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VEGF‐B signaling impairs endothelial glucose transcytosis by decreasing membrane cholesterol content

Moessinger, Christine, Nilsson, Ingrid, Muhl, Lars, Zeitelhofer, Manuel, Heller Sahlgren, Benjamin, Skogsberg, Josefin, Eriksson, Ulf·2020·The EMBO Reports
DOI 10.15252/embr.201949343PMC PMC7332976
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Abstract

Regulation of endothelial nutrient transport is poorly understood. Vascular endothelial growth factor B (VEGF‐B) signaling in endothelial cells promotes uptake and transcytosis of fatty acids from the bloodstream to the underlying tissue, advancing pathological lipid accumulation and lipotoxicity in diabetic complications. Here, we demonstrate that VEGF‐B limits endothelial glucose transport independent of fatty acid uptake. Specifically, VEGF‐B signaling impairs recycling of low‐density lipoprotein receptor (LDLR) to the plasma membrane, leading to reduced cholesterol uptake and membrane cholesterol loading. Reduced cholesterol levels in the membrane leads to a decrease in glucose transporter 1 (GLUT1)‐dependent endothelial glucose uptake. Inhibiting VEGF‐B in vivo reconstitutes membrane cholesterol levels and restores glucose uptake, which is of particular relevance for conditions involving insulin resistance and diabetic complications. In summary, our study reveals a mechanism whereby VEGF‐B regulates endothelial nutrient uptake and highlights the impact of membrane cholesterol for regulation of endothelial glucose transport.

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  • Several DEGs previously associated with lipid metabolism were identified, including MIAT, COMT, NRP1, VEGFB, GRAMD1B, DSEL, and FUT9 associated with glycan structure.

    “We identified several DEGs that have been previously associated with lipid metabolism, including MIAT, COMT, NRP1, VEGFB, GRAMD1B, DSEL56–62, as well as FUT9 associated with glycan structure63,64 (Fig. 4a).”

    From GRAMD1B is a regulator of lipid homeostasis, autophagic flux and phosphorylated tau (2025) · cites this paper as [59]

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Metadata

Authors
Moessinger, C., Nilsson, I., Muhl, L., Zeitelhofer, M., Heller Sahlgren, B., Skogsberg, J., & Eriksson, U.
ORCID
Eriksson, Ulf
Venue
The EMBO Reports
Publisher
Springer Science and Business Media LLC
Published
2020-05-24
Volume
21
Issue
7
ISSN
  • 1469-221X
  • 1469-3178
DOI
10.15252/embr.201949343
PMC
PMC7332976
Cited by
42
References
9
Language
en
Licence
Funders
  • Swedish Research Council (2016‐02593, 2017‐01794)
  • Swedish Heart and Lung Foundation (20120077, 20150547)
  • CSL Ltd
  • Swedish Cancer Society (CAN 2016/633)
  • Novo Nordisk Foundation (NNF16OC0021172, NNF17OC0026942)
  • Karolinska Institutet
  • Swedish Society for Medical Research

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