Limits...
The role of the lymphatic system in cholesterol transport.

Huang LH, Elvington A, Randolph GJ - Front Pharmacol (2015)

Bottom Line: Extracellular cholesterol then is picked up and transported through the lymphatic vasculature before entering into bloodstream.There is increasing evidence supporting a role for enhanced macrophage cholesterol efflux and RCT in ameliorating atherosclerosis, and recent data suggest that these processes may serve as better diagnostic biomarkers than plasma HDL levels.New findings will complement therapeutic strategies for the treatment of atherosclerotic vascular disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Immunology, Washington University School of Medicine , St. Louis, MO, USA.

ABSTRACT
Reverse cholesterol transport (RCT) is the pathway for removal of peripheral tissue cholesterol and involves transport of cholesterol back to liver for excretion, starting from cellular cholesterol efflux facilitated by lipid-free apolipoprotein A1 (ApoA1) or other lipidated high-density lipoprotein (HDL) particles within the interstitial space. Extracellular cholesterol then is picked up and transported through the lymphatic vasculature before entering into bloodstream. There is increasing evidence supporting a role for enhanced macrophage cholesterol efflux and RCT in ameliorating atherosclerosis, and recent data suggest that these processes may serve as better diagnostic biomarkers than plasma HDL levels. Hence, it is important to better understand the processes governing ApoA1 and HDL influx into peripheral tissues from the bloodstream, modification and facilitation of cellular cholesterol removal within the interstitial space, and transport through the lymphatic vasculature. New findings will complement therapeutic strategies for the treatment of atherosclerotic vascular disease.

No MeSH data available.


Related in: MedlinePlus

Lymphatic dependent reverse cholesterol transport within the peripheral tissues. HDL particles cross the vascular endothelium from plasma into interstitial fluid. Lipid-poor ApoA1 facilitates cellular cholesterol efflux through ABCA1-mediated pathway to form preβ-HDL. Lymphatic capillaries have discontinuous “button-like” junctions, which are permeable for optimal fluid uptake. Lymphatic flow is driven by the pumping action of downstream collecting lymphatic vessels (not depicted). Ultimately, lymph ends up in the thoracic duct that crosses the lymphovenous valve and drains into the subclavian vein.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4557107&req=5

Figure 2: Lymphatic dependent reverse cholesterol transport within the peripheral tissues. HDL particles cross the vascular endothelium from plasma into interstitial fluid. Lipid-poor ApoA1 facilitates cellular cholesterol efflux through ABCA1-mediated pathway to form preβ-HDL. Lymphatic capillaries have discontinuous “button-like” junctions, which are permeable for optimal fluid uptake. Lymphatic flow is driven by the pumping action of downstream collecting lymphatic vessels (not depicted). Ultimately, lymph ends up in the thoracic duct that crosses the lymphovenous valve and drains into the subclavian vein.

