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.
Highlights
The endothelium represents the first cell layer that nutrients have to pass on their way from the blood circulation to the underlying parenchyma
Stimulation of endothelial cells (ECs) (HUVECs) with a physiological insulin concentration did not evoke glucose uptake and only a minor increase was observed with a supra-physiological insulin concentration (300 nM, Appendix Fig S1A), which is in accordance with previous findings [32]
B glucose transporter 1 (GLUT1) protein expression in human umbilical vein endothelial cells (HUVEC) treated with vascular endothelial growth factor (VEGF)-B186 for 15 min or 2 h
Summary
The endothelium represents the first cell layer that nutrients have to pass on their way from the blood circulation to the underlying parenchyma. Especially in capillaries, endothelial cells (ECs) are tightly connected forcing most nutrients to be transported through the cell body by specific transport systems. Endothelial glucose uptake relies on specific transporters of the solute carrier (SLC) gene family. Well characterized are the ECs of the blood–brain barrier, highly enriched with the solute carrier family 2 member A1 (SLC2A1, glucose transporter 1 (GLUT1)) [1,2]. Different transporters facilitate fatty acid (FA) uptake from blood, but the exact mechanisms that govern endothelial transcytosis of lipids is largely unknown [3]. In brain ECs, major facilitator superfamily domain-containing protein 2A (MFSD2A) has been identified as a lysolipid transporter governing brain uptake of the essential very-long chain FA docosahexaenoic acid [4,5]
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