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Contribution of Hepatic Steatosis–Intensified Extracellular Vesicle Release to Aggravated Inflammatory Endothelial Injury in Liver-Specific Asah1 Gene Knockout Mice

  • Xinxu Yuan
    Affiliations
    Department of Pharmacology and Toxicology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
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  • Owais M. Bhat
    Affiliations
    Department of Pharmacology and Toxicology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
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  • Yao Zou
    Affiliations
    Department of Pharmacology and Toxicology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
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  • Yang Zhang
    Correspondence
    Address correspondence to Pin-Lan Li, M.D., Ph.D., Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298; or Yang Zhang, Ph.D., Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204-5037.
    Affiliations
    Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, Texas
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  • Pin-Lan Li
    Correspondence
    Address correspondence to Pin-Lan Li, M.D., Ph.D., Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298; or Yang Zhang, Ph.D., Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204-5037.
    Affiliations
    Department of Pharmacology and Toxicology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia
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Published:January 10, 2023DOI:https://doi.org/10.1016/j.ajpath.2022.12.007
      To study the mechanism by which nonalcoholic fatty liver disease (NAFLD) contributes to vascular endothelial Nod-like receptor pyrin domain 3 (NLRP3) inflammasome activation and neointima hyperplasia, NAFLD was established in high-fat diet (HFD)–treated Asah1fl/fl/Albcre (liver-specific deletion of the acid ceramidase gene Asah1) mice. Compared with control mice, Asah1 flox [Asah1fl/fl/wild type (WT)] mice, and wild-type (WT/WT) mice, Asah1fl/fl/Albcre mice exhibited significantly enhanced ceramide levels and lipid deposition on HFD in the liver. Moreover, Asah1fl/fl/Albcre mice showed enhanced expression of extracellular vesicle (EV) markers, CD63 and annexin II, but attenuated lysosome–multivesicular body fusion. All these liver changes were accompanied by significantly increased EV counts in the plasma. In a mouse model of neointima hyperplasia, liver-specific deletion of the Asah1 gene enhanced HFD-induced neointima proliferation, which was associated with increased endothelial NLRP3 inflammasome formation and activation and more severe endothelial damage. The EVs isolated from plasma of Asah1fl/fl/Albcre mice on the HFD were found to markedly enhance NLRP3 inflammasome formation and activation in primary cultures of WT/WT endothelial cells compared with those isolated from WT/WT mice or normal diet–treated Asah1fl/fl/Albcre mice. These results suggest that the acid ceramidase/ceramide signaling pathway importantly controls EV release from the liver, and its deficiency aggravates NAFLD and intensifies hepatic EV release into circulation, which promotes endothelial NLRP3 inflammasome activation and consequent neointima hyperplasia in the mouse carotid arteries.
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