Protective Effect Of HDL Research Articles

Causal association between lipoproteins and risk of coronary artery disease-a systematic review and meta-analysis of Mendelian randomization studies.

To systematically evaluate the causal effect of lipoproteins to the risk of coronary artery disease (CAD) by systematic review and meta-analysis of the associated Mendelian randomization (MR) studies. This systematic review was registered in PROSPERO (ID CRD42023465430). Searches from the databases (e.g., PubMed, Embase, Cochrane, Web of Science) and non-database sources to collect MR studies. The search time frame was from the database inception to August 2023. After data extraction, quality evaluation was performed, and the meta-analysis with bias evaluation was carried out with RevMan software. A total of 5,828,409 participants from 21 records were included. Quality and bias assessment was performed by evaluating the internal three assumptions of MR studies. Meta-analysis for the causal association between non-HDL lipoproteins and CAD showed a significantly positive association between LDL and CAD (OR 1.37, 95% CI 1.26-1.49; P < 0.001, I2 = 95%), apoB and CAD (OR 1.38, 95% CI 1.11-1.71; P = 0.003, I2 = 98%), and Lp(a) and CAD (OR 1.21, 95% CI 1.12-1.31; P < 0.001, I2 = 99%). Interestingly, although there was no statistical significance in the association between VLDL/apoA1 and CAD (both P > 0.05), the pooled non-HDL lipoproteins showed a significantly positive association with CAD (OR 1.28, 95% CI 1.22-1.34; P < 0.001, I2 = 99%). For the HDL lipoproteins, the pooled OR showed a significantly negative association with CAD (OR 0.84, 95% CI 0.72-0.98; P = 0.002, I2 = 72%). However, the protective effect of HDL on CAD diminished when analyzed together with apoA1 and/or apoB (both P > 0.05). The funnel plot did not show serious publication bias, and sensitivity analysis performed relatively well robustness of the causal association of LDL, apoB, Lp(a), and total cholesterol with CAD. The present meta-analysis suggests an overall effect of causal association between lipoproteins and CAD. Most of the non-HDL lipoproteins (LDL, apoB, Lp(a)) promote CAD, while the protective effect of HDL in CAD still needs to be verified in the future.

EL-HDL exhibits increased capacity to attenuate LDL oxidation independent of pon1

Aim: The protective effects of HDL in inhibiting LDL oxidation have been attributed, in part, to the ac-tion of paraoxonase 1 (PON1). Endothelial lipase (EL) modulates structural and functional prop-erties of HDL.

Familial hypercholesterolaemia: cholesterol efflux and coronary disease.

BackgroundCoronary heart disease (CHD) risk inversely associates with levels of high‐density lipoprotein cholesterol (HDL‐C). The protective effect of HDL is thought to depend on its functionality, such as its ability to induce cholesterol efflux.Materials and methodsWe compared plasma cholesterol efflux capacity between male familial hypercholesterolaemia (FH) patients with and without CHD relative to their non‐FH brothers, and examined HDL constituents including sphingosine‐1‐phosphate (S1P) and its carrier apolipoprotein M (apoM).ResultsSeven FH patients were asymptomatic and six had experienced a cardiac event at a mean age of 39 years. Compared to their non‐FH brothers, cholesterol efflux from macrophages to plasma from the FH patients without CHD was 16 ± 22% (mean ± SD) higher and to plasma from the FH patients with CHD was 7 ± 8% lower (P = 0·03, CHD vs. non‐CHD). Compared to their non‐FH brothers, FH patients without CHD displayed significantly higher levels of HDL‐cholesterol, HDL‐S1P and apoM, while FH patients with CHD displayed lower levels than their non‐FH brothers.ConclusionsA higher plasma cholesterol efflux capacity and higher S1P and apoM content of HDL in asymptomatic FH patients may play a role in their apparent protection from premature CHD.

