scholarly journals Lipoprotein atherogenicity: an overview of current mechanisms

1999 ◽  
Vol 58 (1) ◽  
pp. 163-169 ◽  
Author(s):  
Bruce A. Griffin
Keyword(s):  
Particle Size ◽  
Serum Cholesterol ◽  
Arterial Wall ◽  
Cholesterol Content ◽  
Oxidative Modification ◽  
Cross Sectional ◽  
Small Dense Ldl ◽  
Ldl Particles ◽  
Increased Risk ◽  
Tissue Matrix

Raised serum cholesterol does not adequately explain the increased risk of CHD within populations or the relationship between diet and CHD. Nevertheless, the principal transport vehicle of cholesterol in the circulation, LDL, must still be regarded as the most atherogenic lipoprotein species, but not because of its contribution to serum cholesterol. The atherogenic potential of LDL in the majority of individuals arises from an increase in the number of small dense LDL particles and not from its cholesterol content per se. There is now a wealth of evidence from cross-sectional and prospective studies to show that LDL particle size is significantly associated with CHD and predictive of increased coronary risk. Moreover, there are a number of credible mechanisms to link small dense LDL with the atherogenic process. The rate of influx of serum lipoproteins into the arterial wall is a function of particle size, and will thus be more rapid for small dense LDL. Components of the extracellular tissue matrix in the intima, most notably proteoglycans, selectively bind small dense LDL with high affinity, sequestering this lipoprotein in a pro-oxidative environment. The oxidation of LDL promotes the final deposition of cholesterol in the arterial wall, and numerous studies have shown small dense LDL to be more susceptible to oxidative modification than its larger and lighter counterparts. An increase in the number of small dense LDL particles may originate from a defect in the metabolism of triacylglycerol-rich lipoproteins. One mechanism may involve the overproduction and increased residence time of large triacylglycerol-rich VLDL in the postprandial phase, a situation thought to arise through pathways of insulin resistance.

scholarly journals Oxidative Modification of Lipoproteins: A Potential Role of Oxidized Small dense LDL in Enhanced Atherogenicity

2021 ◽  
pp. 118-140
Author(s):  
Mohammed Alsaweed
Keyword(s):  
Arterial Wall ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Predictive Marker ◽  
Oxidative Modification ◽  
Cholesterol Homeostasis ◽  
Low Density ◽  
Small Dense Ldl ◽  
Ldl Particles ◽  
Apoprotein B

Atherosclerosis (AS) is a multifaceted inflammatory syndrome of the arterial wall to which number of mediators have been implicated in lesion progression. Triglyceride (TG)-rich lipoproteins consist of the large diversity of lipoprotein particles that fluctuate in density, size, and apolipoprotein composition. Two foremost phenotypes, on basis of size, chemical configuration, and density, of low-density-lipoprotein (LDL) have been recognized i.e., pattern A, having LDL diameter greater than 25.5nm (large buoyant LDL or lb-LDL) and pattern B, having LDL diameter less than or equal to 25.5nm (small-dense LDL or sd-LDL). Small-dense low-density-lipoprotein (sd-LDL) particles are produced by potential intravascular hydrolysis of TG-rich VLDL particles via lipoprotein lipases (LPLs), hepatic lipases (HLs) and cholesterol ester transfer protein (CETP). sd-LDL is more atherogenic due to its smaller size, increased penetration into the arterial wall, extended plasma half-life, lesser binding affinity for LDL receptors (LDL-R) as well as lower resistance to oxidative stress when equated with lb-LDL. The higher atherogenic potential of sd-LDL is due to its enhanced susceptibility to oxidation, owing to high polyunsaturated fatty acids (PUFA), low cholesterol and Apoprotein B (ApoB) content. An enhanced understanding of sd-LDL metabolism at the molecular level, transport and clearance may result in the development of sd-LDL as an independent predictive marker for AS events and may be used to maintain cholesterol homeostasis and prevent the succession of AS.

scholarly journals Distribution of LDL Particle Size in a Population-Based Sample of Children and Adolescents and Relationship with Other Cardiovascular Risk Factors

