Detergent-Mediated Phospholipidation of Plasma Lipoproteins Increases HDL Cholesterophilicity and Cholesterol Efflux via SR-BI

Abstract

Cellular cholesterol efflux is an early, obligatory step in reverse cholesterol transport, the putative antiatherogenic mechanism by which human plasma high density lipoproteins (HDL) transport cholesterol from peripheral tissue to the liver for recycling or disposal. HDL-phospholipid content is the essential cholesterol-binding component of lipoproteins and therefore a major determinant of cholesterol efflux. Thus, increased phospholipidation of lipoproteins, particularly HDL, is one strategy for increasing cholesterol efflux. This study validates a simple, new detergent perturbation method for the phospholipidation of plasma lipoproteins; we have quantified the cholesterophilicity of human plasma lipoproteins and the effects of lipoprotein phospholipidation on cholesterophilicity and cellular cholesterol efflux mediated by the class B type I scavenger receptor (SR-BI). We determined that low density lipoproteins (LDL) are more cholesterophilic than HDL and that LDL has a higher affinity for phospholipids than HDL whereas HDL has a higher phospholipid capacity than LDL. Phospholipidation of total human plasma lipoproteins enhances cholesterol efflux, an effect that occurs largely through the preferential phospholipidation of HDL. We conclude that increasing HDL phospholipid increases its cholesterophilicity thereby making it a better acceptor of cellular cholesterol efflux. Phospholipidation of lipoproteins by detergent perturbation is a simple way to increase HDL cholesterophilicity and cholesterol efflux in a way that may be clinically useful. KeywordsCholesterol transport; lipoproteins; lipid transport; HDL therapy; SR-BI In spite of progress, management of low plasma high density lipoprotein-cholesterol (HDL-C), a risk factor for cardiovascular disease, 1-5 remains a challenge. Unlike liver, extrahepatic tissues synthesize but do not degrade cholesterol. Thus, unless there is a mechanism for its disposal, cholesterol accumulates in arterial macrophages, a key cell type in atherosclerosis. That mechanism, reverse cholesterol transport (RCT), comprises three steps: 1) cellular cholesterol efflux to HDL; 2) esterfication of HDL-cholesterol by lecithin:cholesterol acyltransferase (LCAT); and 3) selective HDL-lipid uptake by hepatic scavenger receptors class B, type I (SR-BI). RCT requires cholesterophilic HDL and a mechanism for trapping cholesterol in HDL after efflux. Phosphatidylcholine (PC), the essential cholesterophilic component of HDL, 7-11 and the acyl donor for the LCAT, 12 converts cholesterol to its ester, which unlike free cholesterol (FC) does not transfer spontaneously between lipoproteins. † Supported by grants-in-aid from the National Institutes of Health Although the details of RCT have changed as new transporters, enzymes, and receptors have been identified, 13-20 association of cellular FC with HDL has always been considered an obligatory first step. Thus, increasing plasma HDL-PC by phospholipidation should improve RCT.Given that detergents can reconstitute membranes and lipoprotei...

Thermal Transitions in Human Very-Low-Density Lipoprotein: Fusion, Rupture, and Dissociation of HDL-like Particles

“…4B, C) and thereby provides a mechanism for removing excess surface material from the fused particles. Thus, different modes of VLDL perturbation (such as lipase-mediated TG hydrolysis or heatinduced VLDL fusion) may lead to transient formation of similar apoE-containing HDL-like particles.Earlier studies of HDL and LDL have shown that thermal and solute-induced perturbations may mimic aspects of enzymatic lipoprotein remodeling such as particle fusion, apolipoprotein dissociation and phospholipid transfer (10,11,36,37). The results reported here extend this notion to VLDL and suggest that thermal perturbation of VLDL mimics aspects of protein and lipid transfer among TG-rich lipoproteins and HDL pools in plasma.…”

HDL-replacement therapy: mechanism of action, types of agents and potential clinical indications

“…A different approach, involving the phospholipid enrichment of HDL, has also been described but has only been tested in vitro [107]. During this treatment, HDL is incubated in the presence of phospholipid vesicles along with cholate, which are later removed by dialysis.…”

Synthetic dimyristoylphosphatidylcholine liposomes assimilating into high-density lipoprotein promote regression of atherosclerotic lesions in cholesterol-fed rabbits

“…17,18 This suggests that the potency of liposomes to mobilize tissue cholesterol or to regress atherosclerotic lesions in vivo could be influenced by the degree of solubilization of the basic vesicular structure of the liposomes by HDL and other plasma components. The findings reported here suggest that DMPC liposomes behave in a manner similar to egg or soy PC liposomes.…”