HDL superphospholipidation enhances key steps in reverse cholesterol transport

Abstract

HDL-phospholipids (HDL-PL) play an important role in reverse cholesterol transport (RCT). Phosphatidylcholine (PC) is the most important phospholipid in RCT because it is the essential cholesterol-binding component of lipoproteins and is the acyl donor in the esterification of FC by lecithin:cholesterol acyltransferase (LCAT). FC efflux to sera is a positive anti-atherogenic function of HDL-PL. Although PC has long been recognized as an anti-atherogenic agent, developement of new HDL therapies based on PC have been fraught with issues of efficacy, cost, and safety. Moreover, some methods to increase HDL-PC perturb HDL and release lipid-free apolipoproteins (apo) A-I. We developed a new method, HDL SPLn (SPLn) using a modified detergent removal method that obviates these concerns. SPLn can incorporate PC into HDL and increase HDL-PC >10 fold. This is achieved with no loss of apo A-I. According to size exclusion chromatography and native gradient gel electrophoresis, SPLn raises the HDL particle weight in a dose-dependent way, from ~120 kDa to ~350 kDa. Kinetic analysis of FC efflux to the resulting SPLn particles shows that K m and V max for SPLn HDL are lower and higher respectively than for native HDL. As a consequence, the catalytic efficiency, Vmax/Km, increases by more than 400%. Clinically, small increases in serum HDL-PL are associated with significant and profound increases in FC efflux to serum. Treatment of relatively small amounts of plasma by SPLn is a potential method of improving at least one step in RCT.

Modest diet-induced weight loss reduces macrophage cholesterol efflux to plasma of patients with metabolic syndrome

“…Cholesterol efflux is increased by increasing the phospholipid content of acceptors, including whole plasma or purified HDL. 7–11 The kind of phospholipid is also important, with sphingomyelin, which is highly cholesterophilic, 12 being a better acceptor than phosphatidylcholine. 13 The cholesterol to phospholipid ratio of the acceptor is also important; 14 as the cholesterol in reassembled HDL (rHDL) rises above 15 mol%, it becomes a net donor rather than an acceptor.…”

Atheroprotective Reverse Cholesterol Transport Pathway Is Defective in Familial Hypercholesterolemia

“…32,33 Moreover, in good agreement with our present observations, it has recently been demonstrated that specifically increasing PC content in HDL particles leads to improve cholesterol efflux from SR-BIoverexpressing cells, as well as from human THP-1 cholesterol-loaded macrophages. 34 SR-BI mediates bidirectional flux of cholesterol between cell membranes and plasma lipoproteins. On the one hand, SR-BI is responsible for selective HDL lipid uptake in various tissues, including the liver, and on the other hand, SR-BI can mediate free cholesterol efflux from peripheral cells to HDL acceptors.…”

Mass spectrometry analysis of blood plasma lipidome as method of disease diagnostics, evuation of effectiveness and optimization of drug therapy

“…По мнению многих исследователей, основная роль в способности ЛПВП принимать холестерин принадлежит входящим в их состав фосфолипидам [91][92][93][94]. Так, Pownall и Ehnholm [92] отмечают, что Апо А1 (основной апопротеин ЛВП) без фосфолипидов не может служить акцептором холестерина [93].…”

“…Более того, среди веществ, входящих в ЛПВП, только для фосфолипидов показана способность вызывать регрессию экспериментального атеросклероза [96]. Обогащение же ЛПВП фосфолипидами ведёт к повышению их холестерин-акцепторной активности [91,92,94].…”

“…Г) Диаграмма соотношения основных молекулярных форм фосфолипидов в препарате эссенциальных фосфолипидов и в ЛПВП до и после инкубации плазмы крови с этим препаратом (протокол выделения ЛПВП ультрацентрифугированием после инкубации плазмы крови с эссенциальными фосфолипидами описан Krauss и соавт. [94]). Показан пример слабой тропности фосфолипида из препарата с массой 780,5 (1) к ЛПВП, который не приводит к изменению их фосфолипидного состава, и пример высокой тропности фосфолипида из препарата с массой 804,5 (2), который увеличивает вдвое содержание соответствующего фосфолипида в ЛПВП.…”