2005 ◽  
Vol 51 (7) ◽  
pp. 1192-1200 ◽  
Author(s):  
Simona Stan ◽  
Emile Levy ◽  
Edgard E Delvin ◽  
James A Hanley ◽  
Benoît Lamarche ◽  
...  
Keyword(s):  
Risk Factors ◽  
Particle Size ◽  
Plasma Lipid ◽  
Cvd Risk Factors ◽  
Cvd Risk ◽  
Ldl Particle Size ◽  
Small Dense Ldl ◽  
Ldl Particles ◽  
Ldl Size ◽  
Increased Risk

Abstract Background: Smaller, denser LDL particles are associated with an increased risk for cardiovascular diseases (CVD). In youths, data on the distribution of LDL particle size and on its association with other CVD risk factors are limited. Methods: We determined LDL peak particle size by nondenaturing 2%–16% gradient gel electrophoresis in a representative sample of 2249 youths 9, 13, and 16 years of age who participated in a school-based survey conducted in 1999 in the province of Quebec, Canada. Standardized clinical measurements and fasting plasma lipid, glucose, and insulin concentrations were available. Results: The LDL peak particle size distribution was gaussian. The 5th, 50th (median), and 95th percentiles by age and sex were 255.5–258.6, 262.1–263.2, and 268.1–269.5 Å, respectively. The prevalence of the small, dense LDL phenotype (LDL peak particle size ≤255 Å) was 10% in participants with insulin resistance syndrome (IRS), in contrast to 1% in those without IRS. In a multiple regression analysis, the association of LDL size with other CVD risk factors [apolipoprotein B, HDL-cholesterol (HDL-C), triglyceride (TG), and insulin concentrations, and body mass index] was strongest with TG and HDL-C concentrations: a 1 SD increase in loge-transformed TG concentration was associated with a 1.2 Å reduction in LDL size, and a 1 SD increase in HDL-C was associated with a 1.1 Å increase in LDL size. Conclusions: Although the small, dense LDL phenotype is less prevalent in youths than adults, its prevalence is clearly increased in childhood IRS. Metabolic correlates of LDL size are similar in youths and adults.

Oxidative modification of triacylglycerol-rich lipoproteins

2003 ◽  
Vol 31 (5) ◽  
pp. 1062-1065 ◽  
Author(s):  
I.S. Young ◽  
C. McFarlane ◽  
J. McEneny
Keyword(s):  
Particle Size ◽  
Fatty Acid Composition ◽  
Arterial Wall ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Oxidative Modification ◽  
Low Density ◽  
Lipoprotein Oxidation ◽  
Oxidative Reactions ◽  
Mediated Oxidation

Lipoprotein oxidation is thought to play a pivotal role in the evolution of atherosclerosis. Low-density lipoprotein (LDL) is the main source of oxidized lipid in the arterial wall. Oxidation of LDL alters its properties in a number of ways, making it more atherogenic, but oxidation of other lipoprotein classes may also be important. Common mechanisms are likely to contribute to the oxidation of all lipoprotein classes, with enzyme-mediated oxidation likely to be most important. Antioxidant content, fatty acid composition, particle size and the presence of seeding hydroperoxides also influence oxidative reactions. Larger triglyceride-rich lipoproteins are less likely to enter the arterial wall than LDL, but when oxidized will deliver a greater oxidant load to the arterial wall.

Relevance of hepatic lipase to the metabolism of triacylglycerol-rich lipoproteins

2003 ◽  
Vol 31 (5) ◽  
pp. 1070-1074 ◽  
Author(s):  
A. Zambon ◽  
S. Bertocco ◽  
N. Vitturi ◽  
V. Polentarutti ◽  
D. Vianello ◽  
...  
Keyword(s):  
Arterial Wall ◽  
Disease Risk ◽  
Lipolytic Activity ◽  
Hepatic Lipase ◽  
Heparan Sulphate ◽  
Genetic Regulation ◽  
Density Lipoprotein ◽  
Hepatic Uptake ◽  
Small Dense Ldl ◽  
Ldl Particles

