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1.
The Role of Halogenative Stress in Atherogenic Modification of Low-Density Lipoproteins.
Panasenko, OM, Torkhovskaya, TI, Gorudko, IV, Sokolov, AV
Biochemistry. Biokhimiia. 2020;(Suppl 1):S34-S55
Abstract
This review discusses formation of reactive halogen species (RHS) catalyzed by myeloperoxidase (MPO), an enzyme mostly present in leukocytes. An imbalance between the RHS production and body's ability to remove or neutralize them leads to the development of halogenative stress. RHS reactions with proteins, lipids, carbohydrates, and antioxidants in the content of low-density lipoproteins (LDLs) of the human blood are described. MPO binds site-specifically to the LDL surface and modifies LDL properties and structural organization, which leads to the LDL conversion into proatherogenic forms captured by monocytes/macrophages, which causes accumulation of cholesterol and its esters in these cells and their transformation into foam cells, the basis of atherosclerotic plaques. The review describes the biomarkers of MPO enzymatic activity and halogenative stress, as well as the involvement of the latter in the development of atherosclerosis.
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2.
Lipoprotein(a): is it more, less or equal to LDL as a causal factor for cardiovascular disease and mortality?
Langsted, A, Nordestgaard, BG
Current opinion in lipidology. 2020;(3):125-131
Abstract
PURPOSE OF REVIEW To summarize the recent studies directly comparing LDL and lipoprotein(a) as causal factors for cardiovascular disease and mortality. RECENT FINDINGS In approximately 100,000 individuals from the Copenhagen General Population Study for risk of myocardial infarction, in observational analyses per 39 mg/dl (1 mmol/l) cholesterol increase, the hazard ratio was 1.3 (95% confidence interval: 1.2-1.3) for LDL cholesterol and 1.6 (1.4-1.9) for lipoprotein(a) cholesterol. In corresponding genetic analyses, the causal risk ratio was 2.1 (1.3-3.4) for LDL and 2.0 (1.6-2.6) for lipoprotein(a). Also, a 15 mg/dl (0.39 mmol/l) cholesterol increase was associated with a hazard ratio for cardiovascular mortality of 1.05 (1.04-1.07) for LDL cholesterol and 1.18 (1.12-1.25) for lipoprotein(a) cholesterol. Corresponding values for all-cause mortality were 1.01 (1.00-1.01) for LDL cholesterol and 1.07 (1.04-1.10) for lipoprotein(a) cholesterol. In genetic, causal analyses, the mortality increases for elevated lipoprotein(a) appeared to be through apolipoprotein(a) kringle IV-2 rather than through lipoprotein(a) levels per se. SUMMARY On cholesterol scales, lipoprotein(a) and LDL appeared equal as causal factors for myocardial infarction; however, lipoprotein(a) was most important for mortality. Lipoprotein(a) effects may not only be due to cholesterol content but could also be due to the structure of lipoprotein(a) resembling plasminogen.
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3.
The LDL-Receptor and its Molecular Properties: From Theory to Novel Biochemical and Pharmacological Approaches in Reducing LDL-cholesterol.
Petroglou, D, Kanellos, I, Savopoulos, C, Kaiafa, G, Chrysochoou, A, Skantzis, P, Daios, S, Hatzitolios, AI, Giannoglou, G
Current medicinal chemistry. 2020;(2):317-333
Abstract
BACKGROUND The Low-Density Lipoprotein (LDL) Receptor (LDL-R) is a transmembrane protein playing a crucial role in effective lipid homeostasis. Various therapeutic agents have been used in the management of dyslipidemias, however, the outcome of therapeutic target is debated. OBJECTIVE The aim of this review is to summarize and fully understand the current concept regarding LDL-R and its molecular properties, metabolic pathway, factors affecting LDL-R activity and all available pharmacological interventions. Additionally, non-lipid related properties of LDL-R are also referred. METHODS Literature from the PubMed database was extracted to identify papers between 1984 to 2017 regarding LDL-R and therapeutic agents on dyslipidemia management. RESULTS We analyzed basic data regarding agents associated with LDL-R (Sterol Regulating Element-Binding Proteins - SREBPs, Protein ARH, IDOL, Thyroid Hormones, Haematologic Disorders, Protein convertase subtilisin kexintype 9 - PCSK-9, ApoC-III) as well as non-lipid related properties of LDL-R, while all relevant (common and novel) pharmacological interventions (statins, fibrates, cholesterol absorption inhibitors, bile acid sequestrants and PCSK- 9) are also referred. CONCLUSION LDL-R and its molecular properties are involved in lipid homeostasis, so potentially sets the therapeutic goals in cardiovascular patients, which is usually debated. Further research is needed in order to fully understand its properties, as well as to find the potential pharmacological interventions that could be beneficial in cholesterol homeostasis and various morbidities in order to reach the most appropriate therapeutic goal.
