Does Endothelium Buffer Fat?
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Endothelial cells (ECs) are the metabolic gatekeepers of the body. All tissues require nutrients for growth and function, and those nutrients must pass the endothelial layer. In some tissues like the liver, the endothelium is discontinuous and marked by “fenestrae” (from the Latin for “window”), dedicated transcellular openings that allow free movement of nutrients. But in most tissues such as the heart, muscle, and brain, endothelia lack fenestrae, and nutrients must traverse the endothelial wall directly. The list of nutrients that must do so is long and includes sugars, amino acids, and fats. Of those, the latter have received the least attention, although organs like the heart consume copious fatty acids for the generation of ATP.
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Fatty acids travel the blood stream largely in 2 forms: esterified as triglycerides in lipoprotein particles, including chylomicrons and VLDL (very-low–density lipoprotein), or unesterified and noncovalently bound to albumin. Esterified fatty acids are liberated by lipoprotein lipase, which, importantly, is located on the luminal side of the endothelium. Therefore, all fatty acids must traverse the endothelial layer before reaching underlying parenchyma. Recent work has demonstrated that paracrine factors, both proteins and metabolites, secreted by parenchymal cells can promote adjacent endothelium to transport fats. For example, VEGFB (vascular endothelial growth factor B), a VEGF family member, is secreted from fat-consuming oxidative skeletal and heart muscles to promote transendothelial fat transport, thereby coordinating myocyte metabolism with nutrient delivery.1 Similarly, 3-hydroxy-isobutyrate, a metabolite of valine catabolism, is secreted from skeletal muscle to promote transendothelial fatty acid transport, and it may contribute to muscle lipotoxicity and insulin resistance.2
How does the endothelium handle and transport fats in response to these and other signals? Surprisingly little is known about how this process inside ECs occurs. Several mechanisms have been proposed: diffusion within endothelial …