Endothelial cell CD36 regulates membrane ceramide formation, exosome fatty acid transfer and circulating fatty acid levels

Endothelial cell (EC) CD36 controls tissue fatty acid (FA) uptake. Here we examine how ECs transfer FAs. FA interaction with apical membrane CD36 induces Src phosphorylation of caveolin-1 tyrosine-14 (Cav-1Y14) and ceramide generation in caveolae. Ensuing fission of caveolae yields vesicles containi...

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Bibliographic Details
Published in:	Nature communications Vol. 14; no. 1; p. 4029
Main Authors:	Peche, V. S., Pietka, T. A., Jacome-Sosa, M., Samovski, D., Palacios, H., Chatterjee-Basu, G., Dudley, A. C., Beatty, W., Meyer, G. A., Goldberg, I. J., Abumrad, N. A.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 07-07-2023 Nature Publishing Group Nature Portfolio
Subjects:	13/1 13/106 14 14/19 14/28 14/63 38 38/39 38/91 631/45/287/1183 631/80/128/1276 631/80/86/2365 Actin Animals Blood circulation Blood vessels Caveolae Caveolin Caveolin-1 CD36 antigen CD36 Antigens - genetics CD36 Antigens - metabolism CD63 antigen Cell interactions Ceramide Ceramides - metabolism Endocytosis Endothelial cells Endothelial Cells - metabolism Endothelium Exosomes - metabolism Fatty acids Fatty Acids - metabolism Humanities and Social Sciences Membranes Mice multidisciplinary Muscle Fibers, Skeletal - metabolism Muscles Myotubes Parenchyma Phenotypes Phosphorylation Science Science (multidisciplinary) Tyrosine Vesicles
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Summary:	Endothelial cell (EC) CD36 controls tissue fatty acid (FA) uptake. Here we examine how ECs transfer FAs. FA interaction with apical membrane CD36 induces Src phosphorylation of caveolin-1 tyrosine-14 (Cav-1Y14) and ceramide generation in caveolae. Ensuing fission of caveolae yields vesicles containing FAs, CD36 and ceramide that are secreted basolaterally as small (80–100 nm) exosome-like extracellular vesicles (sEVs). We visualize in transwells EC transfer of FAs in sEVs to underlying myotubes. In mice with EC-expression of the exosome marker emeraldGFP-CD63, muscle fibers accumulate circulating FAs in emGFP-labeled puncta. The FA-sEV pathway is mapped through its suppression by CD36 depletion, blocking actin-remodeling, Src inhibition, Cav-1Y14 mutation, and neutral sphingomyelinase 2 inhibition. Suppression of sEV formation in mice reduces muscle FA uptake, raises circulating FAs, which remain in blood vessels, and lowers glucose, mimicking prominent Cd36 −/ − mice phenotypes. The findings show that FA uptake influences membrane ceramide, endocytosis, and EC communication with parenchymal cells. Endothelial cell CD36 controls tissue fatty acid uptake. Here the authors show how fatty acid uptake by endothelial cells involves regulation of membrane ceramide production, caveolae dynamics, and exosome generation, these events facilitate transfer of circulating fatty acids to tissues and communication between endothelium and parenchyma.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-023-39752-3