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

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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
    Washington University School of Medicine)

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.

Suggested Citation

  • 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 & N. A. Abumrad, 2023. "Endothelial cell CD36 regulates membrane ceramide formation, exosome fatty acid transfer and circulating fatty acid levels," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39752-3
    DOI: 10.1038/s41467-023-39752-3
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    References listed on IDEAS

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    1. Hosung Bae & Ki Yong Hong & Choong-kun Lee & Cholsoon Jang & Seung-Jun Lee & Kibaek Choe & Stefan Offermanns & Yulong He & Hyuek Jong Lee & Gou Young Koh, 2020. "Angiopoietin-2–integrin α5β1 signaling enhances vascular fatty acid transport and prevents ectopic lipid-induced insulin resistance," Nature Communications, Nature, vol. 11(1), pages 1-17, December.
    2. Elena Shvets & Vassilis Bitsikas & Gillian Howard & Carsten Gram Hansen & Benjamin J. Nichols, 2015. "Dynamic caveolae exclude bulk membrane proteins and are required for sorting of excess glycosphingolipids," Nature Communications, Nature, vol. 6(1), pages 1-16, November.
    3. Jian-Wei Hao & Juan Wang & Huiling Guo & Yin-Yue Zhao & Hui-Hui Sun & Yi-Fan Li & Xiao-Ying Lai & Ning Zhao & Xu Wang & Changchuan Xie & Lixin Hong & Xi Huang & Hong-Rui Wang & Cheng-Bin Li & Bin Lian, 2020. "CD36 facilitates fatty acid uptake by dynamic palmitoylation-regulated endocytosis," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    4. Fu-Lien Hsieh & Louise Turner & Jani Reddy Bolla & Carol V. Robinson & Thomas Lavstsen & Matthew K. Higgins, 2016. "The structural basis for CD36 binding by the malaria parasite," Nature Communications, Nature, vol. 7(1), pages 1-11, November.
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