It could be possible to modulate the absorption of dietary lipids by targeting two receptors present in the lacteals – the intestinal lymphatic vessels implicated in the assimilation of fat. A promising prospect for the treatment of hyperlipidemia and obesity.
In their quest to develop a non-diabetic obese mouse model using genetic modification, scientists have discovered a hitherto-unknown mechanism of intestinal lipid absorption. In addition, their research shows that this mechanism could be modulated temporarily to reduce the amount of dietary fat absorbed by the body. This new lead represents hope for the management hyperlipidemia – a major cause of cardiac events, as well as that of obesity. It could succeed even faster given that the molecular mechanisms in question are already targeted by a drug prescribed in ophthalmology.
VEGFR-1 (Vascular Endothelial Growth Factor Receptor-1, or FLT1) and NRP1 (Neuropilin-1) are two genes which code for vascular growth factor receptors and which are implicated in the development of type 2 diabetes. By deleting these genes in mice, the team led by Anne Eichmann* wanted to develop animal models which could become obese without developing diabetes. However, after several weeks of a fatty diet, the weight of the mice had not increased much, whereas that of the control mice fed the same diet had doubled. Surprised by this observation, the team set about understanding the factors behind it.
An active absorption mechanism
With the measurement of blood lipids in mutated mice having revealed an absorption deficiency, the team was interested in the mechanisms that regulate lipid absorption in the intestine, in which lacteals play a role. "Lacteals are the intestinal lymphatic network endings. They enable the absorption of fats through pores arranged among the endothelial cells that line these vessels, explains Eichmann. Until now we thought that it was a passive mechanism. But our research has made it possible to observe that the absorption via these pores is an active mechanism, placed under the control of the FLT1 and NRP1 receptors". When these receptors are absent, the pores close and the intestinal absorption of fat -packaged in the form of chylomicrons- is impossible. As such, the weight gain that one would expect with a fatty diet does not occur.
The therapeutic prospects therefore seem evident: "If it is possible to temporarily modulate the pores, it must be possible to develop new treatment strategies in obesity and hyperlipidemia." With this in mind, the fine mechanisms of modulating lacteal pore permeability must be understood.
A drug candidate already lined up
Following additional experiments, the researchers observed that closure of the cell junctions within the lacteals, hindering the absorption of the chylomicrons, depends on VEGF-A, a growth factor promoting vascular permeability, and that of the VEGFR2 receptor expressed by the lacteals. By inhibiting the function of VEGFR2 in mutant mice, the junctions once again become functional and the transport of chylomicrons is restored.
Interestingly, a molecule effective in the treatment of glaucoma could modulate this absorption mechanism. Y27632, a Rho Kinase (ROCK) inhibitor, is known for inhibiting the permeability induced by VEGF in a dose-dependent manner. The tests performed in mice treated with Y27632 were conclusive and show that it is possible to close the junction of the lacteals and reduce the presence of chylomicrons in their lumina.
"We need to validate these results by developing a mouse model in which the ROCK pathway is inactivated in the lacteals. If we confirm that these mice do not absorb the chylomicrons, we will have validated this research avenue. Like that we will be able to begin translational research in order to evaluate whether ROCK inhibitors are effective in regulating lipid absorption in humans". In parallel, more fundamental studies are already underway in order to better understand how these junctions work.
* unit 970 Inserm/Université Paris Descartes, Developmental and pathological angiogenesis team, Paris-Cardiovascular Research Center (PARCC)
Source : Zhang F et coll. Lacteal junction zippering protects against diet-induced obesity. Science. 2018 Aug 10;361(6402):599-603. doi: 10.1126/science.aap9331.