VEGFR-3 Signaling Regulates Triglyceride Retention and Absorption in the Intestine.

Trevor Shew,Vincenza Cifarelli,Nathan E Wolins

doi:10.3389/fphys.2018.01783

Abstract

The lymphatic system transports dietary lipids absorbed and packaged as chylomicrons by enterocytes, for delivery to the bloodstream. Once considered a passive drainage, chylomicron entry into intestinal lymphatic vessels, or lacteals, is now emerging to be an active process controlled by a dynamic and complex regulation. Vascular endothelial growth factor (VEGF)-C, a major lymphangiogenic factor, regulates lacteal maintenance and function. Little is known about the role of its cognate tyrosine kinase VEGF receptor 3 (VEGFR-3) during lipid absorption. Here we investigated role of VEGFR-3 signaling in triglyceride (TG) absorption and distribution into tissues using the Chy mouse model, which bears an inactivating mutation in the tyrosine kinase domain of VEGFR-3 (heterozygous A3157T mutation resulting in I1053F substitution). Our data show that inactivation of VEGFR-3 tyrosine kinase motif leads to retention of TGs in the enterocytes of the small intestine, decreased postprandial levels of TGs in the plasma and increased excretion of free fatty acids (FFAs) and TGs into their stools. We further show that levels of nitric oxide (NO), required for chylomicron mobilization into the bloodstream, are significantly reduced in the Chy intestine after a fat bolus suggesting a critical role for VEGFR-3 signaling in the generation of NO during lipid absorption. Our data support the hypothesis that VEGFR-3 signaling plays an important role in chylomicron-TG entry into lacteals, possibly affecting TG trafficking to peripheral tissues.

Highlights

Dietary long-chain fatty acids (FAs) and monoacylglycerols are absorbed on the apical membrane of enterocytes, repackaged into triglyceride (TG)-rich lipoproteins, or chylomicrons (CMs), and secreted into the intestinal lymphatic vessels, referred to as lacteals (Tso and Balint, 1986; Kohan et al, 2010; Mansbach and Siddiqi, 2010; Cifarelli and Abumrad, 2018)
We further show that levels of nitric oxide (NO), required for chylomicron mobilization into the bloodstream, are significantly reduced in the Chy intestine after a fat bolus suggesting a critical role for Vascular endothelial growth factor (VEGF) receptor 3 (VEGFR-3) signaling in the generation of NO during lipid absorption
Our data show the novel finding that VEGFR-3 signaling regulates absorption and trafficking of dietary lipids from the enterocytes to the circulation

Summary

Introduction

Dietary long-chain fatty acids (FAs) and monoacylglycerols are absorbed on the apical membrane of enterocytes, repackaged into triglyceride (TG)-rich lipoproteins, or chylomicrons (CMs), and secreted into the intestinal lymphatic vessels, referred to as lacteals (Tso and Balint, 1986; Kohan et al, 2010; Mansbach and Siddiqi, 2010; Cifarelli and Abumrad, 2018). VEGF-C, a major lymphangiogenic factor during embryonic development (Makinen et al, 2001; Karkkainen et al, 2004), regulates maintenance and function of intestinal lymphatics in adult mice (Nurmi et al, 2015) by binding its cognate tyrosine kinase VEGF receptor 3 (VEGFR-3), highly expressed in lymphatic endothelial cell (LECs). Postnatal deletion of Vegfc in mice leads to lacteal regression, defective lipid absorption and protects from diet-induced obesity and insulin resistance (Nurmi et al, 2015), without affecting any other lymphatic beds. Similar to Vegfc deletion, genetic ablation of Vegfr in adult mice affects lacteal maintenance and function (Nurmi et al, 2015) impact in lipid absorption was not investigated. The mechanisms through which inactivation of VEGFR-3 signaling pathways affects lipid absorption and trafficking to blood circulation remains unknown

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Conclusion