Major changes in the sphingophospholipidome of HDL in non-diabetic patients with metabolic syndrome

ObjectivePhospholipids and sphingolipids play a critical role in the protective effects of HDL against atherosclerosis. These properties are impaired in patients with metabolic syndrome, before the development of diabetes. We thus investigated whether HDL from patients with metabolic syndrome but normal fasting glycaemia present abnormalities in their sphingophospholipid profile. MethodsUsing liquid chromatography/tandem mass spectrometry, we quantified the different species of the main phospholipids and sphingolipids in the HDL2 and HDL3 from 26 obese patients with metabolic syndrome but normal fasting glycaemia and 50 controls. ResultsPhosphatidylcholines, when expressed as the relative amount compared with total phospholipids and sphingolipids, were similar in both HDL2 and HDL3 in the two groups. Lysophosphatidylcholines were 41% (p = 0.0002) and 86% (p < 0.0001) higher in HDL2 and HDL3, respectively, from patients with metabolic syndrome than in those from controls. Phosphatidylinositols were also higher in HDL2 and HDL3 (respectively, +60 and + 103% (p < 0.0001)). In contrast, both HDL2 and HDL3 from patients with metabolic syndrome showed lower proportions of phosphatidylethanolamine-based plasmalogens (respectively −78 and −73%, p < 0.0001), phosphatidylcholine-based plasmalogens (respectively −44 and −53%, p < 0.0001), d18:1-sphingosine-1-phosphate (respectively −52 and −38%, p < 0.0001) and sphingomyelins (respectively −19% (p < 0.0001) and −24% (p = 0.0006)), than did controls. Moreover, we observed a decrease in C18:2 fatty acid-containing phospholipids and an increase in C20:4 fatty acid-containing phospholipids. ConclusionThe sphingophospholipidome of HDL from normoglycaemic obese patients with metabolic syndrome is profoundly modified, before the dysregulation of glycaemia. Most of the changes observed have pejorative effect in terms of vascular protection.

Abstract 18909: Interaction Between a Novel Protein Glycan Derived Inflammation Biomarker (GlycA) and HDL Particle Subclasses on Mortality in a Cardiac Catheterization Cohort

Background: GlycA, a novel serum inflammatory biomarker composed of enzymatically glycosylated acute phase proteins, is associated with cardiovascular events in a primary prevention population. Emerging data suggest that inflammation may adversely impact HDL function. We sought to define the role of GlycA as a biomarker of adverse events in a secondary prevention population and to understand potential interactions between GlycA and HDL subclasses. Methods: GlycA and medium and small HDL particles (MS-HDL) were measured with NMR spectroscopy in 7,617 individuals in the CATHGEN biorepository. Cox proportional hazards modeling was used to test the relationship of GlycA, MS-HDL and the GlycA*MS-HDL interaction term with time-to-death in multivariable models adjusted for 11 CV risk factors and stratified by diabetes status. We then assessed the ability of GlycA, MS-HDL, and GlycA*MS-HDL to improve risk discrimination in clinical models. Results: Over a mean time-to-event of 2547 days, 2318 individuals died. Higher GlycA levels were associated with increased risk of death (HR 1.34 [1.29-1.39], p&lt;0.0001). In diabetes-stratified models, the greatest quartile of GlycA in patients without diabetes conferred greater risk of mortality than the lowest quartile of GlycA in patients with diabetes. In models containing MS-HDL (main effect HR 0.69 [0.66-0.72], p&lt;0.0001), addition of GlycA (HR 1.28 [1.24-1.32], p&lt;0.0001) and GlycA*MS-HDL (p&lt;0.0001) demonstrated independent associations of these variables with mortality. MS-HDL levels were associated with lower mortality risk at lower GlycA levels but with increased mortality risk at greater GlycA levels. There was an increasing improvement of model fit characteristics with incremental addition of GlycA, MS-HDL and GlycA*MS-HDL to robust clinical models. Conclusion: GlycA is associated with an increased risk of mortality in a secondary prevention population. The interaction of GlycA with MS-HDL suggests that greater systemic inflammation can modify the association of HDL subclasses with clinical outcomes and at the highest levels of GlycA, may reverse the protective effect of HDL. These findings have implications for the interpretation of diagnostic and therapeutic tools involving HDL measurements.

Maintaining vascular health with HDL

Vascular Biology Flow through blood vessels subjects endothelial cells to abnormal shear forces at specific locations. This triggers inflammation, which contributes to atherosclerotic plaque formation. Galvani et al. found that the endothelial cell receptor S1P1, which is activated by a lipid mediator abundant in blood, suppresses vascular inflammation and atherosclerosis in mice. This mediator, S1P, binds to different chaperone proteins and suppresses inflammation in cultured endothelial cells only when bound to the lipoprotein ApoM+HDL. Thus, S1P may contribute to the protective effect of HDL—commonly called “good cholesterol”—in atherosclerosis. Sci. Signal. 8 , ra79 (2015).

