Reverse cholesterol transport is regulated by varying fatty acyl chain saturation and sphingomyelin content in reconstituted high-density lipoproteins

Marmillot, Philippe; Patel, Shailesh; Lakshman, Raj

doi:10.1016/j.metabol.2006.09.021

Cited by 40 publications

(34 citation statements)

References 39 publications

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“…The effects of PC, fatty acid saturation, and addition of SM to rHDL on cholesterol effl ux from J774 macrophages and esterifi ed cholesterol uptake by HepG2 cells were also evaluated by Marmillot, Patel, and Lakshman ( 8 ). In general, the highest cholesterol effl ux was observed for more saturated lipid-based rHDL, such as fully saturated 1,2-distearoyl-PC (DSPC, 18:0) and 1,2-dioleoyl PC (DOPC, 18:1, mono-unsaturated).…”

Section: Discussionmentioning

confidence: 99%

“…SM is also known to form lipid-raft sections in cellular membrane that contain up to 50% cholesterol ( 23 ). The rHDLs made from saturated lipids exhibited greater cholesterol effl ux from macrophages in vitro ( 8,9 ) and cholesterol mobilization in vivo ( 24 ). However, unsaturation enhances rHDL interaction with LCAT ( 11 ), whereas SM was reported to inhibit cholesterol esterifi cation in vitro ( 6 ).…”

Section: Plasma Hdl Remodelingmentioning

confidence: 99%

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The effect of phospholipid composition of reconstituted HDL on its cholesterol efflux and anti-inflammatory properties

Schwendeman

Sviridov

Yuan

et al. 2015

Journal of Lipid Research

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Infusions of cholesterol-free reconstituted HDL (rHDL) particles have been shown to rapidly reverse atherosclerosis in a wide variety of animal models and in clinical trials of acute coronary syndrome patients ( 1-5 ). While a significant emphasis has been placed on investigating the HDL protein component, i.e., ApoA-I, ApoA-I mutants, and mimetic peptides, the importance of HDL phospholipid (PL) composition has not been systematically investigated. Lipid represents 50-80% of the total HDL mass and is known to affect particle stability in vivo, cholesterol effl ux from macrophages, the ability to interact with LCAT, and cholesterol elimination ( 6-11 ). Lipid composition also largely defi nes the size, net charge, and rigidity of the rHDL particles; all are important factors in the pharmacokinetic and pharmacodynamic properties of rHDL. The investigation of the effects of lipid composition on the resulting rHDL properties in vitro and in vivo is the focus of this article. By better defi ning the lipid effect of rHDL, we hope to be able to favorably alter the potency and safety of rHDL, and ultimately advance clinical translation of these potentially life-changing nanomedicines.The PL composition of endogenous HDL contains phosphatidylcholines (PCs), SM, and small amounts of lysophosphatidylcholine (LPC), phosphatidylethanolamine, Abstract The goal of this study was to understand how the reconstituted HDL (rHDL) phospholipid (PL) composition affects its cholesterol effl ux and anti-infl ammatory properties. An ApoA-I mimetic peptide, 5A, was combined with either SM or POPC. Both lipid formulations exhibited similar in vitro cholesterol effl ux by ABCA1, but 5A-SM exhibited higher ABCG1-and SR-BI-mediated effl ux relative to 5A-POPC ( P < 0.05). Injection of both rHDLs in rats resulted in mobilization of plasma cholesterol, although the relative potency was 3-fold higher for the same doses of 5A-SM than for 5A-POPC. Formation of pre ␤ HDL was observed following incubation of rHDLs with both human and rat plasma in vitro, with 5A-SM inducing a higher extent of pre ␤ formation relative to 5A-POPC. Both rHDLs exhibited antiinfl ammatory properties, but 5A-SM showed higher inhibition of TNF-␣ , IL-6, and IL-1 ␤ release than did 5A-POPC ( P < 0.05). Both 5A-SM and 5A-POPC showed reduction in total plaque area in ApoE ؊ / ؊ mice, but only 5A-SM showed a statistically signifi cant reduction over placebo control and baseline ( P < 0.01). The type of PL used to reconstitute peptide has signifi cant infl uence on rHDL's anti-infl ammatory and anti-atherosclerosis properties.

