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Clinical Chemistry Jan 2021Current guidelines target low-density lipoprotein cholesterol (LDL-C) concentrations to reduce atherosclerotic cardiovascular disease (ASCVD) risk, and yet clinical... (Review)
Review
BACKGROUND
Current guidelines target low-density lipoprotein cholesterol (LDL-C) concentrations to reduce atherosclerotic cardiovascular disease (ASCVD) risk, and yet clinical trials demonstrate persistent residual ASCVD risk despite aggressive LDL-C lowering.
CONTENT
Non-LDL-C lipid parameters, most notably triglycerides, triglyceride-rich lipoproteins (TGRLs), and lipoprotein(a), and C-reactive protein as a measure of inflammation are increasingly recognized as associated with residual risk after LDL-C lowering. Eicosapentaenoic acid in statin-treated patients with high triglycerides reduced both triglycerides and ASCVD events. Reducing TGRLs is believed to have beneficial effects on inflammation and atherosclerosis. High lipoprotein(a) concentrations increase ASCVD risk even in individuals with LDL-C < 70 mg/dL. Although statins do not generally lower lipoprotein(a), proprotein convertase subtilisin/kexin type 9 inhibitors reduce lipoprotein(a) and cardiovascular outcomes, and newer approaches are in development. Persistent increases in C-reactive protein after intensive lipid therapy have been consistently associated with increased risk for ASCVD events.
SUMMARY
We review the evidence that biochemical assays to measure TGRLs, lipoprotein(a), and C-reactive protein are associated with residual risk in patients treated to low concentrations of LDL-C. Growing evidence supports a causal role for TGRLs, lipoprotein(a), and inflammation in ASCVD; novel therapies that target TGRLs, lipoprotein(a), and inflammation are in development to reduce residual ASCVD risk.
Topics: Atherosclerosis; Biomarkers; C-Reactive Protein; Cholesterol, LDL; Heart Disease Risk Factors; Humans; Hypolipidemic Agents; Inflammation; Lipoprotein(a); Lipoproteins; Triglycerides
PubMed: 33257928
DOI: 10.1093/clinchem/hvaa252 -
Cardiovascular Research Feb 2022The prothrombotic state in atrial fibrillation (AF) occurs as a result of multifaceted interactions, known as Virchow's triad of hypercoagulability, structural... (Review)
Review
The prothrombotic state in atrial fibrillation (AF) occurs as a result of multifaceted interactions, known as Virchow's triad of hypercoagulability, structural abnormalities, and blood stasis. More recently, there is emerging evidence that lipoproteins are implicated in this process, beyond their traditional role in atherosclerosis. In this review, we provide an overview of the various lipoproteins and explore the association between lipoproteins and AF, the effects of lipoproteins on haemostasis, and the potential contribution of lipoproteins to thrombogenesis in AF. There are several types of lipoproteins based on size, lipid composition, and apolipoprotein category, namely: chylomicrons, very low-density lipoprotein, low-density lipoprotein (LDL), intermediate-density lipoprotein, and high-density lipoprotein. Each of these lipoproteins may contain numerous lipid species and proteins with a variety of different functions. Furthermore, the lipoprotein particles may be oxidized causing an alteration in their structure and content. Of note, there is a paradoxical inverse relationship between total cholesterol and LDL cholesterol (LDL-C) levels, and incident AF. The mechanism by which this occurs may be related to the stabilizing effect of cholesterol on myocardial membranes, along with its role in inflammation. Overall, specific lipoproteins may interact with haemostatic pathways to promote excess platelet activation and thrombin generation, as well as inhibiting fibrinolysis. In this regard, LDL-C has been shown to be an independent risk factor for thromboembolic events in AF. The complex relationship between lipoproteins, thrombosis and AF warrants further research with an aim to improve our knowledge base and contribute to our overall understanding of lipoprotein-mediated thrombosis.
