Intestinal lymphatic vessels and their role in chylomicron absorption and lipid homeostasis.

PURPOSE OF REVIEW: In this review, we describe novel findings related to intestinal lipid transport in lymphatic vessels. RECENT FINDINGS: Studies have shown that chylomicron entry to lacteals and lymph movement in intestinal lymphatic capillaries is an active process. Regulators of this intestinal chylomicron transport include among others the autonomous nervous system, transcription factors like PLAGL2, and molecular regulators, such as VEGF-A/Nrp1/VEGFR1, VEGF-C/VEGFR3, DLL4, CALCRL and GLP-2. Chylomicron transport in intestinal lymphatics is now emerging not only as an option for drug delivery but also as a new candidate for drug targeting in lipid-related disorders. SUMMARY: Dysfunctions of lymphatic lipid transport can result in conditions such as dyslipidaemia. Intestinal lymphatics also provide several potential therapeutic possibilities: molecular regulation of lacteal cell-to-cell junctioning and lymph flow could provide new ways of treating conditions like hyperlipidaemia and associated diseases, such as atherosclerosis and other cardiovascular diseases, obesity, diabetes and fatty-liver disease. The intestinal lymphatic system can also be employed to deliver lipid nanoparticles as drug carriers to the venous circulation for improved treatment outcome. These findings highlight the importance and need for research on the different players of intestinal lymphatics in dietary lipid handling and therapeutic applications.

Recent advances in novel therapies for lipid disorders.

The prevalence of lipid disorders is alarmingly increasing in the Western world. They are the result of either primary causes, such as unhealthy lifestyle choices or inherited risk factors, or secondary causes like other diseases or medication. Atypical changes in the synthesis, processing and catabolism of lipoprotein particles may lead to severe hypercholesterolemia, hypertriglyceridemia or elevated Lp(a). Although cholesterol-lowering drugs are the most prescribed medications, not all patients achieve guideline recommended cholesterol levels with the current treatment options, emphasising the need for new therapies. Also, some lipid disorders do not have any treatment options but rely only on stringent dietary restriction. Patients with untreated lipid disorders carry a severe risk of cardiovascular disease, diabetes, non-alcoholic fatty liver disease and pancreatitis among others. To achieve better treatment outcome, novel selective gene expression and epigenetic targeting therapies are constantly being developed. Therapeutic innovations employing targeted RNA technology utilise small interfering RNAs, antisense oligonucleotides, long non-coding RNAs and microRNAs to regulate target protein production whereas viral gene therapy provides functional therapeutic genes and CRISPR/Cas technology relies on gene editing and transcriptional regulation. In this review, we will discuss the latest advances in clinical trials for novel lipid-lowering therapies and potential new targets in pre-clinical phase.

Deletion of Lymphangiogenic and Angiogenic Growth Factor VEGF-D Leads to Severe Hyperlipidemia and Delayed Clearance of Chylomicron Remnants.

Objective- Dyslipidemia is one of the key factors behind coronary heart disease. Blood and lymphatic vessels play pivotal roles in both lipoprotein metabolism and development of atherosclerotic plaques. Recent studies have linked members of VEGF (vascular endothelial growth factor) family to lipid metabolism, but the function of VEGF-D has remained unexplored. Here, we investigated how the deletion of VEGF-D affects lipid and lipoprotein metabolism in atherogenic LDLR-/- ApoB100/100 mice. Approach and Results- Deletion of VEGF-D (VEGF-D-/-LDLR-/-ApoB100/100) led to markedly elevated plasma cholesterol and triglyceride levels without an increase in atherogenesis. Size distribution and hepatic lipid uptake studies confirmed a delayed clearance of large chylomicron remnant particles that cannot easily penetrate through the vascular endothelium. Mechanistically, the inhibition of VEGF-D signaling significantly decreased the hepatic expression of SDC1 (syndecan 1), which is one of the main receptors for chylomicron remnant uptake when LDLR is absent. Immunohistochemical staining confirmed reduced expression of SDC1 in the sinusoidal surface of hepatocytes in VEGF-D deficient mice. Furthermore, hepatic RNA-sequencing revealed that VEGF-D is also an important regulator of genes related to lipid metabolism and inflammation. The lack of VEGF-D signaling via VEGFR3 (VEGF receptor 3) led to lowered expression of genes regulating triglyceride and cholesterol production, as well as downregulation of peroxisomal ß-oxidation pathway. Conclusions- These results demonstrate that VEGF-D, a powerful lymphangiogenic and angiogenic growth factor, is also a major regulator of chylomicron metabolism in mice.