A proof-of-concept study for predicting the region of atherosclerotic plaque development based on plaque growth modeling in carotid arteries.

In this work, we present a computational model for plaque growth utilizing magnetic resonance data of a patient's carotid artery. More specifically, we model blood flow utilizing the Navier-Stokes equations, as well as LDL and HDL transport using the convection-diffusion equation in the arterial lumen. The accumulated LDL in the arterial wall is oxidized considering the protective effect of HDL. Macrophages recruitment and foam cells formation are the final step of the proposed multi-level modeling approach of the plaque growth. The simulated results of our model are compared with the follow-up MRI findings in 12 months regarding the change to the arterial wall thickness. WSS and LDL may indicate potential regions of plaque growth (R(2)=0.35), but the contribution of foam cells formation, macrophages and oxidized LDL increased the prediction significantly (R(2)=0.75).

Abstract 31: High-density Lipoprotein, a Feed-forward Forechecking Loop

Background: The protective effect of HDL is projected into the cholesterol back-transport of breakdown products of lipid metabolism to the liver. This is a feed-back circuit which controls cholesterol exit. Cholesterol entry could be safeguarded in a feed-forward forechecking loop at the proteoglycan (PG) receptor sites (syndecan, perlecan). HDL is the counter partner in the system of internalization and diffusion control for lipoprotein entry into the vascular wall. Based on stereochemical and chiral conformity with its PG receptor and the much higher negative charge density, HDL owns by far a higher affinity compared with LDL. Methods: Flow-dependent isometric tension, intracellularly recorded membrane potential and cAMP-cGMP were measured in segments of 25 coronaries from heart transplantations. Results and Discussion: Compared to Krebs solution, LDL (100 mg/dL) impaired flow-dilatation and caused a relative contraction by 18.5% (Table). In contrast, HDL (50 mg/dL) and HDL+LDL stimulated flow-dilatation by 31.1% and 41.4%, respectively (p &lt; 0.96). Thus, the contractile effect of LDL was absent in the Krebs-HDL-LDL solution. The same effects were apparent in the membrane potential and cAMP-cGMP-concentrations of the VSM cells. These results are confirmed by ellipsometry measurements, where nanoplaque formation by LDL is suppressed by preincubation with HDL [Siegel, Malmsten, Ermilov: Adv Coll Interface Sci 205 (2014) 275-318]. Conclusion: LDL-cholesterol entry into the vascular wall is effectfully controlled by HDL in a feed-forward forechecking loop (HDL 4х higher affinity constant to the PG receptor). The interaction between both is dominated by competition.

The impact of beef steak thermal processing on lipid oxidation and postprandial inflammation related responses

Oxidised lipid species, their bioavailability and impact on inflammatory responses from cooked beef steak are poorly characterised. Oxidised lipid species from pan-fried (PF) and sous-vide (SV) thermally processed beef were determined with UHPLC-ESI/MS. Twenty-three lipid oxidation products increased with thermal processing and differences between the PF and SV steaks were measured. Fifteen oxidised lipids were measured in post-meal plasma after a cross-over randomised clinical study. Postprandial plasma inflammatory markers tended to remain lower following the SV meal than the PF meal. High levels of conjugated dienes were measured in the HDL fraction, suggesting that the protective effect of HDL may extend to the reverse-transport of oxidised lipid species. Oxidised lipids in a single meal may influence postprandial oxidative stress and inflammation. Further studies are required to examine the lipid oxidative responses to increased dietary oxidative lipid load, including the reverse transport activity of HDL.

