Lymphatic lipid transport: sewer or subway?

Abstract

The lymphatics began receiving attention in the scientific community as early as 1622, when Gasparo Aselli noted the appearance of milky-white vessels in the mesentery of a well-fed dog. Since this time, the lymphatic system has been historically regarded as the sewer of the vasculature, passively draining fluid and proteins from the interstitial spaces (along with lipid from the gut) into the blood. Recent reports, however, suggest that the lymphatic role in lipid transport is an active and intricate process, and that when lymphatic function is compromised, there are systemic consequences to lipid metabolism and transport. This review highlights these recent findings, and suggests future directions for understanding the interplay between lymphatic and lipid biology in health and disease.

Figure 1. The Lymphatic Circulation in Lipid Transport

The lymphatics pump fluid from the interstitial spaces throughout the body into the circulation by driving fluid velocity through the contraction of collecting lymphatics (graph adapted from [9]). Throughout the body there are numerous locations where the lymphatics exist alongside the vasculature and play a crucial role in lipid transport, such as the liver, the skin, and the intestine (image adapted from [29]). Adipocytes form around most of the large collecting lymphatics (see image insert of collecting vessel) and skin lymphatics have been shown to remodel and enlarge in response to high levels of circulating LDL cholesterol (image adapted from [50]). Lacteal from a mouse intestine is stained with CD31 (red, blood vessels) and LYVE1 (green, lymphatic vessel) and DAPI (blue). Collecting vessel is a bright field image taken from a rat mesentery.

Figure 2. Morphology of Initial and Collecting Lymphatics

(a) Initial lymphatics are made of endothelial cells with specialized overlapping junctions that allow for easy entry of fluid, proteins, and cells into the vessel. These lymphatics lack smooth muscle and therefore cannot contract. (b) Collecting lymphatics consist of individual contracting units known as lymphangions, which are lined with smooth muscle and separated by valves. (i) confocal reconstruction of an isolated rat lymphatic vessel showing valve leaflets, courtesy of Dave Zawieja and Anitoliy Gashev. The collecting vessels are under a variety of mechanical loads: hoop stress (σ_hoop), axial stress (σ_axial), and wall shear stress (τ_wall). These forces have been shown to modulate contractile function. For example, an increase in wall shear stress (ii) through enhanced fluid flow has been shown to cause upregulation of eNOS and subsequent release of nitric oxide (NO), which acts as a vasodilator on the smooth muscle and inhibits vessel contraction [38] (Key: blue spheres (water molecules), yellow spheres (lipoproteins), pink (immune cell), orange stars (nitric oxide molecules).

Figure 3. Mechanisms of chylomicron uptake into lacteals

(a) Each villus of the small intestine has a (b)single lymphatic vessel (lacteal) running along the center of the villus. (c) Chylomicrons that are secreted by the intestinal epithelial cells (enterocytes) enter into the lymphatic vessel, not the blood. (d) Transmission electron microscopy images have demonstrated both transcellular transport of chylomicrons through the endothelial cells in vesicles and paracellular transport between cell junctions, yet the relative importance of these two mechanisms remains unclear.