Triacylglycerol-rich lipoproteins and the generation of small, dense low-density lipoprotein

2003 ◽  
Vol 31 (5) ◽  
pp. 1066-1069 ◽  
Author(s):  
C.J. Packard
Keyword(s):  
Residence Time ◽  
Hepatic Lipase ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Predisposing Factor ◽  
Small Dense Ldl ◽  
Lipoprotein Class ◽  
Ldl Particles ◽  
Clinical Benefits

LDL (low-density lipoprotein) is the major carrier of cholesterol in human plasma, and as such is intimately involved in the process of atherosclerosis. The lipoprotein class comprises a number of distinct subfractions, and is commonly divided into large, intermediate and small sized particles. Small, dense LDLs are held to be particularly atherogenic, since these particles are retained preferentially by the artery wall, are readily oxidized and carry an enzyme believed to have an important role in atherosclerosis, i.e. lipoprotein-associated phospholipase A2. Generation of small, dense LDL occurs by intravascular lipoprotein remodelling as a result of disturbances such as Type II diabetes, metabolic syndrome, renal disease and pre-eclampsia. The key predisposing factor is the development of hypertriglyceridaemia, in particular elevation in the plasma concentration of large, triacylglycerol-rich VLDL (very-low-density lipoprotein). This leads to the formation of slowly metabolized LDL particles (5-day residence time), which are subject to exchange processes that remove cholesteryl ester from the particle core and replace it with triacylglycerol. LDL, so altered, is a potential substrate for hepatic lipase; if the activity of the enzyme is high enough, lipolysis will generate smaller, denser particles. Correction of the dyslipidaemia associated with small, dense LDL is possible using fibrates and statins, and this may contribute to the clinical benefits seen with these drugs. Fibrates act to lower plasma triacylglycerol (VLDL) levels, and so correct the underlying metabolic disturbance. Statins remove VLDL particles via receptor-mediated pathways and reduce the residence time (and hence limit the potential for remodelling) of LDL in the circulation.

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 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.

Platelet-activating factor acetylhydrolase and transacetylase activities in human plasma low-density lipoprotein

2001 ◽  
Vol 357 (2) ◽  
pp. 457-464 ◽  
Author(s):  
Demokritos C. TSOUKATOS ◽  
Theodoros A. LIAPIKOS ◽  
Alexandros D. TSELEPIS ◽  
M. John CHAPMAN ◽  
Ewa NINIO
Keyword(s):  
Human Plasma ◽  
Low Density Lipoprotein ◽  
Platelet Activating Factor ◽  
Density Lipoprotein ◽  
Biologically Active ◽  
Low Density ◽  
Ether Linkage ◽  
Small Dense Ldl ◽  
Ldl Particles ◽  
Ldl Subfractions

In this study, we demonstrate the presence of a transacetylase activity in human plasma low-density lipoprotein (LDL) that transfers short-chain fatty acids from platelet-activating factor (PAF) and its close ether- and ester-linked analogues to ether/ester-linked lysophospholipids (lyso-PL). We show evidence that both PAF acetylhydrolase (PAF-AH) and transacetylase activities are inhibited to the same extent by serine esterase inhibitors, are resistant to heat treatment, and exhibit identical distributions in lipoprotein classes and in LDL subfractions. Additionally, the competitive inhibition of PAF-AH by lyso-PL, and the evidence that the recombinant PAF-AH also showed a similar transacetylase activity, suggest that PAF-AH is responsible for both activities. Using PAF as a donor molecule and lyso-PAF (1-O-alkyl-sn-glycero-3-phosphocholine) as an acceptor, the transacetylase activity showed typical allosteric kinetics, due to the positive co-operativity of the substrates, with apparent Vmax = 19.6±3.4nmol/min per mg of protein, apparent h = 2.0±0.3 and apparent [S]0.5 = 9.4±2.3μM at saturation for the concentration of lyso-PAF. The substrate specificity of the donor molecules was decreased by increasing the chain length of the acyl moiety in the sn-2 position of the glycerol. The ether linkage in the sn-1 position of the substrate was 30% more effective than the ester bond; cholesteryl acetate was inactive as an acetyl donor. The two acceptors tested, lyso-PAF and the ester-linked lyso-PC (1-acyl-sn-glycero-3-phosphocholine), showed similar specificity. Addition of exogenous lyso-PAF induced the transient formation of PAF-like aggregating activity predominately in small dense LDL subfractions upon oxidation. We conclude that PAF-AH possesses both transacetylase and acetylhydrolase activities which remove PAF and its ether-linked analogues from LDL particles upon LDL oxidation. However, in atherogenic small dense LDL-5 particles, the transacetylase activity may acetylate extracellular lyso-PAF into biologically active PAF.