Topics: Atrial Fibrillation; Cholesterol, LDL; Humans; Lipoproteins; Lipoproteins, HDL; Lipoproteins, LDL; Thrombosis
PubMed: 33483737
DOI: 10.1093/cvr/cvab017 -
Journal of Lipid Research Dec 1984Plasma lipoprotein metabolism is regulated and controlled by the specific apolipoprotein (apo-) constituents of the various lipoprotein classes. The major... (Review)
Review
Plasma lipoprotein metabolism is regulated and controlled by the specific apolipoprotein (apo-) constituents of the various lipoprotein classes. The major apolipoproteins include apoE, apoB, apoA-I, apoA-II, apoA-IV, apoC-I, apoC-II, and apoC-III. Specific apolipoproteins function in the regulation of lipoprotein metabolism through their involvement in the transport and redistribution of lipids among various cells and tissues, through their role as cofactors for enzymes of lipid metabolism, or through their maintenance of the structure of the lipoprotein particles. The primary structures of most of the apolipoproteins are now known, and various functional domains of these proteins are being mapped using selective chemical modification, synthetic peptides, and monoclonal antibodies. Furthermore, the establishment of structure-function relationships has been greatly advanced by the identification of genetically determined variants of specific apolipoproteins that are associated with a disorder of lipoprotein metabolism. Future studies will rely heavily on the use of recombinant DNA technology and site-specific mutagenesis to elucidate further the correlations between structure and function and the role of specific apolipoproteins in lipoprotein metabolism.
Topics: Apolipoprotein A-I; Apolipoprotein A-II; Apolipoprotein C-I; Apolipoprotein C-II; Apolipoprotein C-III; Apolipoproteins; Apolipoproteins A; Apolipoproteins B; Apolipoproteins C; Apolipoproteins E; Cholesterol; Heparin; Humans; Lipolysis; Lipoproteins; Molecular Conformation; Receptors, Cell Surface; Receptors, Lipoprotein
PubMed: 6099394
DOI: No ID Found -
Journal of the American Heart... Oct 2022In 2019, the European Society of Cardiology/European Atherosclerosis Society stated that apolipoprotein B (apoB) was a more accurate marker of cardiovascular risk than... (Review)
Review
Physiological Bases for the Superiority of Apolipoprotein B Over Low-Density Lipoprotein Cholesterol and Non-High-Density Lipoprotein Cholesterol as a Marker of Cardiovascular Risk.
In 2019, the European Society of Cardiology/European Atherosclerosis Society stated that apolipoprotein B (apoB) was a more accurate marker of cardiovascular risk than low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol. Since then, the evidence has continued to mount in favor of apoB. This review explicates the physiological mechanisms responsible for the superiority of apoB as a marker of the cardiovascular risk attributable to the atherogenic apoB lipoprotein particles chylomicron remnants, very low-density lipoprotein, and low-density lipoprotein particles. First, the nature and relative numbers of these different apoB particles will be outlined. This will make clear why low-density lipoprotein particles are almost always the major determinants of cardiovascular risk and why the concentrations of triglycerides and LDL-C may obscure this relation. Next, the mechanisms that govern the number of very low-density lipoprotein and low-density lipoprotein particles will be outlined because, except for dysbetalipoproteinemia, the total number of apoB particles determines cardiovascular risk, Then, the mechanisms that govern the cholesterol mass within very low-density lipoprotein and low-density lipoprotein particles will be reviewed because these are responsible for the discordance between the mass of cholesterol within apoB particles, measured either as LDL-C or non-high-density lipoprotein cholesterol, and the number of apoB particles measured as apoB, which creates the superior predictive power of apoB over LDL-C and non-high-density lipoprotein cholesterol. Finally, the major apoB dyslipoproteinemias will be briefly outlined. Our objective is to provide a physiological framework for health care givers to understand why apoB is a more accurate marker of cardiovascular risk than LDL-C or non-high-density lipoprotein cholesterol.
Topics: Humans; Cholesterol, LDL; Chylomicron Remnants; Cardiovascular Diseases; Risk Factors; Apolipoproteins B; Cholesterol; Lipoproteins; Biomarkers; Triglycerides; Heart Disease Risk Factors; Atherosclerosis; Lipoproteins, VLDL; Apolipoprotein B-100
PubMed: 36216435
DOI: 10.1161/JAHA.122.025858 -
Advances in Experimental Medicine and... 2022Sphingolipids and cholesterol are two lipid partners on cellular membranes where they form specific microdomains, named lipid rafts, which mediate specific cell...
