Transport of long-chain fatty acids across the muscular endothelium

Abstract

Both skeletal and cardiac muscle cells rely heavily on the oxidation of long-chain fatty acids to utilize chemically stored energy for contractile work. Under normal conditions fatty acids are continuously supplied from the microvascular compartment to the contracting myocytes. Exogenous fatty acids are transported to muscle tissue via the blood either complexed to albumin or covalently bound in triacylglycerols forming the neutral lipid core of circulating lipoproteins such as chylomicrons or very low-density lipoproteins. The first barrier met by fatty acids on their way from the vascular compartment to the myocytes is the endothelium constituting the capillary wall. After dissociation of the albumin-fatty acid complex or release from the triacylglycerol core of lipoproteins, fatty acids most likely transverse the endothelium by crossing the luminal membrane, the cytosol, and subsequently the abluminal wall of the endothelial cell. Transfer through the interendothelial clefts or lateral diffusion within the phospholipid bilayer of the endothelial plasmalemma should be considered as inconsequential. The mechanism responsible for transmembrane movement of fatty acids is incompletely understood, although recent findings suggest the involvement of a number of membrane-associated proteins. Kinetic studies have revealed that interaction of the albumin-fatty acid complex with the endothelial membrane may accelerate the dissociation of the complex, which facilitates the uptake of fatty acids by the endothelium. Albumin-binding proteins (ABP) might be instrumental in this interaction. Moreover, plasmalemmal fatty acid-binding protein (FABPpm), fatty acid translocase (FAT) and fatty acid-transport protein (FATP) are putatively involved in transmembrane movement of the fatty acid molecules. Diffusion through the endothelial cytosol might be facilitated by a cytoplasmic fatty acid-binding protein, the type of which may be related to the epithelial fatty acid-binding protein (E-FAPBc).

Figure 1

Highly schematic representation of the transport route of fatty acids from the vascular compartment to the interior of the myocytes. TG refers to the triacylglycerol core in circulating lipoproteins; alb*FA to the albumin–fatty acid complex; FABP*FA to the fatty acid-binding protein–fatty acid complex. A question mark indicates that details of the transport route are not completely understood.

Figure 2

Schematic representation of the mechanisms possibly involved in the transport of fatty acids across the endothelium. 1, transport through the interendothelial clefts; 2, lateral movement within the plasmalemmal phospholipid bilayer; 3 and 4, transfer across the luminal membrane, cytoplasm and abluminal membrane, respectively. Note that route #3 refers to passive diffusion of fatty acids, whereas route #4 involves a set of proteins facilitating transmembrane and transcytosolic transport. Alb*FA refers to the albumin–fatty acid complex, FA to long-chain fatty acids.

Figure 3

Putative mechanism of fatty acid transfer across the luminal membrane of the endothelial cell. Alb*FA, the albumin–fatty acid complex; ABP, albumin-binding protein; FABP_pm, plasmalemmal fatty acid-binding protein; FAT, fatty acid translocase; FATP, fatty acid-transport protein; FABP_c, a cytosolic fatty acid-binding protein, the nature and quantity of which remain to be established.

Figure 4

Outflow dilution curves from experiments in a single isolated rat heart with, in sequence, perfusion with control perfusion buffer (heart 1, upper left panel) and buffer-containing specific antibody to rat hepatocyte FABP_pm (K 15/6 hybridoma supernatant) (heart 1, lower left panel) and, in a second heart, with control perfusion buffer (heart 2, upper right panel) and buffer-containing non-specific antibody (myeloma NS-1 supernatant) (heart 2, lower right panel). From Goresky et al. with permission.