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Section: Discussionmentioning

confidence: 99%

Section: Plasma Hdl Remodelingmentioning

confidence: 99%

The effect of phospholipid composition of reconstituted HDL on its cholesterol efflux and anti-inflammatory properties

Schwendeman

Sviridov

Yuan

et al. 2015

Journal of Lipid Research

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“…In a similar fashion, high SM content decreases cellular cholesterol effl ux to HDL containing unsaturated lipids in a liquid-crystal state ( 56 ). Indeed, decrease in the fl uidity of surrounding liquid-crystal lipids represents one of the major effects of SM.…”

Section: Anti-infl Ammatory Activitymentioning

confidence: 91%

Unraveling the complexities of the HDL lipidome

Kontush

Lhomme

Chapman

2013

Journal of Lipid Research

316

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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“…It has been proposed that HDL that contain a greater proportion of polyunsaturated fatty acids in lysophosphatidylcholine may have impaired capacity for reverse cholesterol transport. 48 It would be informative if remnant HDL particles could be isolated directly from insulin resistant or hypertriglyceridemic subjects, to determine their precise composition and to test whether they behave in a pattern similar to that observed in our experimental system. Not only is it presently not technically possible to physically separate remnant HDL particles from nonremnant HDL species in human plasma but their more rapid clearance from the circulation in humans who have hypertriglyceridemia and higher HL activity would tend to relatively deplete the remnant HDL fraction, making them harder to isolate.…”

mentioning

confidence: 90%

Enhanced Cellular Uptake of Remnant High-Density Lipoprotein Particles

Xiao

Watanabe

Zhang

et al. 2008

Circulation Research

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Abstract-A low level of high-density lipoprotein (HDL) cholesterol is characteristic of insulin resistance and hypertriglyceridemia and likely contributes to the increased risk of cardiovascular disease associated with these conditions. One pathway involves enhanced clearance of lipolytically modified HDL particles, but the underlying mechanisms remain poorly understood. Here, we examine the effect of triglyceride enrichment and hepatic lipase hydrolysis on HDL binding, internalization, and degradation in cultured liver and kidney cells. Maximal binding of remnant HDL (HDL enriched with triglycerides followed by hepatic lipase hydrolysis), but not binding affinity, was markedly higher than native and triglyceride-rich HDL in both HepG2 cells and HEK293 cells. Compared with native and triglyceride-rich HDL, remnant HDL was internalized to a greater extent in both cell types and was more readily degraded in HEK293 cells. Key Words: HDL Ⅲ hepatic lipase Ⅲ insulin resistance Ⅲ hypertriglyceridemia P opulation studies have shown a highly reproducible, inverse correlation between plasma concentrations of high-density lipoprotein cholesterol (HDL-c), apolipoprotein (apo)A-I and the risk of atherosclerotic cardiovascular diseases. 1,2 A thorough understanding of the cellular/molecular mechanisms regulating HDL metabolism is important to the development of new therapeutic approaches to prevent cardiovascular diseases. 3 Low HDL is a characteristic feature of insulin resistance and hypertriglyceridemia, 4 which is mainly attributable to enhanced clearance but not decreased production of HDL particles. 5 The precise mechanisms underlying enhanced HDL catabolism are not clear. Intravascular remodeling of HDL by lipid transfer factors, lipases, and non-HDL lipoproteins plays a critical role in HDL metabolism. 6 In insulin resistance and hypertriglyceridemia, HDL particles are enriched with triglycerides (TGs) by enhanced lipid exchange with the increased number and size of TG-rich lipoproteins, a process mediated by cholesteryl ester transfer protein. 7 Increased hepatic lipase (HL) activity accompanies TG enrichment of HDL particles in these states. 8 HL hydrolysis of TG-rich HDL induces the formation of pre-␤1-HDL, leaving a residual ␣-migrating HDL particle referred to as remnant HDL. 9,10 Remnant HDL particles have compositional and conformational features that are distinct from TG-rich HDL, and many of these features may affect their affinity and binding to cell surface binding sites. 11,12 Shedding and rapid renal filtration and degradation of lipid-poor or lipid-free apoA-I that results from the HDL lipolysis may contribute to low HDL-c. We have previously demonstrated that TG enrichment in combination with HL lipolysis of HDL enhances HDL catabolism in vivo. [13][14][15][16] The liver, kidney, and steroidogenic tissues are major sites of HDL catabolism. 17,18 The liver has been recognized as the major site for selective 19,20 The kidney is the principal tissue for the uptake of apoA-I, 21,22 possibly through ...

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Reverse cholesterol transport is regulated by varying fatty acyl chain saturation and sphingomyelin content in reconstituted high-density lipoproteins

Cited by 40 publications

References 39 publications

The effect of phospholipid composition of reconstituted HDL on its cholesterol efflux and anti-inflammatory properties

The effect of phospholipid composition of reconstituted HDL on its cholesterol efflux and anti-inflammatory properties

Unraveling the complexities of the HDL lipidome

Enhanced Cellular Uptake of Remnant High-Density Lipoprotein Particles

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