HDL inhibits the effects of oxidized phospholipids on endothelial cell gene expression via multiple mechanisms

Oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phospholcholine (OxPAPC) and its component phospholipids accumulate in atherosclerotic lesions and regulate the expression of >1,000 genes, many proatherogenic, in human aortic endothelial cells (HAECs). In contrast, there is evidence in the literature that HDL protects the vasculature from inflammatory insult. We have previously shown that in HAECs, HDL attenuates the expression of several proatherogenic genes regulated by OxPAPC and 1-palmitoyl-2-(5,6-epoxyisoprostane E2)-sn-glycero-3-phosphocholine. We now demonstrate that HDL reverses >50% of the OxPAPC transcriptional response. Genes reversed by HDL are enriched for inflammatory and vascular development pathways, while genes not affected by HDL are enriched for oxidative stress response pathways. The protective effect of HDL is partially mimicked by cholesterol repletion and treatment with apoA1 but does not require signaling through scavenger receptor class B type I. Furthermore, our data demonstrate that HDL protection requires direct interaction with OxPAPC. HDL-associated platelet-activating factor acetylhydrolase (PAF-AH) hydrolyzes short-chain bioactive phospholipids in OxPAPC; however, inhibiting PAF-AH activity does not prevent HDL protection. Our results are consistent with HDL sequestering specific bioactive lipids in OxPAPC, thereby preventing their regulation of select target genes. Overall, this work implicates HDL as a major regulator of OxPAPC action in endothelial cells via multiple mechanisms.

In This Issue

HomeCirculation ResearchVol. 112, No. 11In This Issue Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBIn This Issue Originally published24 May 2013https://doi.org/10.1161/RES.0b013e31829a38b3Circulation Research. 2013;112:1401Smooth Muscle Cells from Reprogrammed Fibroblasts (p 1433)Karamariti et al devise a new method for generating smooth muscle cells in vitro.Download figureDownload PowerPointSmooth muscle cells (SMCs) are an essential component of blood vessels, and are thus required to engineer functional blood vessels in culture. Tissue engineers need a reliable and plentiful supply of SMCs. However, the methods currently used to obtain these cells - such as retrieving them from adult arteries and expanding them in vitro, or differentiating them from embryonic stem cells - can be inefficient, arduous, or both. Karamariti and colleagues propose a new approach, which involves direct reprogramming of fibroblasts into SMCs, by transfecting human fibroblasts with factors used for making induced pluripotent stem (iPS) cells. But instead of fully dedifferentiating the cells, they plated partially dedifferentiated cells, called PiPS, on collagen IV and induced them to become SMCs. The resulting cells exhibited SMC morphology, expressed SMC-specific markers and were capable of contracting like native SMCs. Through a careful monitoring of the reprogramming process, the researchers also discovered a novel factor, called DKK3, which activated the expression of an important SMC marker. The reprogrammed cells were then used with endothelial cells to build tissue-engineered vessels that functioned like their native counterparts when transplanted into mice. Overall, this new method could improve current approaches to vessel engineering and, as a result, help in the development of vessel grafts for patients.Macrophage ABCA1/G1 Deletion Enhance Atherogenesis (p 1456)Macrophages lacking cholesterol transporters make atherosclerosis much worse, say Westerterp et al.Download figureDownload PowerPointHigh HDL levels in blood are associated with a lower risk of heart disease. The protective effects of HDL have been linked, in part, to its ability to promote cholesterol efflux from macrophages. However, it is unclear whether this efflux is indeed protective. Cholesterol efflux from macrophages is controlled by two transporter proteins, ABCA1 and ABCG1, so Westerterp and colleagues specifically deleted these proteins from the macrophages of atherosclerosis-prone mice. They found that this procedure led to an increase in the lipid content of the macrophages and increased atherogenesis. And while a deficiency in the cell’s cholesterol efflux did play a role in these changes, it was not the only contributing factor. In fact, in mice lacking ABCA1- and ABCG1 transporters in macrophages there was also an increase in monocytes and neutrophils, which led to increased inflammation in atherosclerotic plaques. It turned out that the ABCA1- and ABCG1-deficient macrophages were producing high levels of the cytokines G-CSF and M-CSF, which promote the production of neutrophils and monocytes, respectively. These findings suggest that strategies aimed at promoting cholesterol efflux will prevent the pro-inflammatory and pro-atherogenic potential of macrophages, and furthermore, that monitoring G-CSF and M-CSF levels could help assess the success of such strategies.Antisense Inhibition of ApoC-III (p 1479)Inhibition of ApoC-III by antisense RNA reduces triglyceride levels in both animals and humans.Download figureDownload PowerPointElevated levels of triglycerides in the blood are a well-known risk factor for coronary heart disease. And, therefore, reducing triglyceride levels might reduce that risk. To lower dangerously high triglyceride levels, doctors currently prescribe statins, niacin, fibrates and omega-3-fatty acids, but in many patients, achieving the recommended level is difficult. More effective remedies are therefore required. The glycoprotein ApoC-III is an important regulator of plasma triglyceride, and high levels of ApoC-III are associated with high levels of triglycerides. High ApoC-III levels have also been independently associated with metabolic disorder and type 2 diabetes. Thus, Graham and colleagues investigated lowering ApoC-III levels with antisense nucleotides directed against human and rodent ApoC-III mRNA. The antisense nucleotides successfully reduced plasma levels of both ApoC-III and triglycerides in rats, mice, transgenic mice carrying the human ApoC-III gene, rhesus monkeys, and most importantly, in healthy humans. Although this phase-I trial was performed in just 33 subjects, the results were significant and there were no adverse safety indications. The findings suggest that larger-scale phase-II clinical trials are warranted for this first-of-its-kind antisense ApoC-III therapy. Previous Back to top Next FiguresReferencesRelatedDetails May 24, 2013Vol 112, Issue 11 Advertisement Article InformationMetrics © 2013 American Heart Association, Inc.https://doi.org/10.1161/RES.0b013e31829a38b3 Originally publishedMay 24, 2013 PDF download Advertisement

