Fatty Acid Metabolism in Endothelial Cell

Abstract

The endothelium is a monolayer of cells lining the inner blood vessels. Endothelial cells (ECs) play indispensable roles in angiogenesis, homeostasis, and immune response under normal physiological conditions, and their dysfunction is closely associated with pathologies such as cardiovascular diseases. Abnormal EC metabolism, especially dysfunctional fatty acid (FA) metabolism, contributes to the development of many diseases including pulmonary hypertension (PH). In this review, we focus on discussing the latest advances in FA metabolism in ECs under normal and pathological conditions with an emphasis on PH. We also highlight areas of research that warrant further investigation.

Keywords: endothelium; glycolysis; lipid; vascular biology.

Figure 1

EC FA metabolism. Fatty acids (FAs) are transported in the form of triglyceride (TG)-rich lipoproteins, which are released by lipoprotein lipase (LPL) and GPIHBP1 in the luminal side of ECs. Free FAs are transported across EC membranes by fatty acid transporter protein 3 and 4 (FATP3/4) and CD36. Intracellular FAs transportation is mediated by FABP3 and FABP4. Intracellular FAs could be synthesized by FA synthase (FASN) from Malonyl-CoA and affect mTORC1 activity for angiogenesis. DAGTs and ATGL are key enzymes regulating lipid droplet (LD) storage and lipolysis. FAs are transported into mitochondria via CPT1 for FA oxidation (FAO). Quiescent ECs utilize FAO to maintain redox homeostasis. FAO is required for the generation of dNTPs for EC spouting and angiogenesis. In certain conditions such as glucose depletion, FAO produces ATP in ECs. FAO also produces acetyl-CoA for epigenetic regulation, inhibiting EndoMT. The efflux of FAs to the perivascular cells could be mediated by FABP4/5 and FATP3/4. Many key endothelial signaling including VEGF, NOTCH, and PPAR γ control EC FA transport via regulating FATPs, FABPs, and CD36.

Figure 2

FA metabolism in the lung EC of pulmonary hypertension. Enhanced glycolysis is evident in PAH ECs. Lipid transport via FABP4, lipid synthesis via fatty acid synthase (FASN), and fatty acid oxidation (FAO) are unregulated in pulmonary arterials of PAH patients. Elevation of FA could increase mitochondria FAO, contributing to the generation of dNTPs and ATP. Enhanced FAO and glycolysis lead to PAH EC hyperproliferation and anti-apoptotic phenotypes. Upregulation of FAPB4 could also increase FA efflux to perivascular cells such as pulmonary arterial smooth muscle cells and fibroblasts, and promote pulmonary vascular remodeling and PH.