The Intestinal Lymphatic System: Functions and Metabolic Implications

Abstract

The lymphatic system of the gut plays important roles in the transport of dietary lipids, as well as in immunosurveillance and removal of interstitial fluid. Historically, despite its crucial functions in intestinal homeostasis, the lymphatic system has been poorly studied. In the last 2 decades, identification of specific molecular mediators of lymphatic endothelial cells (LECs) growth together with novel genetic approaches and intravital imaging techniques, have advanced our understanding of the mechanisms regulating intestinal lymphatic physiology in health and disease. As its metabolic implications are gaining recognition, intestinal lymphatic biology is currently experiencing a surge in interest. This review describes current knowledge related to molecular control of intestinal lymphatic vessel structure and function. We discuss regulation of chylomicron entry into lymphatic vessels by vascular endothelial growth factors (VEGFs), hormones, transcription factors and the specific signaling pathways involved. The information covered supports the emerging role of intestinal lymphatics in etiology of the metabolic syndrome and their potential as a therapeutic target.

Keywords: Endothelium; Lacteals; Lipid; Obesity; VEGF Signaling.

Figure 1

Functional structure of lacteals. Schematic showing lacteal structure and drainage of dietary lipids in the intestine. Lacteals are surrounded by villus smooth muscle fibers (in red). The majority of lacteal tips present filopodia, which are cytoplasmic, actin-rich cellular extensions indicating active regeneration. Lacteal LECs have a mix of button- and zipper-like junctions and more filopodia are found on zipper junction–enriched lacteals. Dietary lipids are absorbed on the apical side of enterocytes. Once inside the lacteals, CMs are transported via the lymph through mesenteric lymph nodes and collecting lymphatic vessels, ultimately reaching the thoracic duct, which drains into the venous circulation at the level of the left subclavian vein.

Figure 2

Regulation of chylomicron uptake by VEGF-A. Schematic model of cell-cell junctions in intestinal blood ECs and LECs regulating chylomicron absorption. (A) VEGF-A binding to NRP1/Fms-related tyrosine kinase 1 (FLT1) on blood ECs limits VEGF-A bioavailability for VEGFR-2, resulting in continuous cell junctions in blood ECs and in discontinuous ones on LECs. The discontinuous button-like LEC junctions allow lacteal to take up CMs. (B) Inducible genetic deletion of Nrp1 and Flt1 increase bioavailability of VEGF-A and subsequent signaling through VEGFR-2. High level of VEGF-A promotes transition of button-to-zipper junctions in the lacteals, which inhibits chylomicron entry into the lymphatic capillaries causing lipid malabsorption and reduced weight gain during high-fat feeding. These data support the hypothesis that NRP1 and FLT1 function together as a double decoy receptor system in intestinal blood ECs to limit VEGF-A signaling.