HL (hepatic lipase) is a glycoprotein that is synthesized and secreted by the liver, and which binds to heparan sulphate proteoglycans on the surface of sinusoidal endothelial cells and on the external surface of parenchymal cells in the space of Disse. HL catalyses the hydrolysis of triacylglycerols and phospholipids in different lipoproteins, contributing to the remodelling of VLDL (very-low-density lipoprotein) remnants, as well as IDL, LDL and HDL (intermediate-, low- and high-density lipoprotein respectively). HL deficiency in humans is associated with diminished conversion of VLDL remnants into IDL and a near-complete absence of IDL-to-LDL conversion. Remnant lipoproteins and IDL are major determinants of coronary artery disease risk, and accumulation of these lipoproteins in the presence of low HL activity might lead to increased atherosclerosis. In addition to and independently of its lipolytic activity, HL participates as a ligand in promoting the hepatic uptake of remnants and IDL particles, and the latter may represent an additional mechanism linking low HL levels to plasma accumulation of these atherogenic lipoproteins. On the other hand, high HL activity may also result in an increased atherosclerotic risk by promoting the formation of atherogenic small, dense LDL particles. Finally, HL is also synthesized by human macrophages, suggesting that, at the arterial wall site, HL may also contribute locally to promote atherosclerosis by enhancing the formation and retention in the subendothelial space of the arterial wall of VLDL remnants, IDL and small, dense LDL. In conclusion, by interfering with the metabolism of apolipoprotein B100-containing lipoproteins, HL may have pro- as well as anti-atherogenic effects. The anti- or pro-atherogenic role of HL is likely to be modulated by the concurrent presence of other lipid abnormalities (i.e. LDL-cholesterol levels), as well as by the genetic regulation of other enzymes involved in lipoprotein metabolism.

scholarly journals Arterial Wall Inflammation and Increased Hematopoietic Activity in Patients With Primary Aldosteronism

2019 ◽  
Vol 105 (5) ◽  
pp. e1967-e1980 ◽  
Author(s):  
Charlotte D C C van der Heijden ◽  
Esther M M Smeets ◽  
Erik H J G Aarntzen ◽  
Marlies P Noz ◽  
Houshang Monajemi ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Systemic Inflammation ◽  
Primary Aldosteronism ◽  
Arterial Wall ◽  
Production Capacity ◽  
Cvd Risk ◽  
Cross Sectional ◽  
Bone Marrow Uptake ◽  
Increased Risk ◽  
18F Fdg

Abstract Context Primary aldosteronism (PA) confers an increased risk of cardiovascular disease (CVD), independent of blood pressure. Animal models have shown that aldosterone accelerates atherosclerosis through proinflammatory changes in innate immune cells; human data are scarce. Objective The objective of this article is to explore whether patients with PA have increased arterial wall inflammation, systemic inflammation, and reprogramming of monocytes. Design A cross-sectional cohort study compared vascular inflammation on 2’-deoxy-2’-(18F)fluoro-D-glucose; (18F-FDG) positron emission tomography–computed tomography, systemic inflammation, and monocyte phenotypes and transcriptome between PA patients and controls. Setting This study took place at Radboudumc and Rijnstate Hospital, the Netherlands. Patients Fifteen patients with PA and 15 age-, sex-, and blood pressure-matched controls with essential hypertension (EHT) participated. Main Outcome Measures and Results PA patients displayed a higher arterial 18F-FDG uptake in the descending and abdominal aorta (P < .01, P < .05) and carotid and iliac arteries (both P < .01). In addition, bone marrow uptake was higher in PA patients (P < .05). Although PA patients had a higher monocyte-to-lymphocyte ratio (P < .05), systemic inflammatory markers, cytokine production capacity, and transcriptome of circulating monocytes did not differ. Monocyte-derived macrophages from PA patients expressed more TNFA; monocyte-derived macrophages of healthy donors cultured in PA serum displayed increased interleukin-6 and tumor necrosis factor-α production. Conclusions Because increased arterial wall inflammation is associated with accelerated atherogenesis and unstable plaques, this might importantly contribute to the increased CVD risk in PA patients. We did not observe inflammatory reprogramming of circulating monocytes. However, subtle inflammatory changes are present in the peripheral blood cell composition and monocyte transcriptome of PA patients, and in their monocyte-derived macrophages. Most likely, arterial inflammation in PA requires interaction between various cell types.

