scholarly journals 4-oxo-2-nonenal Adducts In HDL Are Elevated In Familial Hypercholesterolemia: Identification Of Modified Sites And Functional Consequences

2019 ◽  
Author(s):  
Linda S. May-Zhang ◽  
Valery Yermalitsky ◽  
John T. Melchior ◽  
Jamie Morris ◽  
Keri A. Tallman ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Fatty Acids ◽  
Familial Hypercholesterolemia ◽  
Cholesterol Efflux ◽  
Density Lipoprotein ◽  
Healthy Controls ◽  
Reactive Protein ◽  
Macrophage Cholesterol Efflux ◽  
Hdl Dysfunction ◽  
Functional Consequences

ABSTRACTThe lipid aldehyde 4-oxo-2-nonenal (ONE) derived from peroxidation of n-6 polyunsaturated fatty acids and generated in parallel to 4-hydroxynonenal (HNE) is a highly reactive protein crosslinker. Crosslinking of proteins in high-density lipoprotein (HDL) by lipid peroxidation products causes HDL dysfunction and contributes to atherogenesis. While HNE is relatively well studied, the relevance of ONE in atherosclerosis and in modifying HDL has not been examined. In the present study, we found a significant increase in ONE-ketoamide (lysine) adducts in HDL derived from patients with familial hypercholesterolemia (FH) (1620 ± 985.4 pmol/mg) compared to healthy controls (664 ± 219.5 pmol/mg). ONE crosslinked apoA-I on HDL at a concentration of >3 mol ONE per 10 mol apoA-I (0.3 eq), which is 100-fold lower than HNE but comparable to the potent protein crosslinker, isolevuglandin. ONE-modified HDL partially inhibited the ability of HDL to protect against LPS-induced TNFα and IL-1β mRNA expression in murine macrophages. At 3 eq., ONE dramatically decreased the ability of apoA-I to exchange from HDL, from ~46.5% to only ~18.4% (P<0.001). Surprisingly, ONE-modification of HDL or apoA-I did not alter macrophage cholesterol efflux capacity. LC/MS/MS analysis showed modification of Lys12, Lys23, Lys96, and Lys226 of apoA-I by ONE-ketoamide adducts. Compared to other dicarbonyl scavengers, pentylpyridoxamine (PPM) was most efficacious at blocking ONE-induced protein crosslinking in HDL. Our studies show that ONE HDL adducts are elevated in FH who have severe hypercholesterolemia and atherosclerosis and causes HDL dysfunction. We demonstrate the use of PPM in preferentially scavenging ONE in biological systems.

Abstract 43: Cholesterol Efflux Pathways Suppress Inflammasome Activation in Mice and Humans

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Marit Westerterp ◽  
Panagiotis Fotakis ◽  
Mireille Ouimet ◽  
Andrea E Bochem ◽  
Hanrui Zhang ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Cholesterol Efflux ◽  
Foam Cell ◽  
Cell Formation ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Inflammasome Activation ◽  
Loss Of Function ◽  
Caspase 1 ◽  
Macrophage Cholesterol Efflux

Plasma high-density-lipoprotein (HDL) has several anti-atherogenic properties, including its key role in functioning as acceptor for ATP-binding cassette A1 and G1 (ABCA1 and ABCG1) mediated cholesterol efflux. We have shown previously that macrophage Abca1/g1 deficiency accelerates atherosclerosis, by enhancing foam cell formation and inflammatory cytokine expression in atherosclerotic plaques. Macrophage cholesterol accumulation activates the inflammasome, leading to caspase-1 cleavage, required for IL-1β and IL-18 secretion. Several studies have suggested that inflammasome activation accelerates atherogenesis. We hypothesized that macrophage Abca1/g1 deficiency activates the inflammasome. In Ldlr -/- mice fed a Western type diet (WTD), macrophage Abca1/g1 deficiency increased IL-1β and IL-18 plasma levels (2-fold; P <0.001), and induced caspase-1 cleavage. Deficiency of the inflammasome components Nlrp3 or caspase-1 in macrophage Abca1/g1 knockouts reversed the increase in plasma IL-18 levels ( P <0.001), indicating these changes were inflammasome dependent. We found that macrophage Abca1/g1 deficiency induced caspase-1 cleavage in splenic CD115 + monocytes and CD11b + macrophages. While mitochondrial ROS production or lysosomal function were not affected, macrophage Abca1/g1 deficiency led to an increased splenic population of monocytes (2.5-fold; P <0.01). Monocytes secrete ATP, and as a result, ATP secretion from total splenic cells was increased (2.5-fold; P <0.01), likely contributing to inflammasome activation. Caspase-1 deficiency decreased atherosclerosis in macrophage Abca1/g1 deficient Ldlr -/- mice fed WTD for 8 weeks (225822 vs 138606 μm 2 ; P <0.05). Of therapeutic interest, one injection of reconstituted HDL (100 mg/kg) in macrophage Abca1/g1 knockouts decreased plasma IL-18 levels ( P <0.05). Tangier disease patients, with a homozygous loss-of-function for ABCA1, showed increased IL-1β and IL-18 plasma levels (3-fold; P <0.001), suggesting that cholesterol efflux pathways also suppress inflammasome activation in humans. These findings suggest that macrophage cholesterol efflux pathways suppress inflammasome activation, possibly contributing to the anti-atherogenic effects of HDL treatment.