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4.
Non-HDL-cholesterol and apolipoprotein B compared with LDL-cholesterol in atherosclerotic cardiovascular disease risk assessment.
Carr, SS, Hooper, AJ, Sullivan, DR, Burnett, JR
Pathology. 2019;(2):148-154
Abstract
Low density lipoprotein (LDL) is the predominant atherogenic lipoprotein particle in the circulation. Conventionally, a fasting lipid profile has been used for atherosclerotic cardiovascular disease (ASCVD) risk assessment. A non-fasting sample is now regarded as a suitable alternative to a fasting sample. In routine clinical practice, the Friedewald equation is used to estimate LDL-cholesterol, but it has limitations. Commercially available direct measures of LDL-cholesterol are not standardised. LDL-cholesterol is a well-established risk factor for ASCVD, being the primary therapeutic target in both primary and secondary prevention. Non-high-density lipoprotein (HDL)-cholesterol is a measure of the cholesterol content in the atherogenic lipoproteins, but it does not reflect the particle number. Non-HDL-cholesterol has the advantage over LDL-cholesterol of including remnant cholesterol and being independent of triglyceride variability, but it is compromised by the non-specificity bias of direct HDL-cholesterol methods used in the calculation. Apolipoprotein (apo) B, the major structural protein in very low-density lipoprotein, intermediate density lipoprotein, LDL and lipoprotein (a), is a measure of the number of atherogenic lipoproteins. ApoB methods are standardised, but the assay comes at an additional, albeit relatively low cost. Non-HDL-cholesterol and apoB are more accurate measures than LDL-cholesterol in hypertriglyceridaemic individuals, non-fasting samples, and in those with very-low LDL-cholesterol concentrations. Accumulating evidence suggests that non-HDL-cholesterol and apoB are superior to LDL-cholesterol in predicting ASCVD risk, and both have been designated as secondary targets in some treatment guidelines. We review the measurement, potential role, utility and current status of non-HDL-cholesterol and apoB when compared with LDL-cholesterol in ASCVD risk assessment.
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Favorable effects of hydroxychloroquine on serum low density lipid in patients with systemic lupus erythematosus: A systematic review and meta-analysis.
Babary, H, Liu, X, Ayatollahi, Y, Chen, XP, Doo, L, Uppaluru, LK, Kwak, MK, Kulaga, C, Modjinou, D, Olech, E, et al
International journal of rheumatic diseases. 2018;(1):84-92
Abstract
AIMS: Hydroxychloroquine (HCQ) has shown to have significant immunomodulatory effects in the treatment of systemic lupus erythematosus (SLE). Current studies show favorable effects of HCQ on traditional cardiac risk factors in patients with SLE. This review examined the effects of HCQ on serum low-density lipoprotein (LDL) level in patients with SLE. METHODS A systematic search of seven major literature search databases from their inception until 3 April, 2017 identified nine studies. Random-effects pooled mean difference with corresponding 95% confidence intervals (CI) were estimated. Heterogeneity was measured by I2 . Publication bias was assessed by visual inspection of funnel plots. Sensitivity analysis examined whether HCQ effect on serum total cholesterol level was similar to the main analysis. The Grading of Recommendations Assessment, Development, and Evaluation system was used to assess the overall quality of evidence. RESULTS Pooled study participants were 559 patients from eight observation studies (two before-after studies; six case-control studies) examining the effects of HCQ on serum LDL. Pooled study participants' characteristics were as follows: mean age 45.719, female 95.262%, and prednisone use 58.366%. HCQ reduced mean LDL levels by 24.397 mg/dL (95% CI 8.921-39.872; P = 0.002). The number of studies identifying statin use was too few to perform meta-regression analysis of statin use. Heterogeneity was extensive (I2 = 94.739%). Symmetrical funnel plot visualized no evidence of publication bias. CONCLUSION HCQ was associated with serum LDL level reduction by mean 24.397 mg/dL in patients with SLE. Future prospective studies are need to fully characterize the treatment effect.
