Abstract | BACKGROUND & AIMS: METHODS: EVs were isolated, quantified and characterized from steatotic hepatocytes. An endothelial cell-specific PCR array was used to screen the functional properties of EVs. Profiling of global microRNA expression was conducted in EVs. The expression level and biological function of microRNA-1 (miR-1) was determined by quantitative PCR, immunoblot and reporter gene assays, respectively. The in vivo effect of miR-1 on atherogenesis was investigated in apolipoprotein E ( ApoE)-deficient mice administered with a miR-1-specific inhibitor, antagomiR-1. RESULTS: Steatotic hepatocytes released more EVs, which had significantly altered miRNA expression profiles compared to the EVs released by control hepatocytes. Endothelial cells co-cultured with steatotic hepatocytes, or treated with their EVs or miR-1, expressed significantly more proinflammatory molecules, as well as exhibiting increased NF-κB activity and reduced Kruppel-like factor 4 (KLF4) expression. EV-induced endothelial inflammation was prevented by either downregulation or inhibition of miR-1. While miR-1 treatment suppressed KLF4 expression and reporter gene activity, overexpression of KLF4 dramatically abolished the miR-1-induced endothelial inflammation. Moreover, not only did the miR-1 inhibitor reduce endothelial inflammation in vitro, but it also attenuated atherogenesis in ApoE-deficient mice. CONCLUSION: Steatotic hepatocyte-derived EVs promote endothelial inflammation and facilitate atherogenesis by miR-1 delivery, KLF4 suppression and NF-κB activation. The findings illustrate an important role of hepatocyte-derived EVs in distant communications between the liver and vasculature, suggesting a new mechanism underlying the link between NAFLD and CVD. LAY SUMMARY:
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Authors | Fangjie Jiang, Qi Chen, Wei Wang, Yan Ling, Yan Yan, Pu Xia |
Journal | Journal of hepatology
(J Hepatol)
Vol. 72
Issue 1
Pg. 156-166
(01 2020)
ISSN: 1600-0641 [Electronic] Netherlands |
PMID | 31568800
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. |
Chemical References |
- Antagomirs
- KLF4 protein, human
- Klf4 protein, mouse
- Kruppel-Like Factor 4
- MIRN1 microRNA, human
- MicroRNAs
- Mirn1 microRNA, mouse
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Topics |
- Animals
- Antagomirs
(pharmacology)
- Atherosclerosis
(metabolism)
- Coculture Techniques
- Disease Models, Animal
- Extracellular Vesicles
(metabolism)
- HEK293 Cells
- Hepatocytes
(metabolism)
- Human Umbilical Vein Endothelial Cells
(metabolism)
- Humans
- Inflammation
(metabolism)
- Kruppel-Like Factor 4
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout, ApoE
- MicroRNAs
(antagonists & inhibitors, genetics, metabolism)
- Non-alcoholic Fatty Liver Disease
(metabolism, pathology)
- Signal Transduction
(genetics)
- THP-1 Cells
- Transfection
- Up-Regulation
(genetics)
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