scholarly journals Combined effects of a dietary portfolio of plant sterols, vegetable protein, viscous fibre and almonds on LDL particle size

2004 ◽  
Vol 92 (4) ◽  
pp. 657-663 ◽  
Author(s):  
Benoît Lamarche ◽  
Sophie Desroches ◽  
David J. A. Jenkins ◽  
Cyril W. C. Kendall ◽  
Augustine Marchie ◽  
...  
Keyword(s):  
Particle Size ◽  
Blood Lipids ◽  
Saturated Fat ◽  
Plant Sterols ◽  
Ldl Particle Size ◽  
Small Dense Ldl ◽  
Ldl Particles ◽  
Dietary Components ◽  
Dietary Portfolio ◽  
Combined Impact

Studies conducted in the last 20 years have led to the identification of small dense LDL as an important risk factor for CVD. Consumption of plant sterols, soyabean proteins, viscous fibre and nuts are known to modulate the risk of CVD favourably through their cholesterol (Chol)-lowering properties, both independently and more recently in combination. Nevertheless, their combined impact on the LDL particle size phenotype has never been tested. In the present study, we assessed the effect of incorporating concurrently plant sterols (1 g/4·2 MJ), soyabean protein (23 g/4·2 MJ), viscous fibre (9 g/4·2 MJ) and almonds (15 g/4·2 MJ) into a diet very low in saturated fat in twelve patients with mildly elevated plasma LDL-Chol levels. Fasting blood lipids were obtained at the start of the study and at 2-week intervals during the 4-week study. The diet-induced reduction in plasma LDL-Chol of 30·0 (SE 3·0) % (P<0·0001) was attributed to concurrent reductions in the serum Chol concentrations of large (>26.0 nm−30 (SE 8) %,P<0·001), medium (25·5–26·0 nm−29 (SE 3) %,P<0·001) and small (<25·5 nm − 21 (SD 6) %,P<0·01) LDL particles, with near maximal reductions seen by week 2. These results indicate that foods and dietary components advocated for their potential to reduce the risk of CVD are effective in reducing serum concentrations of all LDL fractions including small dense LDL, thus potentially further contributing to an overall lower risk of CVD.

scholarly journals Pathophysiology and clinical significance of atherogenic lipoprotein phenotype and small dense LDL particles

2003 ◽  
Vol 22 (2) ◽  
pp. 101-107 ◽  
Author(s):  
Mirjana Djeric
Keyword(s):  
Serum Cholesterol ◽  
Hdl Cholesterol ◽  
Cholesterol Concentration ◽  
Lipid Transfer ◽  
Serum Triglycerides ◽  
Small Dense Ldl ◽  
Atherogenic Lipoprotein ◽  
Ldl Particles ◽  
Atherogenic Lipoprotein Phenotype ◽  
Lipoprotein Phenotype

In spite of strong proofs supporting cholesterol hypothesis, serum cholesterol concentration is not a good discriminative factor in assessing the risk of coronary heart disease. The degree of reduction of coronary risk depends also on the level of serum triglycerides. Namely, within metabolic disturbance of triglyceride rich lipoproteins, a reciprocal lipid transfer takes place in the course of delipidation cascade, yielding the remodelling of all the classes of lipoproteins and establishing the so-called atherogenic lipoprotein phenotype (increase in triglycerides, small dense LDL, and apolipoprotein B, and decrease in HDL cholesterol and apolipoprotein A-I). A major part of the atherogenic potential of this phenotype is related to the increase in the number of small dense LDL particles (phenotype B), and not because of the contribution to the serum cholesterol, but due to their lower affinity to LDL receptors, easier penetration to arterial intima, longer retention in subendothelium accelerated oxidation, prompt takeover by macrophages and establishing of endothelial dysfunction.

