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

V. S. Peche (), T. A. Pietka, M. Jacome-Sosa, D. Samovski, H. Palacios, G. Chatterjee-Basu, A. C. Dudley, W. Beatty, G. A. Meyer, I. J. Goldberg and N. A. Abumrad ()
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V. S. Peche: Washington University School of Medicine
T. A. Pietka: Washington University School of Medicine
M. Jacome-Sosa: Washington University School of Medicine
D. Samovski: Washington University School of Medicine
H. Palacios: Washington University School of Medicine
G. Chatterjee-Basu: Washington University School of Medicine
A. C. Dudley: University of Virginia
W. Beatty: Washington University School of Medicine
G. A. Meyer: Washington University School of Medicine
I. J. Goldberg: New York University Grossman School of Medicine
N. A. Abumrad: Washington University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-39752-3

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