Abstract 37: Association between High-Density Lipoprotein Cholesterol Subfractions and Carotid Intima-Media Thickness

Background Recent trials have challenged the protective effect of HDL in atherosclerosis, implicating the need to shift the focus from total HDL concentration to its function and major subfractions. The objective of this cross-sectional study was to investigate the relation between HDL2 and HDL3 subfractions and carotid intima-media thickness (IMT), an early indicator of atherosclerosis and surrogate marker of ischemic stroke. Methods In NOMAS, a prospective population-based study of the incidence and risk factors of stroke, we evaluated 1041 participants (mean age 68±9 years; 38% men; 62% Hispanic, 19% black, 17% white) with available data on HDL subfractions and carotid IMT assessed by a high-resolution 2D carotid ultrasound. Carotid IMT was a composite measure of the mean IMT in all carotid artery segments. The cross-sectional association between HDL-subfractions and IMT was analyzed by multiple linear regression. Results We mean±SD of total HDL was 46.15±14.25 mg/dl (median = 44.00), HDL2 14.59±8.29 mg/dl (median = 13.00), HDL3 31.06±8.32 mg/dl (median = 32.00). The mean IMT was 0.90±0.08 mm. After controlling for demographics, LDL, triglycerides, and cholesterol-lowering medication, a strong association was observed between total HDL (per SD, beta=-0.008, p= 0.01), HDL2 (per SD, beta=-0.006, p=0.03) and HDL3 (per SD, beta=-0.007 p=0.01) in relation to IMT. A significant interaction was observed between diabetes (vs. non-diabetes) and HDL2 in relation to IMT (p=0.01; -0.018mm). Conclusion The observed strong independent inverse associations between HDL, HDL2 and HDL3 and carotid IMT. HDL2 was only significantly associated with IMT among individuals with diabetes. These observations show novel evidence for a potential role of HDL2 and HDL3 subfractions, providing the opportunity to develop novel HDL-targeted therapies for the prevention of atherosclerosis.

Chronic pharmacological activation of P2Y13 receptor in mice decreases HDL-cholesterol level by increasing hepatic HDL uptake and bile acid secretion

High level of high-density lipoprotein cholesterol (HDL-cholesterol) is inversely correlated to the risk of atherosclerotic cardiovascular disease. The protective effect of HDL is mostly attributed to their metabolic functions in reverse cholesterol transport (RCT), a process whereby excess cell cholesterol is taken up from peripheral cells and processed in HDL particles, and is later delivered to the liver for further metabolism and bile excretion. We have previously demonstrated that P2Y13 receptor is critical for RCT and that intravenous bolus injection of cangrelor (AR-C69931MX), a partial agonist of P2Y13 receptor, can stimulate hepatic HDL uptake and subsequent lipid biliary secretion without any change in plasma lipid levels. In the present study, we investigated the effect of longer-term treatment with cangrelor on lipoprotein metabolism in mice. We observed that continuous delivery of cangrelor at a rate of 35μg/day/kg body weight for 3days markedly decreased plasma HDL-cholesterol level, by increasing the clearance of HDL particles by the liver. These effects were correlated to an increase in the rate of biliary bile acid secretion. An increased expression of SREBP-regulated genes of cholesterol metabolism was also observed without any change of hepatic lipid levels as compared to non-treated mice. Thus, 3-day cangrelor treatment markedly increases the flux of HDL-cholesterol from the plasma to the liver for bile acid secretion. Taken together our results suggest that P2Y13 appears a promising target for therapeutic intervention aimed at preventing or reducing cardiovascular risk.

