TY - JOUR
T1 - Endothelial cell CD36 regulates membrane ceramide formation, exosome fatty acid transfer and circulating fatty acid levels
AU - Peche, V. S.
AU - Pietka, T. A.
AU - Jacome-Sosa, M.
AU - Samovski, D.
AU - Palacios, H.
AU - Chatterjee-Basu, G.
AU - Dudley, A. C.
AU - Beatty, W.
AU - Meyer, G. A.
AU - Goldberg, I. J.
AU - Abumrad, N. A.
N1 - Funding Information:
We acknowledge assistance of the Washington University (Wash U) Center for Cellular Imaging (WUCCI) and access to a Zeiss LSM 880 Airyscan confocal microscope purchased with support from Office of Research Infrastructure Programs (ORIP), National Institute of Health (NIH) Office of the Director award OD021629. Nanogold EM was conducted at the Wash U Molecular Microbiology Imaging Facility. The Cellular and Molecular Biology Core (CMBC) of the Nutrition and Obesity Research Center (NORC, P30 DK056341) assisted with NTA analysis of sEVs. This work was supported by R01 HL045095 (IJG/NAA) and R01DK060022 (NAA). We acknowledge helpful discussions about the ceramide studies with Dr. Yusuf Hannun, the late Dr. Lina Obeid, and Dr. Daniel Canals at Stony Brook University, and about Caveolin-1 with Dr. Philip Scherer at UT Southwestern.
Funding Information:
We acknowledge assistance of the Washington University (Wash U) Center for Cellular Imaging (WUCCI) and access to a Zeiss LSM 880 Airyscan confocal microscope purchased with support from Office of Research Infrastructure Programs (ORIP), National Institute of Health (NIH) Office of the Director award OD021629. Nanogold EM was conducted at the Wash U Molecular Microbiology Imaging Facility. The Cellular and Molecular Biology Core (CMBC) of the Nutrition and Obesity Research Center (NORC, P30 DK056341) assisted with NTA analysis of sEVs. This work was supported by R01 HL045095 (IJG/NAA) and R01DK060022 (NAA). We acknowledge helpful discussions about the ceramide studies with Dr. Yusuf Hannun, the late Dr. Lina Obeid, and Dr. Daniel Canals at Stony Brook University, and about Caveolin-1 with Dr. Philip Scherer at UT Southwestern.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85164130008&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-39752-3
DO - 10.1038/s41467-023-39752-3
M3 - Article
C2 - 37419919
AN - SCOPUS:85164130008
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4029
ER -