scholarly journals Electronic and Tobacco Cigarettes Alter Polyunsaturated Fatty Acids and Oxidative Biomarkers

2021 ◽  
Author(s):  
Rajat Gupta ◽  
Yan Lin ◽  
Karla Luna ◽  
Anjali Logue ◽  
Alexander J Yoon ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Fatty Acids ◽  
Cardiovascular Risk ◽  
Polyunsaturated Fatty Acids ◽  
Low Density Lipoprotein ◽  
Plasma Concentrations ◽  
Multivariable Analysis ◽  
Plasma Lipid ◽  
Density Lipoprotein ◽  
Heme Oxygenase 1

Rationale: Chronic electronic cigarette (EC) users exhibit a higher susceptibility of low-density lipoprotein (LDL) to undergo oxidation as compared to non-user controls. However, there is a paucity of data regarding EC effects on lipid peroxidation in the blood and their relationship to cardiovascular risk. Objective: To test the hypothesis that chronic (≥1 year) EC use exerts intermediate effects on plasma lipid peroxidation and/or antioxidant defense compared to chronic tobacco cigarette (TC) smoking. Methods and Results: We enrolled EC-users (n=32), TC-smokers (n=29) and non-users (n=45), with mean ages of 28.3, 27.8 and 27.4 years, respectively. Plasma concentrations of free polyunsaturated fatty acids and oxidized metabolites were assessed by mass spectrometry. Total antioxidant capacity (TAC), concentrations of glutathione, bilirubin, heme oxygenase-1 (HO-1), and functional activity of paraoxonase1 (PON1) were determined by colorimetric and enzymatic assays. Multivariable analysis was performed using classification models for segregating participants based on biomarker profiles. Plasma arachidonic acid (AA) concentration was higher in TC-smokers but lower in EC-users, together with linoleic acid (LA) concentration, as compared to TC-smokers and non-users (p<0.05). Oxidized LA metabolites (9- and 13-hydroxyoctadecadienoic acid (HODE)) were lower in EC-users and TC-smokers as compared to non-users (p<0.001). Consistently, TAC and bilirubin were elevated in EC-users and TC-smokers as compared to non-users (p<0.05). Of interest, plasma HO-1 concentration was higher in TC-smokers as compared to non-users (p=0.01) with intermediate levels in EC-users. Multivariable analysis identified 5 biomarkers (13-HODE, LA, 9-HODE, 12-hydroxyeicosatetraenoic acid (HETE), AA) that discriminated EC-users from TC-smokers and non-users with an accuracy of 73.4%. Conclusions: Chronic use of EC induces common (i.e. lower 9- and/or 13-HODEs and higher TAC and bilirubin) as well as differential effects (i.e. altered AA and LA concentrations) to those induced by TC, along with intermediate plasma HO-1 concentration, suggesting that EC, likewise TC smoke, could impact cardiovascular risk.

scholarly journals Diet and Cardiovascular Disease Risk Among Individuals with Familial Hypercholesterolemia: Systematic Review and Meta-Analysis

2020 ◽  
Author(s):  
Fotios Barkas ◽  
Tzortzis Nomikos ◽  
Evangelos Liberopoulos ◽  
Demosthenes Panagiotakos
Keyword(s):  
Fatty Acids ◽  
Familial Hypercholesterolemia ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Plant Sterols ◽  
Low Density ◽  
Omega 3 Fatty Acids ◽  
Omega 3 ◽  
Low Density Lipoprotein Cholesterol ◽  
Cholesterol Lowering

