The role of lacteal integrity and junction transformation in obesity: A promising therapeutic target?

Abstract

Lacteals are the central lymphatic vessels in the villi of the small intestine and perform nutrient absorption, especially dietary lipids, and the transportation of antigen and antigen-presenting cells. Remodeling, proliferation, and cell-cell junctions of lymphatic endothelial cells (LECs) in lacteals are the basis of the maintenance of lacteal integrity and dietary lipid absorption. Normal lipid absorption in the diet depends on sound lacteal development and proliferation, especially integrity maintenance, namely, maintaining the appropriate proportion of button-like and zipper-like junctions. Maintaining the integrity and transforming button-to-zipper junctions in lacteals are strongly connected with obesity, which could be regulated by intestinal flora and molecular signalings, such as vascular endothelial growth factor C-vascular endothelial growth receptor 3 (VEGFC-VEGFR3) signaling, Hippo signaling, Notch signaling, angiopoietin-TIE signaling, VEGF-A/VEGFR2 signaling, and PROX1. This manuscript reviews the molecular mechanism of development, integrity maintenance, and junction transformation in lacteal related to obesity.

Keywords: button-like junction; lacteal; lipid uptake; obesity; zipper-like junction.

Figure 1

Junctions between LECs and the molecular mechanism of maintaining lacteal integrity. Tight junctions between LECs are composed of button-like junctions and zipper-like junctions in lacteal tissue. Button-like junctions mainly perform lipid absorption functions, whereas zipper-like junctions are found in collecting lymphatic vessels. In angiopoietin-TIE signaling, ANG2 plays a critical role in transforming zipper-like junctions to button-like junctions to maintain normal lipid uptake. The crosstalk between Hippo and VEGF-C/VEGFR3 signaling is essential for mediating the formation of button-like junctions. Elevated zipper-like junctions and increased VEGF-C levels have been observed in YAP/TAZ hyperactivated mice. Vascular endothelial growth factor C, VEGF-C; Vascular endothelial growth factor receptor, VEGFR3; Lymphatic epithelium cell, LEC. TEA domain transcription factors, TEAD.

Figure 2

Dietary lipid absorption in lacteals. (A) Dietary lipids are incorporated into chylomicrons in enterocytes. Pancreatic TAG lipases convert TAG into FFAs and MAG by the biological process of hydrolysis. Then, the products of hydrolysis are transported in enterocytes after recognition of L-FABP and I-FABP. Subsequently, lipid-synthesizing enzymes turn FFAs and MAG into TAG in the ER, which is incorporated into prechylomicron and embodied in PCTV. Ultimately, after the second incorporation in the Golgi, PCTV is transported near the cell membrane. (B) Chylomicron uptake and transportation in lacteal. Chylomicron get access to lacteal lumen through button-like junctions between LECs, and contraction of SMCs close to lacteal provide the power for chylomicron uptake which is controlled by autonomous nervous system. Triacylglycerol, TAG; Free fatty acids, FFAs; FA-binding proteins, FABPs; Sn-2-monoacylglycerol, MAG; Endoplasmic reticulum, ER; Prechylomicron transport vesicle, PCTV.

Figure 3

Mechanism of junction transformation and integrity of lacteals related to obesity. Promoting the transformation of button-to-zipper junctions in lacteal LECs is resistant to the obese phenotype of mice, which may be associated with impaired lipid uptake. Activation of VEGF-A/VEGFR2 signaling and inactivation of AM and Notch signaling enhance the proportion of zipper-like junctions of LECs which reduce lipid uptake in the small intestine to prevent obesity. In comparison, the gut microbiota is essential in maintaining normal lipid uptake in lacteals by MyD88/VEGF-C/VEGFR3 signaling. In contrast, the augmented level of VEGF-C promotes lacteal growth and proliferation in obese rodents, which enhances dietary lipid absorption to increase aberrant lipid metabolism, obesity, and insulin resistance. Vascular endothelial growth factor C, VEGF-C; Vascular endothelial growth factor receptor, VEGFR3; Lymphatic epithelium cell, LEC; Myeloid differentiation primary response protein 88, MyD88; Adrenomedullin, AM.