Plasma Paraoxonase-1, Oxidized Low-Density Lipoprotein and Lipid Peroxidation Levels in Gout Patients

Gout patients have a high incidence of atherosclerotic coronary heart disease. Low serum paraoxonase (PON) activity is considered a risk factor for atherosclerosis. The relationships among paraoxonase-1 (PON1) activity, oxidative stress parameters, and atherosclerosis in gout is not known. Therefore, we determined the plasma levels of malondialdehyde (MDA), oxidized low-density lipoprotein (Ox-LDL), and activities of PON1/superoxide dismutase (SOD) activities in 49 gout patients (mean age 44.2 ± 7.0 years) and 42 healthy, age-matched controls (mean age 45.0 ± 9.3 years). PON1 was measured spectrophotometrically, MDA by thiobarbituric acid method, SOD by Griess reaction, and Ox-LDL by sandwich ELISA. Lipid and other biochemical parameters were determined by routine laboratory methods. In gout patients, PON1/SOD activities and MDA/Ox-LDL levels were 131.3 ± 25.3/75.3 ± 28.9 kU l(-1) and 6.12 ± 1.67 nmol ml(-1)/690.1 ± 180.2 μg l(-1), respectively. In controls, these were 172.5 ± 27.8/94.0 ± 26.3 kU l(-1) and 4.10 ± 1.25 nmol ml(-1)/452.3 ± 152.1 μg l(-1), respectively. Thus, in gout patients, there was a significant decrease in PON1 (P < 0.01) and SOD (P < 0.05) activities, and an increase in MDA (P < 0.01) and Ox-LDL (P < 0.01) levels compared with controls. PON1 activity correlated positively with SOD (P < 0.05), and negatively with MDA (P < 0.01) and Ox-LDL (P < 0.01). These results suggest that gout patients were in a state of oxidative stress and the protective effects of HDL against atherosclerosis maybe dependent on PON1 activity. These findings may explain in part the reported increase in cardiovascular mortality in gout patients.

The role of the proteoglycan receptor in lipoprotein binding

Heparan sulfate proteoglycan can be adsorbed to a methylated silica surface in a monomolecular layer via its transmembrane hydrophobic protein core domain. Due to electrostatic repulsion, its anionic glycosaminoglycan side chains are stretched out into the blood substitute solution representing one receptor site for specific lipoprotein binding through basic amino acid-rich residues within their apolipoproteins. A second lipoprotein binding site has been localized to four copies of LDL receptor repeats of core domain II. The binding process was studied by ellipsometric techniques showing that HDL has a high binding affinity to the receptor and a protective effect on interfacial heparan sulfate proteoglycan layers with respect to LDL and Ca2+ complexation. LDL was found to deposit strongly at the proteoheparan sulfate, particularly in the presence of Ca2+, thus creating the complex formation ‘proteoglycan—low density lipoprotein—calcium’. This ternary complex build-up may be interpreted as arteriosclerotic nanoplaque formation on the molecular level responsible for the arteriosclerotic primary lesion. On the other hand, HDL bound to heparan sulfate proteoglycan protected against LDL docking and completely suppressed calcification of the proteoglycan-lipoprotein complex. In addition, HDL was able to both reduce the ternary complex deposition and to disintegrate HS-PG/LDL/Ca2+ aggregates. Therefore, HDL attached to its proteoglycan receptor sites is thought to raise a multidomain barrier, selection and control motif for transmembrane and paracellular lipoprotein uptake into the arterial wall. Although much remains unclear regarding the mechanism of lipoprotein depositions at proteoglycan-coated surfaces, it seems clear that the use of such systems offers possibilities for investigating lipoprotein deposition at a ‘nanoscopic’ level under close to physiological conditions. In particular, Ca2+-promoted LDL deposition and the protective effect of HDL, even at high Ca2+ and LDL concentrations, agree well with previous clinical observations regarding risk and beneficial factors for early stages of atherosclerosis.

