Hepatocyte-derived extracellular vesicles promote endothelial inflammation and atherogenesis via microRNA-1

Abstract

BACKGROUND AND AIMS Clinical evidence has indicated a close relationship between non-alcoholic fatty liver disease (NAFLD) and cardiovascular diseases (CVD). However, the underlying mechanism remains to be elucidated. This study aimed to explore a potential role of hepatocyte-derived extracellular vesicles (EVs) in endothelial inflammation and atherogenesis under NAFLD status. METHODS AND RESULTS By using an endothelial cell-specific PCR array, we identified that hepatocyte-derived EVs from the fatty liver are a potent inducer of endothelial inflammation. Through profiling and functional analysis of the global microRNA in the EVs, we found that microRNA-1 (miR-1) is a key EV cargo that mediates the pro-inflammatory effect of EVs by down-regulation of KLF4 and activation of the NF-κB pathway in endothelial cells. Moreover, not only did the inhibition of miR-1 reduce endothelial inflammation in vitro but 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 the NF-κB pathway activation. The findings illustrate an important role for hepatocyte-derived EVs in distant communications between the liver and vasculature, suggesting a new mechanism underlying the link between NAFLD and CVD. LAY SUMMARY Non-alcoholic fatty liver disease (NAFLD), a condition highly prevalent in obese or diabetic patients, is emerging at a high risk for the development of cardiovascular diseases (CVD). In the current study, we identified a kind of toxic particles, namely extracellular vesicles, released by hepatocytes under NAFLD conditions, which causes vascular endothelial inflammation and promotes atherosclerosis. Furthermore, we identified a small molecular cargo in the toxic particles, which is a potent inducer of endothelial inflammation. By inhibiting this cargo function, a specific gene-based inhibitor profoundly attenuated atherogenesis in mice. Thus, our study uncovers a novel mechanism for distant communications between the liver and blood vessels and suggests a new way to prevention and treatment of CVD, especially for NAFLD patients.