Intralysosomal Accumulation of Colloidal Gold-Low Density Lipoprotein Conjugates in Chloroquine-Treated Fibroblasts

1985 ◽  
Vol 43 ◽  
pp. 546-547 ◽  
Author(s):  
Dean A. Handley ◽  
Cynthia M. Arbeeny ◽  
Larry D. Witte
Keyword(s):  
Colloidal Gold ◽  
Cultured Cells ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Coated Vesicle ◽  
Low Density ◽  
Cholesterol Esters ◽  
Cultured Fibroblasts ◽  
Surface Receptors ◽  
Ldl Particles

Low density lipoproteins (LDL) are the major cholesterol carrying particles in the blood. Using cultured cells, it has been shown that LDL particles interact with specific surface receptors and are internalized via a coated pit-coated vesicle pathway for lysosomal catabolism. This (Pathway has been visualized using LDL labeled to ferritin or colloidal gold. It is now recognized that certain lysomotropic agents, such as chloroquine, inhibit lysosomal enzymes that degrade protein and cholesterol esters. By interrupting cholesterol ester hydrolysis, chloroquine treatment results in lysosomal accumulation of cholesterol esters from internalized LDL. Using LDL conjugated to colloidal gold, we have examined the ultrastructural effects of chloroquine on lipoprotein uptake by normal cultured fibroblasts.

scholarly journals Aggregation Susceptibility of Low-Density Lipoproteins—A Novel Modifiable Biomarker of Cardiovascular Risk

2021 ◽  
Vol 10 (8) ◽  
pp. 1769
Author(s):  
Katariina Öörni ◽  
Petri T. Kovanen
Keyword(s):  
Ex Vivo ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Atherosclerotic Cardiovascular Disease ◽  
Low Density ◽  
Cholesterol Crystals ◽  
Ldl Particles ◽  
Arterial Intima ◽  
Matrix Bound ◽  
Atherosclerotic Cardiovascular Diseases

Circulating low-density lipoprotein (LDL) particles enter the arterial intima where they bind to the extracellular matrix and become modified by lipases, proteases, and oxidizing enzymes and agents. The modified LDL particles aggregate and fuse into larger matrix-bound lipid droplets and, upon generation of unesterified cholesterol, cholesterol crystals are also formed. Uptake of the aggregated/fused particles and cholesterol crystals by macrophages and smooth muscle cells induces their inflammatory activation and conversion into foam cells. In this review, we summarize the causes and consequences of LDL aggregation and describe the development and applications of an assay capable of determining the susceptibility of isolated LDL particles to aggregate when exposed to human recombinant sphingomyelinase enzyme ex vivo. Significant person-to-person differences in the aggregation susceptibility of LDL particles were observed, and such individual differences largely depended on particle lipid composition. The presence of aggregation-prone LDL in the circulation predicted future cardiovascular events in patients with atherosclerotic cardiovascular disease. We also discuss means capable of reducing LDL particles’ aggregation susceptibility that could potentially inhibit LDL aggregation in the arterial wall. Whether reductions in LDL aggregation susceptibility are associated with attenuated atherogenesis and a reduced risk of atherosclerotic cardiovascular diseases remains to be studied.

scholarly journals Pemafibrate decreases triglycerides and small, dense LDL, but increases LDL-C depending on baseline triglycerides and LDL-C in type 2 diabetes patients with hypertriglyceridemia: an observational study

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Ichiro Komiya ◽  
Akira Yamamoto ◽  
Suguru Sunakawa ◽  
Tamio Wakugami
Keyword(s):  
Type 2 Diabetes ◽  
Disease Risk ◽  
Direct Method ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Density ◽  
Small Dense Ldl ◽  
Group I ◽  
Diabetes Patients

