Human macrophage cholesterol efflux potential is enhanced by HDL-associated 17β-estradiol fatty acyl esters

Badeau, Robert M.; Metso, Jari; Wähälä, Kristiina; Tikkanen, Matti J.; Jauhiainen, Matti

doi:10.1016/j.jsbmb.2009.04.008

Cited by 46 publications

(34 citation statements)

References 34 publications

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“…Although no CETP-mediated transfer of E 2 fatty acyl ester was observed on the MD simulation scale, its potent anchoring role probably explains the enhanced atheroprotective role of HDL associated with E 2 fatty acyl ester claimed earlier ( 9 ). It facilitates the CETP-HDL complex and the opening formations.…”

Section: Discussionmentioning

confidence: 81%

“…2 ) To explore a possible lipid transfer mechanism mediated by CETP upon penetration. 3 ) ␤ -Estradiol (E 2 ) molecules are transported in plasma lipoproteins mostly as fatty acyl derivatives, HDL, in particular, is reported to be a good carrier for E 2 fatty acyl ester ( 6, 7 ) and the HDL/E 2 fatty acyl ester complex has an enhanced atheroprotective role, at least in vitro, particularly among women ( 6,8,9 ). Furthermore, experimental fi ndings indicate that esterifi ed estradiol molecules are transferred from HDL to LDL particles via a CETP-mediated process, the details of which are unknown ( 10 ).…”

Section: Atomistic MD Simulation Parameters and Force Fi Eldmentioning

confidence: 99%

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Atomistic MD simulation reveals the mechanism by which CETP penetrates into HDL enabling lipid transfer from HDL to CETP

Cilpa-Karhu

Jauhiainen

Riekkola

2015

Journal of Lipid Research

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This article is available online at http://www.jlr.org the atheroprotective functions of HDL ( 1 ) have been driving forces for research on HDL as a potential therapeutic target ( 2 ). Several therapies aimed at increasing HDL-C levels have been tested. Among them is the inhibition of cholesterol ester transfer protein (CETP) ( 2, 3 ), a plasma neutral lipid transfer protein that mediates exchange/ transfer of neutral lipids between HDL and apoB-100-containing lipoproteins and is involved in the reverse cholesterol transport process. Despite an increase in the level of HDL-C, there was no decrease in cardiovascular risk. This outcome shows that the direct relationship between increase in HDL-C and decrease in the risk for cardiovascular disease is not clear and some of the characteristics of HDL and/or CETP are not yet known, preventing full comprehension of the mechanism by which CETP interacts with HDL to facilitate lipid transfer in the circulation. Our objective was then to clarify the process by which CETP binds and interacts with HDL.Atomistic molecular dynamics (MD) and coarse graining dynamics studies ( 4 ) have previously been applied to clarify the lipid transfer from HDL mediated by CETP. The HDL model was a lipid-mimicking droplet of HDL containing phospholipids (POPC) and cholesteryl ester, lacking the HDL main protein, apoA-I. While these previous computational studies considered a match to match curvature CETP-HDL, a recent experimental study relying on advanced electron microscopy (EM) technique and 3D reconstruction demonstrated that CETP and HDL form a binary complex by partial penetration of CETP into the lipid-apolipoprotein monolayer surface of HDL, with The well-recognized associations between the plasma level of HDL-cholesterol (HDL-C), HDL metabolism, and

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Section: Discussionmentioning

confidence: 81%

Section: Atomistic MD Simulation Parameters and Force Fi Eldmentioning

confidence: 99%

Atomistic MD simulation reveals the mechanism by which CETP penetrates into HDL enabling lipid transfer from HDL to CETP

Cilpa-Karhu

Jauhiainen

Riekkola

2015

Journal of Lipid Research

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“…HDL-derived estradiol stimulates endothelial relaxation through induction of eNOS ( 86 ), an effect that can be related to the stimulation of cellular cholesterol effl ux ( 87 ). Another potent vascular relaxant, dehydroepiandrosterone, is present in HDL in its naturally occurring lipophilic esterifi ed form.…”

