Organ-specific lymphatics play distinct roles in regulating HDL trafficking and composition

Abstract

Recently, peripheral lymphatic vessels were found to transport high-density lipoprotein (HDL) from interstitial tissues to the blood circulation during reverse cholesterol transport. This function is thought to be critical to the clearance of cholesterol from atherosclerotic plaques. The role of organ-specific lymphatics in modulating HDL transport and composition is, however, incompletely understood. This study aimed to 1) determine the contribution of the lymphatics draining the intestine and liver (which are major sites of HDL synthesis) to total (thoracic) lymph HDL transport and 2) verify whether the HDLs in lymph are derived from specific organs and are modified during trafficking in lymph. The mesenteric, hepatic, or thoracic lymph duct was cannulated in nonfasted Sprague-Dawley rats, and lymph was collected over 5 h under anesthesia. Whole lymph and specific lymph lipoproteins (isolated by ultracentrifugation) were analyzed for protein and lipid composition. The majority of thoracic lymph fluid, protein, and lipid mass was sourced from the mesenteric, and to a lesser extent, hepatic lymph. Mesenteric and thoracic lymph were both rich in chylomicrons and very low-density lipoprotein, whereas hepatic lymph and plasma were HDL-rich. The protein and lipid mass in thoracic lymph HDL was mostly sourced from mesenteric lymph, whereas the cholesterol mass was equally sourced from mesenteric and hepatic lymph. HDLs were compositionally distinct across the lymph sources and plasma. The composition of HDL also appeared to be modified during passage from the mesenteric and hepatic to the thoracic lymph duct. Overall, this study demonstrates that the lipoproteins in lymph are organ specific in composition, and the intestine and liver appear to be the main source of HDL in the lymph. NEW & NOTEWORTHY High-density lipoprotein in lymph are organ-specific in composition and derive mostly from the intestine and liver. High-density lipoprotein also appears to be remodeled during transport through the lymphatics. These findings have implications to cardiometabolic diseases that involve perturbations in lipoprotein distribution and metabolism.

High-Density Lipoprotein Composition Influences Lymphatic Transport after Subcutaneous Administration

“…We recently reported that lymph HDLs, which vary with the collection site, are less stable than plasma HDL and are modified during passage through lymphatics. 27 The thoracic lymph HDLs here were spherical particles 8−20 nm in diameter. This is unlike published reports that have observed traces of discoidal particles in rat mesenteric lymph 24,25 and human leg lymph HDL fractions.…”

Intestinal epithelium-derived high density lipoprotein restrains liver injury via the portal vein

“…HDL 2 may be too large to enter the fenestrated blood vessels that drain to the portal blood, such that only intestine-derived HDL 3 gains efficient access. Consistent with this possibility, mesenteric lymph is relatively deficient in the smaller HDL 3 particles while relatively enriched in HDL 2 ( 35 ).…”

The role of lymphangiogenesis in cardiovascular diseases and heart transplantation

“…Recently, particular attention has been paid to RCT and atherosclerosis development, as well as their relation with arterial lymphatic drainage. However, the role of organspecific lymphatics in modulating HDL transport and composition is incompletely understood [44]. Especially, the lymphatic origin and flow vary among tissues, e.g., lymphatic drainage in the skin, intestine, liver and peritoneal cavity, which may further reflect the importance of lymphatics in RCT and atherosclerosis.…”

“…Initial lymphatics draining the peritoneal submesothelial layer have favorable absorption of lipophilic and unionized compounds [47]. The study by using nonfasted rats has demonstrated that the lipoproteins in lymph are organ specific in composition, and the intestine and liver appear to be the main source of HDL that is modified during transport from the mesenteric and hepatic lymphatics to the thoracic duct [44]. The lymph lipoprotein remodeling may indicate an alteration of its biological properties and potentially impact on the development of atherosclerosis.…”