRNA-7
description	Abstract Background A recent study has reported that patients with nonalcoholic fatty liver disease (NAFLD) are more susceptible to coronary microvascular dysfunction (CMD), which may predict major adverse cardiac events. However, little is known regarding the causes of CMD during NAFLD. In this study, we aimed to explore the role of hepatic small extracellular vesicles (sEVs) in regulating the endothelial dysfunction of coronary microvessels during NAFLD. Results We established two murine NAFLD models by feeding mice a methionine-choline-deficient (MCD) diet for 4 weeks or a high-fat diet (HFD) for 16 weeks. We found that the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-dependent endothelial hyperpermeability occurred in coronary microvessels during both MCD diet and HFD-induced NAFLD. The in vivo and in vitro experiments proved that novel-microRNA(miR)-7-abundant hepatic sEVs were responsible for NLRP3 inflammasome-dependent endothelial barrier dysfunction. Mechanistically, novel-miR-7 directly targeted lysosomal associated membrane protein 1 (LAMP1) and promotes lysosomal membrane permeability (LMP), which in turn induced Cathepsin B-dependent NLRP3 inflammasome activation and microvascular endothelial hyperpermeability. Conversely, a specific novel-miR-7 inhibitor markedly improved endothelial barrier integrity. Finally, we proved that steatotic hepatocyte was a significant source of novel-miR-7-contained hepatic sEVs, and steatotic hepatocyte-derived sEVs were able to promote NLRP3 inflammasome-dependent microvascular endothelial hyperpermeability through novel-miR-7. Conclusions Hepatic sEVs contribute to endothelial hyperpermeability in coronary microvessels by delivering novel-miR-7 and targeting the LAMP1/Cathepsin B/NLRP3 inflammasome axis during NAFLD. Our study brings new insights into the liver-to-microvessel cross-talk and may provide a new diagnostic biomarker and treatment target for microvascular complications of NAFLD. Graphical Abstract
format	article
author	Rui Zuo Li-Feng Ye Yi Huang Zi-Qing Song Lei Wang Hui Zhi Min-Yi Zhang Jie-Yi Li Li Zhu Wen-Jing Xiao Hong-Cai Shang Yang Zhang Rong-Rong He Yang Chen
author_facet	Rui Zuo Li-Feng Ye Yi Huang Zi-Qing Song Lei Wang Hui Zhi Min-Yi Zhang Jie-Yi Li Li Zhu Wen-Jing Xiao Hong-Cai Shang Yang Zhang Rong-Rong He Yang Chen
author_sort	Rui Zuo
title	Hepatic small extracellular vesicles promote microvascular endothelial hyperpermeability during NAFLD via novel-miRNA-7
title_short	Hepatic small extracellular vesicles promote microvascular endothelial hyperpermeability during NAFLD via novel-miRNA-7
title_full	Hepatic small extracellular vesicles promote microvascular endothelial hyperpermeability during NAFLD via novel-miRNA-7
title_fullStr	Hepatic small extracellular vesicles promote microvascular endothelial hyperpermeability during NAFLD via novel-miRNA-7
title_full_unstemmed	Hepatic small extracellular vesicles promote microvascular endothelial hyperpermeability during NAFLD via novel-miRNA-7
title_sort	hepatic small extracellular vesicles promote microvascular endothelial hyperpermeability during nafld via novel-mirna-7
publisher	BMC
publishDate	2021
url	https://doaj.org/article/bc64632446ca46b9b30060575477167b
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Hepatic small extracellular vesicles promote microvascular endothelial hyperpermeability during NAFLD via novel-miRNA-7

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