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Aggravated Endothelial Inflammasome Activation and Neointima Proliferation by Hepatic Steotosis‐intensified Exosome Release in Liver‐Specific Asah1 Gene Knockout Mice

Nonalcoholic fatty liver disease (NAFLD) has been reported to be independently associated with increased traditional risk for cardiovascular diseases (CVDs). However, the mechanism underpinning the association between NAFLD and CVD remains poorly understood. The present study hypothesized that circulatory exosomes released from liver during NAFLD contribute to vascular endothelial inflammasome activation and neointima proliferation. In mice with liver‐specific deletion of Asah1 gene, a gene coding mouse acid ceramidase (Asah1fl/fl/Albcre), we found significantly enhanced liver lipid deposition when they were fed the high fat diet (HFD), as shown by HE staining and Oil Red Staining. These mice also had augmented expression of exosome marker, CD63 in the liver, and exosomes in their plasma was significantly increased as measured by Nanoparticle Tracking Analysis (NTA) compared to WT/WT mice. In partial ligated carotid artery, we observed that Asah1fl/fl/Albcre mice with HFD treatment markedly increased Nod‐like receptor pyrin domain 3 (NLRP3) inflammasome formation as shown by the colacolization of NLRP3 with apoptosis‐associated speck‐like protein gene (ASC) or caspase‐1. Enhanced colocaziation of fluorescent labeled inhibitor of caspases (FLICA) with endothelial cell marker, vWF and increased IL‐1β level in the carotid intima demonstrate NLRP3 inflammasome activation. Correspondingly, more severe vascular endothelial injury was found in Asah1fl/fl/Albcre mice as shown by reduction of vWF and endothelial junction protein, ZO‐1, which was accompaned by increased neointima proliferation. These results suggest that acid ceramidase importantly controls exosome release from the liver and its decifiency intensifies NAFLD and thereby releasees more exosomes to promote endothelial NLRP3 inflammasome activation and consequent neointiam proliferation.