Endothelium as a gatekeeper of fatty acid transport

Abstract

The endothelium transcends all clinical disciplines and is crucial to the function of every organ system. A critical, but poorly understood, role of the endothelium is its ability to control the transport of energy supply according to organ needs. Fatty acids (FAs) in particular represent a key energy source that is utilized by a number of tissues, but utilization must be tightly regulated to avoid potentially deleterious consequences of excess accumulation, including insulin resistance. Recent studies have identified important endothelial signaling mechanisms, involving vascular endothelial growth factor-B, peroxisome proliferator-activated receptor-γ, and apelin, that mediate endothelial regulation of FA transport. In this review, we discuss the mechanisms by which these signaling pathways regulate this key endothelial function.

Keywords: PPAR-γ; VEGF-B; apelin; endothelium; fatty acid transport.

Copyright © 2013 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Mechanism of VEGF-B mediated FA uptake

Vascular endothelial growth factor B (VEGF-B) expressed in skeletal muscle, heart, and brown adipose tissue (BAT) binds to VEGF receptor-1 (VEGFR1) and neuropillin 1 (NRP1) on the endothelial cells to induce expression of fatty acid transport proteins 3 and 4 (FATP3/FATP4). Increased fatty acid (FA) uptake in these tissues in diabetic mice result in insulin resistance and increased blood glucose. WAT: white adipose tissue.

Figure 2. Endothelial PPAR-γ regulates fatty acid transport

PPAR-γ in endothelial cells regulates the transcription of fatty acid binding protein 4 (FABP4) and fatty acid translocase CD36, which increases endothelial transport of FAs to the surrounding tissues, including heart, skeletal muscle, and white adipose tissue (WAT). Disruption of endothelial PPAR-γ results in improved insulin sensitivity and glucose tolerance. PPRE: PPAR responsive element.

Figure 3. Apelin regulates vascular permeability and fatty acid accumulation

Apelin regulates endothelial permeability/integrity via stabilization of VE-cadherin, which inhibits fatty acid (FA) uptake into white adipose tissue (WAT). Unresolved questions are whether apelin acts directly on the skeletal myocytes to improve insulin sensitivity, and whether the apelin's effect on vascular integrity affects FA uptake in other tissues such as the heart and skeletal muscles.