Sphingolipids and cholesterol are two lipid partners on cellular membranes where they form specific microdomains, named lipid rafts, which mediate specific cell functions. Sphingomyelin (SM) is one of the major sphingolipids. SM and free cholesterol are also two key lipids on the monolayer of plasma lipoproteins, including chylomicron, very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL), which participate in lipid transport in the circulation. Thus, sphingolipids and cholesterol play a fundamental role in cell membrane structure and blood lipid transport. In this chapter we will discuss the relationship between both lipids, on the cell membrane and in the circulation, as well as the impact of such relationship in the development of metabolic diseases.
Topics: Cholesterol; Lipids; Lipoproteins; Lipoproteins, LDL; Sphingolipids
PubMed: 35503170
DOI: 10.1007/978-981-19-0394-6_1 -
Advanced Drug Delivery Reviews 2020Lipoproteins (LPs) are circulating heterogeneous nanoparticles produced by the liver and intestines. LPs play a major role in the transport of dietary and endogenous... (Review)
Review
Lipoproteins (LPs) are circulating heterogeneous nanoparticles produced by the liver and intestines. LPs play a major role in the transport of dietary and endogenous lipids to target cells through cell membrane receptors or cell surface-bound lipoprotein lipase. The stability, biocompatibility, and selective transport of LPs make them promising delivery vehicles for various therapeutic and imaging agents. This review discusses isolation, manufacturing, and drug loading techniques used for LP-based drug delivery, as well as recent applications for diagnosis and treatment of cancer, atherosclerosis, and other life-threatening diseases.
Topics: Animals; Drug Delivery Systems; Humans; Lipoproteins
PubMed: 32791075
DOI: 10.1016/j.addr.2020.08.003 -
Arteriosclerosis, Thrombosis, and... Jul 2023APOA1 and APOB are the structural proteins of high-density lipoprotein and APOB-containing lipoproteins, such as low-density lipoprotein and very low-density... (Review)
Review
APOA1 and APOB are the structural proteins of high-density lipoprotein and APOB-containing lipoproteins, such as low-density lipoprotein and very low-density lipoprotein, respectively. The 4 smaller APOCs (APOC1, APOC2, APOC3, and APOC4) are exchangeable apolipoproteins; they are readily transferred among high-density lipoproteins and APOB-containing lipoproteins. The APOCs regulate plasma triglyceride and cholesterol levels by modulating substrate availability and activities of enzymes interacting with lipoproteins and by interfering with APOB-containing lipoprotein uptake through hepatic receptors. Of the 4 APOCs, APOC3 has been best studied in relation to diabetes. Elevated serum APOC3 levels predict incident cardiovascular disease and progression of kidney disease in people with type 1 diabetes. Insulin suppresses APOC3 levels, and accordingly, elevated APOC3 levels associate with insulin deficiency and insulin resistance. Mechanistic studies in a mouse model of type 1 diabetes have demonstrated that APOC3 acts in the causal pathway of diabetes-accelerated atherosclerosis. The mechanism is likely due to the ability of APOC3 to slow the clearance of triglyceride-rich lipoproteins and their remnants, thereby causing an increased accumulation of atherogenic lipoprotein remnants in lesions of atherosclerosis. Less is known about the roles of APOC1, APOC2, and APOC4 in diabetes.