Abstract 538: LDL Particle Core Enrichment in Cholesteryl Oleate Results in Increased Binding to Arterial Wall Proteoglycans and Increased Atherosclerosis

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
John Melchior ◽  
Kathryn Kelley ◽  
Martha Wilson ◽  
Janet Sawyer ◽  
Roy Hantgan ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Arterial Wall ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Surface Characteristics ◽  
Cholesterol Content ◽  
Cholesteryl Oleate ◽  
Size Exclusion ◽  
Apo B ◽  
Ldl Particles

INTRODUCTION: Accumulation of lipids in the artery wall, particularly cholesteryl esters (CE), is a classic feature of atherosclerosis. Apo B-containing lipoprotein particles are the primary vehicles by which CEs are delivered across the endothelial barrier into the intima and once present in the subendothelial space these particles are subject to sequestration by native proteoglycans. Several studies in both non-human primate and murine models of atherosclerosis strongly suggest that core enrichment in cholesteryl oleate of low-density lipoprotein (LDL) particles play a significant role in determination of the extent of atherosclerosis. It has also been shown that Acyl-CoA:cholesterol O-acyltransferase 2 (ACAT2) is the enzyme responsible for cholesteryl oleate enrichment of apo B-containing lipoproteins and gene deletion of ACAT2 in animal models is protective against the development of atherosclerosis. Thus, we hypothesized that the selective accumulation of LDL within the intima is the result of LDL particle core enrichment of cholesteryl oleate that results in modification of key surface characteristics of ApoB promoting interaction with resident proteoglycans. METHODS: Apo B-100 only, LDLr -/- mice (W/T) and Apo B-100 only, LDLr-/-, ACAT2 -/- (KO) mice were fed diets enriched in either cis-monounsaturated fatty acids (cis-MUFA) or n-3 polyunsaturated fatty acids (n-3 PUFA) for 16 weeks. Blood and plasma was harvested and LDL particles were isolated by size exclusion chromatography. The major lipid constituents of the LDL particle were measured along with the fatty acids of the cholesteryl ester fraction of the particle core. LDL affinity to arterial proteoglycans was determined using an immunocapture surface plasmon resonance (SPR) technique we developed. Atherosclerosis was quantified by measuring the cholesterol content of the aorta. RESULTS: W/T mice fed a cis-MUFA diet displayed the highest degree of cholesteryl oleate packaging into the particle core and the highest propensity to bind to arterial proteoglycans. Feeding a diet enriched in n-3 PUFA and/or knocking out ACAT2 successfully inhibited the packaging of cholesteryl oleate into the LDL particles. Accompanying this decrease in cholesteryl oleate content was a significant decrease in binding to arterial proteoglycans and development of atherosclerosis. CONCLUSION: Elimination of cholesteryl oleate from the LDL particle core results in significantly less binding to arterial wall proteoglycans and in turn, less development of atherosclerosis.

scholarly journals The effects of fat consumption on low-density lipoprotein particle size in healthy individuals: a narrative review

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Erik Froyen
Keyword(s):  
Fatty Acids ◽  
Particle Size ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Healthy Individuals ◽  
Cvd Risk ◽  
Small Dense Ldl ◽  
Ldl Particles ◽  
Fat Consumption

AbstractCardiovascular disease (CVD) is the number one contributor to death in the United States and worldwide. A risk factor for CVD is high serum low-density lipoprotein cholesterol (LDL-C) concentrations; however, LDL particles exist in a variety of sizes that may differentially affect the progression of CVD. The small, dense LDL particles, compared to the large, buoyant LDL subclass, are considered to be more atherogenic. It has been suggested that replacing saturated fatty acids with monounsaturated and polyunsaturated fatty acids decreases the risk for CVD. However, certain studies are not in agreement with this recommendation, as saturated fatty acid intake did not increase the risk for CVD, cardiovascular events, and/or mortality. Furthermore, consumption of saturated fat has been demonstrated to increase large, buoyant LDL particles, which may explain, in part, for the differing outcomes regarding fat consumption on CVD risk. Therefore, the objective was to review intervention trials that explored the effects of fat consumption on LDL particle size in healthy individuals. PubMed and Web of Science were utilized during the search process for journal articles. The results of this review provided evidence that fat consumption increases large, buoyant LDL and/or decreases small, dense LDL particles, and therefore, influences CVD risk.

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