Background: Although a cholesterol-lowering diet and the addition of plant sterols and stanols are suggested for the lipid management of children and adults with familial hypercholesterolemia, there is limited evidence evaluating such interventions in this population. Objectives: To investigate the impact of cholesterol-lowering diet and other dietary interventions on the incidence or mortality of cardiovascular disease and lipid profile of patients with familial hypercholesterolemia. Search methods: Relevant trials were identified by searching US National Library of Medicine National Institutes of Health Metabolism Trials Register and clinicaltrials.gov.gr using the following terms: diet, dietary, plant sterols, stanols, omega-3 fatty acids, fiber and familial hypercholesterolemia. Selection criteria: Randomized controlled trials evaluating the effect of cholesterol-lowering diet or other dietary interventions in children and adults with familial hypercholesterolemia were included. Data collection and analysis: Two authors independently assessed the trial eligibility and bias risk and one extracted the data, with independent verification of data extraction by a colleague. Results: A total of 17 trials were finally included, with a total of 376 participants across 8 comparison groups. The included trials had either a low or unclear bias risk for most of the parameters used for risk assessment. Cardiovascular incidence or mortality were not evaluated in any of the included trials. Among the planned comparisons regarding patients&rsquo; lipidemic profile, a significant difference was noticed for the following comparisons and outcomes: omega-3 fatty acids reduced triglycerides (mean difference [MD]: -0.27 mmol/L, 95% confidence interval [CI]: -0.47 to -0.07, p&lt;0.01) when compared with placebo. A non-significant trend towards a reduction in subjects&rsquo; total cholesterol (MD: -0.34, 95% CI: -0.68 to 0, mmol/L, p=0.05) and low-density lipoprotein cholesterol (MD: -0.31, 95% CI: -0.61 to 0, mmol/L, p=0.05) was noticed. In comparison with cholesterol-lowering diet, the additional consumption of plant stanols decreased total cholesterol (MD: -0.62 mmol/l, 95% CI: -1.13 to -0.11, p=0.02) and low-density lipoprotein cholesterol (MD: -0.58 mmol/l, 95% CI: -1.08 to -0.09, p=0.02). The same was by plant sterols (MD: -0.46 mmol/l, 95% CI: -0.76 to -0.17, p&lt;0.01 for cholesterol, and MD: -0.45 mmol/l, 95% CI: -0.74 to -0.16, p&lt;0.01 for low-density lipoprotein cholesterol). No heterogeneity was noticed among the studies included in these analyses. Conclusions: Available trials confirm that the addition of plant sterols or stanols has a cholesterol-lowering effect on such individuals. On the other hand, supplementation with omega-3 fatty acids effectively reduces triglycerides and might have a role in lowering the cholesterol of patients with familial hypercholesterolemia. Additional studies are needed to investigate the effectiveness of a cholesterol-lowering diet or the addition of soya protein and dietary fibers to a cholesterol-lowering diet in familial hypercholesterolemia.

scholarly journals Cholesterol Efflux Capacity and Cardiovascular Disease: The Ludwigshafen Risk and Cardiovascular Health (LURIC) Study

Biomedicines ◽  
2020 ◽  
Vol 8 (11) ◽  
pp. 524
Author(s):  
Andreas Ritsch ◽  
Angela Duerr ◽  
Patrick Kahler ◽  
Monika Hunjadi ◽  
Tatjana Stojakovic ◽  
...  
Keyword(s):  
Coronary Angiography ◽  
Cardiovascular Mortality ◽  
Cholesterol Efflux ◽  
Cardiovascular Health ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Reactive Protein ◽  
Amyloid A ◽  
Artery Disease

(1) Background and Aims: Efforts to reduce coronary artery disease (CAD) by raising high-density lipoprotein (HDL) cholesterol (HDL-C) have not been uniformly successful. A more important factor than HDL-C may be cellular cholesterol efflux mediated by HDL, which has been shown to be associated with CAD. In this report, we analyzed the influence of cardiovascular biomarkers and risk factors on cholesterol efflux in a prospective observational study of patients referred to coronary angiography. (2) Methods: HDL-mediated efflux capacity was determined for 2468 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study who were referred to coronary angiography at baseline between 1997 and 2000. Median follow-up time was 9.9 years. Primary and secondary endpoints were cardiovascular and all-cause mortality, respectively. (3) Results: Cholesterol efflux strongly correlated with HDL-related markers including HDL cholesterol, HDL phospholipids, and apolipoproteins AI and AII, as well as HDL particle concentration, which was not seen for low density lipoprotein (LDL) markers including LDL cholesterol and apoB. Cholesterol efflux was associated negatively with C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6), and serum amyloid A. Cardiovascular mortality was higher in patients in the lowest cholesterol efflux quartile. This association was weakened, but not fully abolished, after adjustment for HDL cholesterol. (4) Conclusions: We demonstrate that cholesterol efflux was associated with HDL-composition as well as inflammatory burden in patients referred for coronary angiography, and that this inversely predicts cardiovascular mortality independently of HDL cholesterol.