Hepatic SR-BI, not endothelial lipase, expression determines biliary cholesterol secretion in mice

High density lipoprotein cholesterol is thought to represent a preferred source of sterols secreted into bile following hepatic uptake by scavenger receptor class B type I (SR-BI). The present study aimed to determine the metabolic effects of an endothelial lipase (EL)-mediated stimulation of HDL cholesterol uptake on liver lipid metabolism and biliary cholesterol secretion in wild-type, SR-BI knockout, and SR-BI overexpressing mice. In each model, injection of an EL expressing adenovirus decreased plasma HDL cholesterol (P < 0.001) whereas hepatic cholesterol content increased (P < 0.05), translating into decreased expression of sterol-regulatory element binding protein 2 (SREBP2) and its target genes HMG-CoA reductase and LDL receptor (each P < 0.01). Biliary cholesterol secretion was dependent on hepatic SR-BI expression, being decreased in SR-BI knockouts (P < 0.001) and increased following hepatic SR-BI overexpression (P < 0.001). However, in each model, biliary secretion of cholesterol, bile acids, and phospholipids as well as fecal bile acid and neutral sterol content, remained unchanged in response to EL overexpression. Importantly, hepatic ABCG5/G8 expression did not correlate with biliary cholesterol secretion rates under these conditions. These results demonstrate that an acute decrease of plasma HDL cholesterol levels by overexpressing EL increases hepatic cholesterol content but leaves biliary sterol secretion unaltered. Instead, biliary cholesterol secretion rates are related to the hepatic expression level of SR-BI. These data stress the importance of SR-BI for biliary cholesterol secretion and might have relevance for concepts of reverse cholesterol transport.

Abstract 1184: Hdl Protects Macrophages From Oxidized Ldl-induced Apoptosis By Promoting Efflux Of 7-ketocholesterol Via Abcg1

Oxidized sterols consumed in the diet or formed on low-density lipoprotein (LDL) are toxic to endothelial cells and macrophages and are thought to have a central role in promoting atherogenesis. The ATP-binding cassette transporter ABCG1 was recently shown to promote efflux of cholesterol from macrophages to HDL. We show that HDL protects macrophages from apoptosis induced by loading with free cholesterol or oxidized LDL (oxLDL). The protective effect of HDL was reduced in Abcg1 −/− macrophages, especially after loading with oxidized LDL. Similarly, HDL exerted a protective effect against apoptosis induced by 7-ketocholesterol, the major oxysterol present in oxLDL and atherosclerotic lesions, in Abcg1 +/+ but not in Abcg1 −/− macrophages. In transfected 293 cells, efflux of 7-ketocholesterol was completely dependent on expression of ABCG1 and presence of HDL in media. In contrast, ABCA1 and apoA-1 did not stimulate efflux of 7-ketocholesterol into media. HDL stimulated efflux of 7-ketocholesterol from Abcg1 +/+ but not from Abcg1 −/− macrophages, and Abcg1 −/− macrophages accumulated 7-ketocholesterol in mice fed the Western diet. The findings indicate a specific role of ABCG1 in promoting efflux of 7-ketocholesterol from macrophages onto HDL, and in protecting these cells from oxysterol-induced toxicity.