Abstract Background Pemafibrate, a selective PPARα modulator, has the beneficial effects on serum triglycerides (TGs) and very low density lipoprotein (VLDL), especially in patients with diabetes mellitus or metabolic syndrome. However, its effect on the low density lipoprotein cholesterol (LDL-C) levels is still undefined. LDL-C increased in some cases together with a decrease in TGs, and the profile of lipids, especially LDL-C, during pemafibrate administration was evaluated. Methods Pemafibrate was administered to type 2 diabetes patients with hypertriglyceridemia. Fifty-one type 2 diabetes patients (mean age 62 ± 13 years) with a high rate of hypertension and no renal insufficiency were analyzed. Pemafibrate 0.2 mg (0.1 mg twice daily) was administered, and serum lipids were monitored every 4–8 weeks from 8 weeks before administration to 24 weeks after administration. LDL-C was measured by the direct method. Lipoprotein fractions were measured by electrophoresis (polyacrylamide gel, PAG), and LDL-migration index (LDL-MI) was calculated to estimate small, dense LDL. Results Pemafibrate reduced serum TGs, midband and VLDL fractions by PAG. Pemafibrate increased LDL-C levels from baseline by 5.3% (− 3.8–19.1, IQR). Patients were divided into 2 groups: LDL-C increase of > 5.3% (group I, n = 25) and < 5.3% (group NI, n = 26) after pemafibrate. Compared to group NI, group I had lower LDL-C (2.53 [1.96–3.26] vs. 3.36 [3.05–3.72] mmol/L, P = 0.0009), higher TGs (3.71 [2.62–6.69] vs. 3.25 [2.64–3.80] mmol/L), lower LDL by PAG (34.2 [14.5, SD] vs. 46.4% [6.5], P = 0.0011), higher VLDL by PAG (28.2 [10.8] vs. 22.0% [5.2], P = 0.0234), and higher LDL-MI (0.421 [0.391–0.450] vs. 0.354 [0.341–0.396], P < 0.0001) at baseline. Pemafibrate decreased LDL-MI in group I, and the differences between the groups disappeared. These results showed contradictory effects of pemafibrate on LDL-C levels, and these effects were dependent on the baseline levels of LDL-C and TGs. Conclusions Pemafibrate significantly reduced TGs, VLDL, midband, and small, dense LDL, but increased LDL-C in diabetes patients with higher baseline TGs and lower baseline LDL-C. Even if pre-dose LDL-C remains in the normal range, pemafibrate improves LDL composition and may reduce cardiovascular disease risk.

scholarly journals Long-term fasting improves lipoprotein-associated atherogenic risk in humans

2021 ◽  
Author(s):  
Franziska Grundler ◽  
Dietmar Plonné ◽  
Robin Mesnage ◽  
Diethard Müller ◽  
Cesare R. Sirtori ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Plasma Lipid ◽  
Density Lipoprotein ◽  
Apolipoprotein A1 ◽  
Health Concern ◽  
Low Density ◽  
Lipoprotein Subclasses ◽  
Ldl Particles ◽  
Increased Risk

Abstract Purpose Dyslipidemia is a major health concern associated with an increased risk of cardiovascular mortality. Long-term fasting (LF) has been shown to improve plasma lipid profile. We performed an in-depth investigation of lipoprotein composition. Methods This observational study included 40 volunteers (50% men, aged 32–65 years), who underwent a medically supervised fast of 14 days (250 kcal/day). Changes in lipid and lipoprotein levels, as well as in lipoprotein subclasses and particles, were measured by ultracentrifugation and nuclear magnetic resonance (NMR) at baseline, and after 7 and 14 fasting days. Results The largest changes were found after 14 fasting days. There were significant reductions in triglycerides (TG, − 0.35 ± 0.1 mmol/L), very low-density lipoprotein (VLDL)-TG (− 0.46 ± 0.08 mmol/L), VLDL-cholesterol (VLDL-C, − 0.16 ± 0.03 mmol/L) and low-density lipoprotein (LDL)-C (− 0.72 ± 0.14 mmol/L). Analysis of LDL subclasses showed a significant decrease in LDL1-C (− 0.16 ± 0.05 mmol/L), LDL2-C (− 0.30 ± 0.06 mmol/L) and LDL3-C (− 0.27 ± 0.05 mmol/L). NMR spectroscopy showed a significant reduction in large VLDL particles (− 5.18 ± 1.26 nmol/L), as well as large (− 244.13 ± 39.45 nmol/L) and small LDL particles (− 38.45 ± 44.04 nmol/L). A significant decrease in high-density lipoprotein (HDL)-C (− 0.16 ± 0.04 mmol/L) was observed. By contrast, the concentration in large HDL particles was significantly raised. Apolipoprotein A1 decreased significantly whereas apolipoprotein B, lipoprotein(a), fibrinogen and high-sensitivity C-reactive protein were unchanged. Conclusion Our results suggest that LF improves lipoprotein levels and lipoprotein subclasses and ameliorates the lipoprotein-associated atherogenic risk profile, suggesting a reduction in the cardiovascular risk linked to dyslipidemia. Trial Registration Study registration number: DRKS-ID: DRKS00010111 Date of registration: 03/06/2016 “retrospectively registered”.

scholarly journals Markedly Increased Small Dense Low-Density Lipoprotein During Acute Phase in Childhood and Adolescent Nephrotic Syndrome