Section: Vasodilatory Activitymentioning

confidence: 99%

Unraveling the complexities of the HDL lipidome

Kontush

Lhomme

Chapman

2013

Journal of Lipid Research

311

247

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This article is available online at http://www.jlr.org For many years, HDL lipids were predominantly characterized in terms of the content of their major classes, notably phospholipids, unesterifi ed (free) sterols (predominantly cholesterol), cholesteryl esters, and triglycerides. Cholesterol is the most characteristic component of the HDL lipidome as, in the form of HDL-cholesterol, it represents a major independent negative risk factor for cardiovascular disease (see other reviews in this Thematic Series). It is not cholesterol, however, but phospholipids that quantitatively predominate in the HDL lipidome, accounting, together with sphingomyelin (SM), for 40-60 wt% of total lipid, with lesser proportions of cholesteryl esters (30-40%), triglycerides (5-12%), and free cholesterol (5-10%). Structurally, individual HDL lipid classes fulfi ll distinct functions; phospholipids constitute the surface lipid monolayer of HDL, whereas cholesteryl esters and triglycerides form the hydrophobic lipid core. Unesterifi ed sterols are predominantly located to the surface monolayer, partially penetrating the core.Recent technological advances in mass spectrometry (MS) have enabled application of this powerful technique to provide a detailed identifi cation and quantifi cation of individual molecular species of lipids in the framework of the fi eld known as lipidomics. Application of this approach to plasma lipoproteins has revealed complex profi les consisting of hundreds of molecular lipid species that have been quantifi ed in major lipoprotein classes, including HDL (reviewed in Refs. 1-3 High density lipoproteins (HDL) are small, dense, protein-rich particles compared with other plasma lipoprotein classes. Despite the elevated abundance of multiple structural and functional proteins in HDL particles (see other reviews in this Thematic Series), roughly half of total HDL mass is accounted for by lipid components.

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“…In addition, E 2 was reported to reduce macrophage uptake of modified LDLs such as acetylated, oxidized, or aggregated LDL, and this latter effect was found to specifically depend on the ERa-mediated suppression of the expression of scavenger receptor CD36 (Sulistiyani & St Clair 1997, McCrohon et al 1999, Allred et al 2006, Wilson et al 2008. More recently, ERa-deficient macrophages were shown to express reduced amounts of proteins involved in cholesterol efflux such as ABCA1 and APOE and to export less cholesterol when incubated with HDL, whereas E 2 associated with HDL particles was found to potentiate HDL-induced cholesterol efflux mediated by scavenger receptor class B type I (SR-BI (SCARB1)) (Badeau et al 2009, Ribas et al 2011. Several studies documented that HDL carries E 2 in the form of fatty acyl esters produced in a reaction catalyzed by lecithin-cholesterol acyltransferase (LCAT; Helisten et al 2001, Höckerstedt et al 2002.…”

Section: Involvement Of Macrophages Dendritic Cells and Lymphocytesmentioning

confidence: 99%

“…Several studies documented that HDL carries E 2 in the form of fatty acyl esters produced in a reaction catalyzed by lecithin-cholesterol acyltransferase (LCAT; Helisten et al 2001, Höckerstedt et al 2002. HDL-derived E 2 esters are internalized via LDLR-and/or SR-BImediated mechanisms and subsequently hydrolyzed intracellularly to unfold their effects (Badeau et al 2007a(Badeau et al , 2009). In addition, E 2 esters are transferred by cholesterol ester transfer protein to LDL particles, where they reduce oxidation by free radicals produced in copious amounts by activated macrophages (Helisten et al 2001, Höckerstedt et al 2002.…”

Section: Involvement Of Macrophages Dendritic Cells and Lymphocytesmentioning

confidence: 99%

Estrogens and atherosclerosis: insights from animal models and cell systems

Nofer

2012

Journal of Molecular Endocrinology

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Estrogens not only play a pivotal role in sexual development but are also involved in several physiological processes in various tissues including vasculature. While several epidemiological studies documented an inverse relationship between plasma estrogen levels and the incidence of cardiovascular disease and related it to the inhibition of atherosclerosis, an interventional trial showed an increase in cardiovascular events among postmenopausal women on estrogen treatment. The development of atherosclerotic lesions involves complex interplay between various pro-or anti-atherogenic processes that can be effectively studied only in vivo in appropriate animal models. With the advent of genetic engineering, transgenic mouse models of atherosclerosis have supplemented classical dietary cholesterolinduced disease models such as the cholesterol-fed rabbit. In the last two decades, these models were widely applied along with in vitro cell systems to specifically investigate the influence of estrogens on the development of early and advanced atherosclerotic lesions. The present review summarizes the results of these studies and assesses their contribution toward better understanding of molecular mechanisms underlying anti-and/or pro-atherogenic effects of estrogens in humans.

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Human macrophage cholesterol efflux potential is enhanced by HDL-associated 17β-estradiol fatty acyl esters

Cited by 46 publications

References 34 publications

Atomistic MD simulation reveals the mechanism by which CETP penetrates into HDL enabling lipid transfer from HDL to CETP

Atomistic MD simulation reveals the mechanism by which CETP penetrates into HDL enabling lipid transfer from HDL to CETP

Unraveling the complexities of the HDL lipidome

Estrogens and atherosclerosis: insights from animal models and cell systems

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