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6.
Incretins and Lipid Metabolism.
Tsimihodimos, V, Elisaf, M
Current medicinal chemistry. 2018;(18):2133-2139
Abstract
BACKGROUND Recent findings indicate that incretin hormones and incretin-based therapies may affect the metabolism of lipoproteins, although the corresponding mechanisms are not clearly defined. OBJECTIVE To summarize the available data on the mechanisms linking incretins with the characteristics of serum lipoproteins and discuss the clinical implications of these relationships. METHODS PubMed was searched using the terms "incretins", "GLP-1", "GIP" and "lipids", "dyslipidemia", "triglycerides", "apolipoprotein B48". All articles published in the English language until June 2016 were assessed and the relevant information is presented here. RESULTS GLP-1, and therapies that increase its activity, exert a beneficial effect on lipoprotein metabolism that is translated in a reduction in the fasting and postprandial concentration of triglycerides and a small improvement in the concentration and function of HDLs. In addition, a shift towards larger, less atherogenic particles usually follows the administration of GLP-1 receptor agonists. The mechanisms that underlie these changes involve a direct effect of GLP- 1 on the hepatic and intestinal production of triglyceride-rich lipoproteins, the GLP-1 induced increase in the production and function of insulin, the activation of specific areas of central nervous system as well as the increase in the peripheral utilization of triglycerides for energy production. On the other hand, GLP-2 increases the absorption of dietary fat and the production of triglyceride-rich lipoproteins while the role of GIP on lipid metabolism remains indeterminate. CONCLUSION GLP-1 and incretin-based therapies favorably affect lipid metabolism. These effects may contribute to the beneficial effects of incretin-based therapies on atherosclerosis and fatty liver disease.
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7.
The enigmatic membrane fatty acid transporter CD36: New insights into fatty acid binding and their effects on uptake of oxidized LDL.
Jay, AG, Hamilton, JA
Prostaglandins, leukotrienes, and essential fatty acids. 2018;:64-70
Abstract
The scavenger receptor CD36 binds numerous small biomolecules, including fatty acids, and even large ligands such as oxidized LDL, for which it is considered a receptor. Although CD36 has often been postulated to "transport" fatty acids across the plasma membrane, fatty acids translocation (mass transport or kinetics) was not affected by expression of CD36 in HEK293 cells; however, esterification of fatty acids (cellular uptake) was increased. These recent results from our lab are consistent with the established mechanism of fatty acid entry into cells by passive diffusion (flip-flop) and also with the well-documented enhancement of uptake of fatty acids by CD36 in other cell types. A fascinating new discovery is that CD36 has multiple fatty acid binding sites on the extracellular domain of CD36. As illuminated by new methodologies that we have applied, these sites have high affinity and exhibit rapid exchange with the medium. In an initial study of functional consequences of binding, several dietary fatty acids enhanced uptake of oxidized LDL into HEK293 cells expressing CD36. This is the first established link between physical binding of fatty acids and a function of CD36, and has implications for obesity and atherosclerosis. New methods as those used in our study could also be applied to elucidate other functional roles of fatty acid binding to CD36.
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8.
Association Between Circulating Oxidized LDL and Atherosclerotic Cardiovascular Disease: A Meta-analysis of Observational Studies.
Gao, S, Zhao, D, Wang, M, Zhao, F, Han, X, Qi, Y, Liu, J
The Canadian journal of cardiology. 2017;(12):1624-1632
Abstract
BACKGROUND Although basic research has suggested that oxidized low-density lipoprotein (ox-LDL) is involved in the pathogenesis of atherosclerosis, population observational studies have yielded conflicting results about the association between circulating ox-LDL and atherosclerotic cardiovascular disease (ASCVD). Therefore, we performed a systematic review and meta-analysis of currently available observational studies to verify the association between circulating ox-LDL and ASCVD. METHODS We systematically searched PubMed and the Cochrane Library from their inception to March 27, 2017, for nested case-control studies, case-cohort studies, and prospective cohort studies on the relationship between ox-LDL and ASCVD. Studies that did not assess the hazard ratio, relative risk, or odds ratio of ox-LDL or did not adjust for other risk factors, or those without examination of ox-LDL before collection of ASCVD occurrences were excluded. The summarized effect size was combined using fixed effect models. Subgroup analyses were performed on the basis of study quality, study design, definition of ASCVD events, effect size types, types of ox-LDL assay, ox-LDL contrast level, and whether low-density lipoprotein cholesterol was adjusted in a multivariate model. RESULTS A total of 12 included studies consisted of 3 nested case-control studies, 1 case-cohort study, 5 hospital-based cohort studies, and 3 community-based cohort studies. The summary effect size of increased circulating ox-LDL was 1.79 (95% confidence interval, 1.56-2.05) for ASCVD. Similar associations were shown in all subgroups. CONCLUSIONS Our findings indicate that increased levels of circulating ox-LDL are associated with clinical ASCVD events. Further well designed community-based cohort studies or intervention studies are needed to confirm our findings.