2020 ◽  
Author(s):  
Keisuke Sugimoto ◽  
Kohei Miyazaki ◽  
Takuji Enya ◽  
Tomoki Miyazawa ◽  
Yuichi Morimoto ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Acute Phase ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Profiles ◽  
Atherogenic Index ◽  
Childhood And Adolescence ◽  
Low Density ◽  
Ldl Particles ◽  
Initial Onset

Abstract Background: Hyperlipidemia is an important characteristic feature of idiopathic nephrotic syndrome (NS) in children. This study was conducted to examine the lipid profiles, including small dense low-density lipoprotein (sdLDL-C), in childhood-onset NS.Methods: This retrospective study enrolled patients diagnosed with initial-onset NS in childhood and adolescence. Study parameters included lipid profiles. The “alternative LDL window” comprises the number and sizes of LDL particles estimated according to non-HDL-C and TG levels.Results: A total of 39 patients were enrolled who exhibited markedly increased lipid abnormalities, including TC, TG, LDL-C, and non-HDL-C levels (TC, 409.7 TC, TG, and sizes of LDL particles estimated as non-HDL-C, 332.3). Of the 39 patients, 32 (82%) were categorized in the area of hyper-TG/-non-HDL levels, which is considered as sdLDL. A positive correlation was found between non-HDL-C and TC (r = 0.96, P < 0.001), TG (r = 0.38, P = 0.018), LDL-C (r = 0.84, P < 0.001), TC/HDL (r = 0.53, P < 0.001), and atherogenic index of plasma (r = 0.42, P = 0.008).Conclusions: Our study demonstrated markedly increased lipid profiles during the acute phase of NS. Evaluation of lipid profiles using the “alternative LDL window” may help understand the state of hyperlipidemia in NS.

Abstract 566: MicroRNA-146a Deficiency Prevents PCSK9 Gain-of-Function Mutation-induced Hypercholesterolemia in Mice

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Shayan Mohammadmoradi ◽  
Aida Javidan ◽  
Weihua Jiang ◽  
Jessica Moorleghen ◽  
Venkateswaran Subramanian
Keyword(s):  
Plasma Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Western Diet ◽  
Size Exclusion ◽  
Gel Chromatography ◽  
Low Density ◽  
Distribution Analysis ◽  
Gain Of Function ◽  
Ldl Particles

Background and Objective: Mimetic mediated activation of microRNA 146a (miR-146a) reduces atherosclerosis via suppression of nuclear factor-κB-driven inflammation in mice. The purpose of this study was to determine whether miR-146a influences plasma cholesterol in hypercholesterolemic mice. Methods and Results: To induce hypercholesterolemia, female C57BL/6 miR-146a WT (n=8) and miR-146a KO (n=8) mice were injected intraperitoneally with an adeno-associated viral vector (AAV) expressing the proprotein convertase subtilisin/kexin type 9 (PSCK9 D377Y) gain-of-function mutant at a dose of 3 x 10 10 genomic copies/mouse. After infection, mice were fed a Western diet (21% wt/wt milk fat; 0.15% wt/wt cholesterol) for sixteen weeks, and plasma PCSK9 and total cholesterol concentrations were monitored monthly using an enzymatic assay. Plasma PCSK9 concentrations were profoundly increased 4 weeks post injection (Baseline: WT - 179 ± 12 vs KO - 207 ± 12; Week 4: WT - 1700 ± 148 vs KO - 2689 ± 305 ng/ml) and remained significantly high during 16 weeks (WT - 882 ± 142 vs KO - 718 ± 109 ng/ml; p<0.05 vs baseline) of Western diet feeding. Consistent with increased plasma PCSK9 concentrations, plasma cholesterol concentrations were increased in both groups of mice. Interestingly, miR-146a KO group mice showed less significant increase in plasma cholesterol compared to WT group (Baseline: WT - 88 ± 3 vs KO - 83 ± 3; Week 4: WT - 328 ± 25 vs KO - 195 ± 18 mg/dl) irrespective of the comparable plasma PCSK9 concentrations. Also, lipoprotein distribution analysis with size exclusion gel chromatography revealed that miR-146a KO mice showed a strong reduction in high density lipoprotein (HDL) particles while very low density lipoprotein (VLDL) and low density lipoprotein (LDL) particles were not affected. Conclusion: Our findings suggests that miR146a plays a critical role in the regulation of HDL particles in PCSK9 gain-of-function mutant-induced hypercholesterolemia in mice. Future studies will identify gene targets influenced by miR-146a in regulating HDL-cholesterol in hypercholesterolemic mice.

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