Mentions: While HDL is measured in the plasma, much of the life cycle of HDL is spent within the tissue (Rudra et al., 1984; Miller et al., 2013; Randolph and Miller, 2014) and its migration from that tissue back to the blood compartment occurs via trafficking through the lymphatic system. Radiolabeled cholesterol was identified in the lymph and tissue compartments immediately after i.v., administration in human patients (Reichl et al., 1973). Several weeks following administration, radiolabeled tissue cholesterol was higher in lymph than in plasma, indicating that cholesterol in lymph was derived from plasma (Samuel et al., 1972; Reichl et al., 1973). HDL particles have been proposed to cross the vascular endothelium from plasma into interstitial fluid through receptor-mediated transcytosis based on in vitro studies (Rohrer et al., 2006) and/or passive diffusion through intercellular pores (Nordestgaard and Nielsen, 1994; Michel et al., 2015; Figure 2). Using aortic endothelial cells in vitro, Cavelier et al. (2006) showed that lipid-free ApoA1 binds and is internalized and transported in an ABCA1 dependent manner, generating lipidated particles through this process. Also using aortic endothelial cells in vitro, Rohrer et al. (2009) demonstrated HDL particles bind, are internalized, and are transported in a SR-B1 and ABCG1, but not ABCA1, dependent process, reducing particle size without degrading the protein moiety. However, in rabbits fed a high cholesterol diet, the influx into the arterial space of plasma lipoproteins, such as LDL, VLDL, and HDL, decreases linearly with the logarithm of particle diameter (Stender and Zilversmit, 1981), suggesting that lipoproteins cross the endothelium in a size-dependent manner. Michel et al. (2015) demonstrated in vivo that HDL and LDL transport from the plasma to the interstitial space occurs passively through endothelial intercellular pores and that active receptor-mediated transcytosis is unnecessary. If transport is predominantly passive, particle size would be expected to limit the transfer rate. Indeed, studies indicate that an HDL size increase from average 4.5–6 nm lowers its clearance rate by 12% (Michel et al., 2015). When vascular permeability is increased, influx of HDL into interstitial fluid is enhanced, and the rate of RCT is increased. The result supports the observation of the importance of passive HDL transport (Kareinen et al., 2015). Adenoviral overexpression of PLTP in hepatocytes generates larger particle size (<7.1 nm but larger than lipid-free ApoA1; Ji et al., 2014) and also increases atherosclerotic lesion size in PLTP overexpressing ApoE deficient mice (Zhang et al., 2014), although the causal relationship between PLTP and CVD is still under debate (Vergeer et al., 2010; Kim et al., 2015). In line with the mechanism proposed by Zhang et al. (2014), the increased HDL particle size resulting from PLTP overexpression impaired RCT (Samyn et al., 2009), perhaps impairing movement of HDL into the interstitium, limiting cholesterol uptake from extravascular spaces like plaque, and ultimately increasing atherosclerotic disease progression. Whether increased HDL particle size affects HDL transport and/or RCT requires further investigation.


The role of the lymphatic system in cholesterol transport.

Huang LH, Elvington A, Randolph GJ - Front Pharmacol (2015)

Lymphatic dependent reverse cholesterol transport within the peripheral tissues. HDL particles cross the vascular endothelium from plasma into interstitial fluid. Lipid-poor ApoA1 facilitates cellular cholesterol efflux through ABCA1-mediated pathway to form preβ-HDL. Lymphatic capillaries have discontinuous “button-like” junctions, which are permeable for optimal fluid uptake. Lymphatic flow is driven by the pumping action of downstream collecting lymphatic vessels (not depicted). Ultimately, lymph ends up in the thoracic duct that crosses the lymphovenous valve and drains into the subclavian vein.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4557107&req=5