scholarly journals LDL Receptor Regulates the Reverse Transport of Macrophage-Derived Unesterified Cholesterol via Concerted Action of the HDL-LDL Axis

2020 ◽  
Vol 127 (6) ◽  
pp. 778-792 ◽  
Author(s):  
Lídia Cedó ◽  
Jari Metso ◽  
David Santos ◽  
Annabel García-León ◽  
Núria Plana ◽  
...  
Keyword(s):  
Familial Hypercholesterolemia ◽  
Cholesterol Efflux ◽  
Culture Media ◽  
Critical Role ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Fecal Excretion ◽  
Unesterified Cholesterol ◽  
Cholesterol Efflux Capacity

Rationale: The HDL (high-density lipoprotein)-mediated stimulation of cellular cholesterol efflux initiates macrophage-specific reverse cholesterol transport (m-RCT), which ends in the fecal excretion of macrophage-derived unesterified cholesterol (UC). Early studies established that LDL (low-density lipoprotein) particles could act as efficient intermediate acceptors of cellular-derived UC, thereby preventing the saturation of HDL particles and facilitating their cholesterol efflux capacity. However, the capacity of LDL to act as a plasma cholesterol reservoir and its potential impact in supporting the m-RCT pathway in vivo both remain unknown. Objective: We investigated LDL contributions to the m-RCT pathway in hypercholesterolemic mice. Methods and Results: Macrophage cholesterol efflux induced in vitro by LDL added to the culture media either alone or together with HDL or ex vivo by plasma derived from subjects with familial hypercholesterolemia was assessed. In vivo, m-RCT was evaluated in mouse models of hypercholesterolemia that were naturally deficient in CETP (cholesteryl ester transfer protein) and fed a Western-type diet. LDL induced the efflux of radiolabeled UC from cultured macrophages, and, in the simultaneous presence of HDL, a rapid transfer of the radiolabeled UC from HDL to LDL occurred. However, LDL did not exert a synergistic effect on HDL cholesterol efflux capacity in the familial hypercholesterolemia plasma. The m-RCT rates of the LDLr (LDL receptor)-KO (knockout), LDLr-KO/APOB100, and PCSK9 (proprotein convertase subtilisin/kexin type 9)-overexpressing mice were all significantly reduced relative to the wild-type mice. In contrast, m-RCT remained unchanged in HAPOB100 Tg (human APOB100 transgenic) mice with fully functional LDLr, despite increased levels of plasma APO (apolipoprotein)-B–containing lipoproteins. Conclusions: Hepatic LDLr plays a critical role in the flow of macrophage-derived UC to feces, while the plasma increase of APOB-containing lipoproteins is unable to stimulate m-RCT. The results indicate that, besides the major HDL-dependent m-RCT pathway via SR-BI (scavenger receptor class B type 1) to the liver, a CETP-independent m-RCT path exists, in which LDL mediates the transfer of cholesterol from macrophages to feces. Graphical Abstract: A graphical abstract is available for this article.

Cholesterol Efflux Effect of High Density Lipoprotein is Impaired by Whole Cigarette Smoke Extracts Through Lipid Peroxidation

1998 ◽  
Vol 24 (1) ◽  
pp. 182-190 ◽  
Author(s):  
Kazuhisa Ueyama ◽  
Masayuki Yokode ◽  
Hidenori Arai ◽  
Yutaka Nagano ◽  
Li Zhi-Xiang ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
High Density Lipoprotein ◽  
Cigarette Smoke ◽  
Cholesterol Efflux ◽  
Density Lipoprotein ◽  
High Density

Statin-treated familial hypercholesterolemia patients with coronary heart disease and pronounced atherosclerosis do not have more brain lesions than healthy controls in later middle age

