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

Journal of Nanobiotechnology

Yang Zhang¹  Lei Wang²  Hui Zhi²  Li Zhu²  Zi-Qing Song²  Jie-Yi Li²  Wen-Jing Xiao²  Rui Zuo²  Li-Feng Ye²  Min-Yi Zhang²  Yang Chen²  Yi Huang³  Rong-Rong He⁴  Hong-Cai Shang⁵ 

[1] Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 4849 Calhoun Road, 77204-5037, Houston, TX, USA;Department of Pharmacology, School of Pharmaceutical, Guangzhou University of Chinese Medicine, 232, Waihuan East Road, Guangzhou Higher Education Mega Center, Panyu District, 510000, Guangzhou, China;Department of Stomatology, The First Affiliated Hospital, The School of Dental Medicine, Jinan University, Guangzhou, China;Guangdong Engineering Research Center of Chinese Medicine and Disease Susceptibility, Jinan University, 601, West Huangpu Road, 510632, Guangzhou, China;Key Laboratory of Chinese Internal Medicine of Ministry of Education and Beijing, Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine, 5 Hai Yun Cang, Dongcheng District, 100700, Beijing, China;

关键词: Liver inflammation;    Microvascular endothelial dysfunction;    Inter-organ communication;    Tight junction;    NLRP3 inflammasome;   

DOI  :  10.1186/s12951-021-01137-3

来源: Springer

【 摘 要 】

BackgroundA 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.ResultsWe 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.ConclusionsHepatic 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

【 授权许可】

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