Abstract
Disruption of lymphatic lipid transport is linked to obesity and type 2 diabetes (T2D), but regulation of lymphatic vessel function and its link to disease remain unclear. Here we show that intestinal lymphatic endothelial cells (LECs) have an increasing CD36 expression from lymphatic capillaries (lacteals) to collecting vessels, and that LEC CD36 regulates lymphatic integrity and optimizes lipid transport. Inducible deletion of CD36 in LECs in adult mice (Cd36ΔLEC) increases discontinuity of LEC VE-cadherin junctions in lacteals and collecting vessels. Cd36ΔLEC mice display slower transport of absorbed lipid, more permeable mesenteric lymphatics, accumulation of inflamed visceral fat and impaired glucose disposal. CD36 silencing in cultured LECs suppresses cell respiration, reduces VEGF-C-mediated VEGFR2/AKT phosphorylation and destabilizes VE-cadherin junctions. Thus, LEC CD36 optimizes lymphatic junctions and integrity of lymphatic lipid transport, and its loss in mice causes lymph leakage, visceral adiposity and glucose intolerance, phenotypes that increase risk of T2D.
Highlights
Disruption of lymphatic lipid transport is linked to obesity and type 2 diabetes (T2D), but regulation of lymphatic vessel function and its link to disease remain unclear
The current study increases our understanding of the regulation of intestinal lymphatics by documenting the role of the fatty acid transporter CD36 in the maintenance of lymphatic vessel integrity
We show that CD36 is abundantly expressed in intestinal lymphatic endothelial cells (LECs), not all Lyve-1 expressing cells have CD36, which is in line with the reported heterogeneity of gene expression and function of LECs33
Summary
Disruption of lymphatic lipid transport is linked to obesity and type 2 diabetes (T2D), but regulation of lymphatic vessel function and its link to disease remain unclear. We show that intestinal lymphatic endothelial cells (LECs) have an increasing CD36 expression from lymphatic capillaries (lacteals) to collecting vessels, and that LEC CD36 regulates lymphatic integrity and optimizes lipid transport. Inducible deletion of CD36 in LECs in adult mice (Cd36ΔLEC) increases discontinuity of LEC VE-cadherin junctions in lacteals and collecting vessels. The “zippering” of VE-cadherin junctions, through deletion of neuropilin[1] and vascular endothelial growth factor receptor 1 (VEGFR1), prevents chylomicron uptake by lacteals and fat absorption protecting against dietinduced obesity and systemic glucose intolerance[2]. To understand the role of CD36 in LEC function, we generated a mouse with inducible Cd36 deletion in LECs (Prox1-CreERT2-tdTomatoCd36−/−, hereafter referred to as Cd36ΔLEC) and assessed VE-cadherin morphological status in gut lymphatics, lymph transport, and metabolic phenotypes.
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