Figure 2: Lymphatic dependent reverse cholesterol transport within the peripheral tissues. HDL particles cross the vascular endothelium from plasma into interstitial fluid. Lipid-poor ApoA1 facilitates cellular cholesterol efflux through ABCA1-mediated pathway to form preβ-HDL. Lymphatic capillaries have discontinuous “button-like” junctions, which are permeable for optimal fluid uptake. Lymphatic flow is driven by the pumping action of downstream collecting lymphatic vessels (not depicted). Ultimately, lymph ends up in the thoracic duct that crosses the lymphovenous valve and drains into the subclavian vein.
Mentions: While HDL is measured in the plasma, much of the life cycle of HDL is spent within the tissue (Rudra et al., 1984; Miller et al., 2013; Randolph and Miller, 2014) and its migration from that tissue back to the blood compartment occurs via trafficking through the lymphatic system. Radiolabeled cholesterol was identified in the lymph and tissue compartments immediately after i.v., administration in human patients (Reichl et al., 1973). Several weeks following administration, radiolabeled tissue cholesterol was higher in lymph than in plasma, indicating that cholesterol in lymph was derived from plasma (Samuel et al., 1972; Reichl et al., 1973). HDL particles have been proposed to cross the vascular endothelium from plasma into interstitial fluid through receptor-mediated transcytosis based on in vitro studies (Rohrer et al., 2006) and/or passive diffusion through intercellular pores (Nordestgaard and Nielsen, 1994; Michel et al., 2015; Figure 2). Using aortic endothelial cells in vitro, Cavelier et al. (2006) showed that lipid-free ApoA1 binds and is internalized and transported in an ABCA1 dependent manner, generating lipidated particles through this process. Also using aortic endothelial cells in vitro, Rohrer et al. (2009) demonstrated HDL particles bind, are internalized, and are transported in a SR-B1 and ABCG1, but not ABCA1, dependent process, reducing particle size without degrading the protein moiety. However, in rabbits fed a high cholesterol diet, the influx into the arterial space of plasma lipoproteins, such as LDL, VLDL, and HDL, decreases linearly with the logarithm of particle diameter (Stender and Zilversmit, 1981), suggesting that lipoproteins cross the endothelium in a size-dependent manner. Michel et al. (2015) demonstrated in vivo that HDL and LDL transport from the plasma to the interstitial space occurs passively through endothelial intercellular pores and that active receptor-mediated transcytosis is unnecessary. If transport is predominantly passive, particle size would be expected to limit the transfer rate. Indeed, studies indicate that an HDL size increase from average 4.5–6 nm lowers its clearance rate by 12% (Michel et al., 2015). When vascular permeability is increased, influx of HDL into interstitial fluid is enhanced, and the rate of RCT is increased. The result supports the observation of the importance of passive HDL transport (Kareinen et al., 2015). Adenoviral overexpression of PLTP in hepatocytes generates larger particle size (<7.1 nm but larger than lipid-free ApoA1; Ji et al., 2014) and also increases atherosclerotic lesion size in PLTP overexpressing ApoE deficient mice (Zhang et al., 2014), although the causal relationship between PLTP and CVD is still under debate (Vergeer et al., 2010; Kim et al., 2015). In line with the mechanism proposed by Zhang et al. (2014), the increased HDL particle size resulting from PLTP overexpression impaired RCT (Samyn et al., 2009), perhaps impairing movement of HDL into the interstitium, limiting cholesterol uptake from extravascular spaces like plaque, and ultimately increasing atherosclerotic disease progression. Whether increased HDL particle size affects HDL transport and/or RCT requires further investigation.

Bottom Line: Extracellular cholesterol then is picked up and transported through the lymphatic vasculature before entering into bloodstream.There is increasing evidence supporting a role for enhanced macrophage cholesterol efflux and RCT in ameliorating atherosclerosis, and recent data suggest that these processes may serve as better diagnostic biomarkers than plasma HDL levels.New findings will complement therapeutic strategies for the treatment of atherosclerotic vascular disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Immunology, Washington University School of Medicine , St. Louis, MO, USA.

ABSTRACT
Reverse cholesterol transport (RCT) is the pathway for removal of peripheral tissue cholesterol and involves transport of cholesterol back to liver for excretion, starting from cellular cholesterol efflux facilitated by lipid-free apolipoprotein A1 (ApoA1) or other lipidated high-density lipoprotein (HDL) particles within the interstitial space. Extracellular cholesterol then is picked up and transported through the lymphatic vasculature before entering into bloodstream. There is increasing evidence supporting a role for enhanced macrophage cholesterol efflux and RCT in ameliorating atherosclerosis, and recent data suggest that these processes may serve as better diagnostic biomarkers than plasma HDL levels. Hence, it is important to better understand the processes governing ApoA1 and HDL influx into peripheral tissues from the bloodstream, modification and facilitation of cellular cholesterol removal within the interstitial space, and transport through the lymphatic vasculature. New findings will complement therapeutic strategies for the treatment of atherosclerotic vascular disease.

No MeSH data available.


Related in: MedlinePlus