HDL-c is a powerful lipid predictor of cardiovascular diseases

RELATIONSHIP BETWEEN HDL-C AND CARDIOVASCULAR DISEASES: Beyond the role of low-density lipoprotein cholesterol (LDL-c) in the development of atherosclerosis, growing evidence suggest that high-density lipoprotein cholesterol (HDL-c) is a powerful predictor of cardiovascular disease. Indeed, epidemiological, mechanistic and intervention studies suggest that low HDL-c is a major cardiovascular risk factor and that increasing HDL-c plasma levels may be beneficial, particularly in patients with low HDL-c levels. The inverse association between HDL-c concentrations and cardiovascular risk is continuous without threshold value. Thus, any categorical definition of low HDL-c is arbitrary. PROTECTIVE EFFECTS OF HDL: HDL particles are highly heterogeneous in structure and intravascular metabolism. Antiatherogenic properties of HDL include its role in the reverse cholesterol transfer, besides its antioxidant, anti-inflammatory and antiapoptotic activities. WHAT SHOULD CLINICIANS DO?: From a practical point of view, HDL-c should be systematically measured to assess the cardiovascular risk in patients. The first step to consider in subjects with low HDL-c is to look for specific causes and give advice to change inappropriate lifestyle components associated with low HDL-c, such as smoking, lack of physical exercise and overweight. Patients with very low HDL-c need a thorough evaluation by specialist physicians. Statins are associated with a modest increase of HDL-c (5%) while fibrates and nicotinic acid increase HDL-c by 10% and 20% respectively.

Serum Oxidized Low Density Lipoprotein, Paraoxonase 1 and Lipid Peroxidation Levels during Oral Glucose Tolerance Test

Increasing evidence suggests that the postprandial state is a contributing factor to the development of atherosclerosis. To evaluate the effects of acute hyperglycemia on the oxidative stress, concentrations of serum-oxidized low density lipoprotein (oxLDL), paraoxonase 1 (PON1), and thiobarbituric acid reactive substances (TBARS) were measured in subjects with normal glucose tolerance (NGT) (n=35), impaired glucose tolerance (IGT) (n=25), and diabetic glucose tolerance (DGT) (n=20). In NGT group, the 2 hours' TBARS and oxLDL levels were not statistically different when compared to baseline, and 2 hours' PON1 activities were higher when compared to baseline (p<0.01). Subjects with IGT and DGT have higher 2 hours' serum TBARS and oxLDL levels than their baseline levels (p<0.01, for each). Baseline oxLDL levels of both IGT and DGT groups were higher than NGT group (p<0.01 and p<0.01, respectively). While there were not any significant differences in 2 hours' versus baseline PON1 activities in the IGT group, the 2 hours' versus baseline PON1 activities in the DGT group were significantly lower (p<0.01). The postchallenge 2 hours' PON1 activities of both IGT and DGT groups were lower than NGT group (p<0.01 and p<0.01, respectively). Baseline oxLDL was positively correlated with 2 hours' glucose (r=0.613, p<0.01) in IGT and DGT groups. PON1 activities were correlated with HDL-cholesterol, total cholesterol, and fasting glucose (r=0.680, r=0.698 and r=0.431, respectively, for each p<0.01) in NGT. In conclusion, oxidative stress occurs at an early stage in diabetes, and protective effects of HDL against atherosclerosis may be dependent on the PON1 activities.

LDL resistance to oxidation: Effects of lipid phenotype, autologous HDL and alanine

Background Although LDL resistance to copper-induced oxidation is a time-honoured method, how it is modulated by the physiologic variability of lipid phenotype and what influences the protective action of homologous HDL and exogenous alanine is still unclear. Methods In 159 subjects without severe dyslipidemias, LDL resistance to copper-induced oxidation (lag phase) was measured under standardised conditions, with alanine and with autologous HDL. Results Lag phase was normally distributed and averaged 68 ± 10 min (range: 40–105 min). Both VLDL-triglycerides (37 ± 5, 52 ± 7, 59 ± 7, 53 ± 5 mg/dl, p < 0.05) and LDL-triglycerides (27 ± 2, 27 ± 1, 30 ± 2, 35 ± 3 mg/dl, p < 0.01) increased across quartiles of lag phase. The relative LDL enrichment in triglycerides (triglycerides percent or triglycerides/cholesterol ratio) was strongly related to lag phase ( r = 0.29 and r = 0.31, p < 0.0005 for both) independently of age, gender, BMI, and presence of diabetes or hypertension. The protective effect of HDL was variable (+ 42 ± 18 min) and largely dependent on the capacity of HDL to resist oxidation ( r = 0.69, p < 0.0001). Alanine induced a rather constant lag phase prolongation (+ 32 ± 7 min) that was weakly related only to baseline lag phase ( r = 0.17, p < 0.05). Conclusions Relative triglyceride abundance protects LDL from ex-vivo oxidation, HDL particles protect LDL mainly through substrate dilution and alanine probably through a direct anti-oxidant effect.