2007 ◽  
Vol 48 (8) ◽  
pp. 894-899 ◽  
Author(s):  
S. Soljanlahti ◽  
R. Raininko ◽  
L. Hyttinen ◽  
K. Lauerma ◽  
P. Keto ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Familial Hypercholesterolemia ◽  
Mr Angiography ◽  
Small Vessel Disease ◽  
Brain Mri ◽  
Density Lipoprotein ◽  
Brain Lesions ◽  
Healthy Controls ◽  
Increased Risk

Background: Clinically silent brain lesions detected with magnetic resonance imaging (MRI) are associated with increased risk for stroke, while stroke risk is controversial in familial hypercholesterolemia (FH). Purpose: To determine whether the occurrence and size of clinically silent brain lesions in FH patients with coronary heart disease (CHD) is higher than in neurologically healthy controls without CHD. Material and Methods: Brain MRI (1.5T) was performed on 19 DNA-test-verified FH patients with CHD and on 29 cardiovascularly and neurologically healthy controls, all aged 48 to 64 years. All patients were on cardiovascular medication. Intracranial arteries were evaluated by MR angiography. Infarcts, including lacunas, and white matter T2 hyperintensities (WMHI), considered as signs of small vessel disease, were recorded. A venous blood sample was obtained for assessment of risk factors. Carotid and femoral intima-media thicknesses (IMT), assessed with ultrasound, were indicators of overall atherosclerosis. Results: On intracranial MR angiography, three patients showed irregular walls or narrowed lumens in intracranial carotid arteries. No silent infarcts appeared, and no differences in numbers or sizes of WMHIs between groups were recorded. Patients had greater carotid and femoral IMTs, and a greater number of carotid and femoral plaques. Cholesterol-years score, level of low-density lipoprotein (LDL) cholesterol, and level of high-sensitivity C-reactive protein (hsCRP) of the FH-North Karelia patients were higher than those of the controls, while the level of high-density lipoprotein (HDL) cholesterol in controls was higher. Conclusion: FH patients with CHD and adequate cardiovascular risk-factor treatment showed no difference in the amount or size of clinically silent brain lesions compared to controls, despite patients' more severe atherosclerosis.

scholarly journals Olive oil containing olive oil fatty acid esters of plant sterols and dietary diacylglycerol reduces low-density lipoprotein cholesterol and decreases the tendency for peroxidation in hypercholesterolaemic subjects

2007 ◽  
Vol 98 (3) ◽  
pp. 563-570 ◽  
Author(s):  
Yen-Ming Chan ◽  
Isabelle Demonty ◽  
Dori Pelled ◽  
Peter J. H. Jones
Keyword(s):  
Lipid Peroxidation ◽  
Fatty Acids ◽  
Lipid Profile ◽  
Olive Oil ◽  
Plasma Lipid ◽  
Density Lipoprotein ◽  
Plant Sterols ◽  
Fatty Acid Esters ◽  
Blood Lipid Profile ◽  
Apo B

Plant sterols (PS) and MUFA are well-documented cholesterol lowering agents. We aimed to determine the effect of PS esterified to olive oil fatty acids (PS-OO) on blood lipid profile and lipid peroxidation in hypercholesterolaemic subjects. Twenty-one moderately overweight, hypercholesterolaemic subjects consumed three consecutive treatment diets, each lasting 28 d and separated by 4-week washout periods, using a randomized crossover design. Diets contained 30 % energy as fat, 70 % of which was provided by olive oil (OO), and differed only in the treatment oils: OO, PS esterified to sunflower oil fatty acids (PS-SO), and PS-OO. Both PS-SO and PS-OO treatments provided 1·7 g PS /d. PS-OO and PS-SO consumption resulted in a decrease (P = 0·0483) in LDL-cholesterol (LDL-C) concentrations compared with the OO diet. Although total cholesterol and apo B-100 levels were not significantly affected, PS-SO and, to some extent, PS-OO reduced the total:HDL-cholesterol (HDL-C) ratio (P = 0·0142) and the apo B-100:apo A-I ratio (P = 0·0168) compared with the OO diet. There were no differences across diets in lipoprotein(a) (Lp(a)) and lipid peroxidation levels. However, following consumption of OO and PS-SO, Lp(a) concentrations increased (P = 0·0050 and 0·0421, respectively), while PS-OO treatment did not affect Lp(a) levels. Furthermore, there was a decrease (P = 0·0097) in lipid peroxidation levels with PS-OO treatment during the supplementation phase. Our results suggest that supplementing an OO-rich diet with PS-OO favourably alters the plasma lipid profile and may decrease the susceptibility of LDL-C to lipid peroxidation in hypercholesterolaemic subjects.

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