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9.
Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.
Ference, BA, Ginsberg, HN, Graham, I, Ray, KK, Packard, CJ, Bruckert, E, Hegele, RA, Krauss, RM, Raal, FJ, Schunkert, H, et al
European heart journal. 2017;(32):2459-2472
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Abstract
AIMS: To appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD). METHODS AND RESULTS We assessed whether the association between LDL and ASCVD fulfils the criteria for causality by evaluating the totality of evidence from genetic studies, prospective epidemiologic cohort studies, Mendelian randomization studies, and randomized trials of LDL-lowering therapies. In clinical studies, plasma LDL burden is usually estimated by determination of plasma LDL cholesterol level (LDL-C). Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD, whereas rare variants leading to lower LDL-C are associated with a correspondingly lower risk of ASCVD. Separate meta-analyses of over 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of ASCVD; and this effect appears to increase with increasing duration of exposure to LDL-C. Both the naturally randomized genetic studies and the randomized intervention trials consistently demonstrate that any mechanism of lowering plasma LDL particle concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C, provided that the achieved reduction in LDL-C is concordant with the reduction in LDL particle number and that there are no competing deleterious off-target effects. CONCLUSION Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD.
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Omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and their mechanisms of action on apolipoprotein B-containing lipoproteins in humans: a review.
Oscarsson, J, Hurt-Camejo, E
Lipids in health and disease. 2017;(1):149
Abstract
BACKGROUND Epidemiological and genetic studies suggest that elevated triglyceride (TG)-rich lipoprotein levels in the circulation increase the risk of cardiovascular disease. Prescription formulations of omega-3 fatty acids (OM3FAs), mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), reduce plasma TG levels and are approved for the treatment of patients with severe hypertriglyceridemia. Many preclinical studies have investigated the TG-lowering mechanisms of action of OM3FAs, but less is known from clinical studies. METHODS We conducted a review, using systematic methodology, of studies in humans assessing the mechanisms of action of EPA and DHA on apolipoprotein B-containing lipoproteins, including TG-rich lipoproteins and low-density lipoproteins (LDLs). A systematic search of PubMed retrieved 55 articles, of which 30 were used in the review; 35 additional arrticles were also included. RESULTS In humans, dietary DHA is retroconverted to EPA, while production of DHA from EPA is not observed. Dietary DHA is preferentially esterified into TGs, while EPA is more evenly esterified into TGs, cholesterol esters and phospholipids. The preferential esterification of DHA into TGs likely explains the higher turnover of DHA than EPA in plasma. The main effects of both EPA and DHA are decreased fasting and postprandial serum TG levels, through reduction of hepatic very-low-density lipoprotein (VLDL)-TG production. The exact mechanism for reduced VLDL production is not clear but does not include retention of lipids in the liver; rather, increased hepatic fatty acid oxidation is likely. The postprandial reduction in TG levels is caused by increased lipoprotein lipase activity and reduced serum VLDL-TG concentrations, resulting in enhanced chylomicron clearance. Overall, no clear differences between the effects of EPA and DHA on TG levels, or on turnover of TG-rich lipoproteins, have been observed. Effects on LDL are complex and may be influenced by genetics, such as APOE genotype. CONCLUSIONS EPA and DHA diminish fasting circulating TG levels via reduced production of VLDL. The mechanism of reduced VLDL production does not involve hepatic retention of lipids. Lowered postprandial TG levels are also explained by increased chylomicron clearance. Little is known about the specific cellular and biochemical mechanisms underlying the TG-lowering effects of EPA and DHA in humans.