Topics: Mice; Animals; Apolipoprotein C-II; Diabetes Mellitus, Type 1; Lipoproteins; Triglycerides; Lipoproteins, HDL; Apolipoprotein C-III; Lipoproteins, LDL; Atherosclerosis; Apolipoproteins B; Insulins
PubMed: 37226733
DOI: 10.1161/ATVBAHA.122.318290 -
Lipids in Health and Disease Jun 2022Preeclampsia (PE) is a multisystemic syndrome specific to pregnancy. Although PE is the leading cause of death from complications associated with pregnancy, its... (Review)
Review
Preeclampsia (PE) is a multisystemic syndrome specific to pregnancy. Although PE is the leading cause of death from complications associated with pregnancy, its aetiology is still unknown. In PE, lipid metabolism is altered. When lipids are damaged, both the mother and the foetus may be at risk. Lipoproteins contain apolipoproteins, triacylglycerols, free and esterified cholesterol, and phospholipids, all of which are susceptible to oxidative stress when high levels of oxygen and nitrogen free radicals are present. Lipoperoxidation can occur in three stages: mild, moderate, and severe. In severe lipid damage, highly toxic products such as malondialdehyde (MDA) can be generated; under these conditions, low-density lipoprotein (LDL) proteins can be oxidized (oxLDL). oxLDL is a biomolecule that can affect the production of nitric oxide (NO), the main vasodilator derived from the endothelium. oxLDL can interfere with the transduction of the signals responsible for triggering the activation of endothelial nitric oxide synthase (eNOS), causing reduced vasodilation and endothelial dysfunction, which are the main characteristics of preeclampsia. The objective of the review was to analyse the information the current information about exists about the impact generated by the oxidation of LDL and HDL lipoproteins in neonates of women with preeclampsia and how these alterations can predispose the neonate to develop diseases in adulthood.PE can cause foetal loss, intrauterine growth restriction, or developmental complications. Neonates of mothers with PE have a high risk of cardiovascular diseases, stroke, mental retardation, sensory deficiencies and an increased risk of developing metabolic diseases. PE not only affects the foetus, generating complications during pregnancy but also predisposes them to chronic diseases in adulthood.
Topics: Female; Fetus; Humans; Infant, Newborn; Lipoproteins; Lipoproteins, HDL; Lipoproteins, LDL; Malondialdehyde; Pre-Eclampsia; Pregnancy
PubMed: 35658865
DOI: 10.1186/s12944-022-01663-5 -
Endocrinology and Metabolism Clinics of... Sep 1998Lipoproteins are spherical macromolecular complexes in which hydrophobic molecules of triglyceride and cholesteryl ester are enveloped within a monolayer of amphipathic... (Review)
Review
Lipoproteins are spherical macromolecular complexes in which hydrophobic molecules of triglyceride and cholesteryl ester are enveloped within a monolayer of amphipathic molecules of phospholipids, free cholesterol, and apoproteins. The major lipoprotein classes include intestinally derived chylomicrons that transport dietary fats and cholesterol, hepatic-derived VLDL, IDL, and LDL that can be atherogenic, and hepatic- and intestinally derived HDL that are anti-atherogenic. Apoprotein B is necessary for the secretion of chylomicrons (apo B48) and VLDL, IDL, and LDL (apo B100). Post-translational regulation of the assembly of apo B-containing lipoproteins by core lipid availability seems to be the major mechanism for variations in secretion. Plasma levels of VLDL triglycerides are determined mainly by rates of secretion and LPL lipolytic activity; plasma levels of LDL cholesterol are determined mainly by the secretion of apo B100 into plasma, the efficacy with which VLDL are converted to LDL and by LDL receptor-mediated clearance. Regulation of HDL cholesterol levels is complex and is affected by rates of synthesis of its apoproteins, rates of esterification of free cholesterol to cholesteryl ester by LCAT, levels of triglyceride-rich lipoproteins and CETP-mediated transfer of cholesteryl esters from HDL, and clearance from plasma of HDL lipids and apoproteins. Normal lipoprotein transport is associated with low levels of triglycerides and LDL cholesterol and high levels of HDL cholesterol. When lipoprotein transport is abnormal, lipoproteins levels can change in ways that predispose individuals to atherosclerosis.
Topics: Animals; Biological Transport; Dietary Fats; Enzymes; Humans; Lipid Metabolism; Lipoproteins
PubMed: 9785050
DOI: 10.1016/s0889-8529(05)70023-2 -
Journal of the American Heart... Aug 2023Concern continues about whether the measurement of apolipoprotein B (apoB) is adequately standardized, and therefore, whether apoB should be applied widely in clinical... (Review)
Review
Concern continues about whether the measurement of apolipoprotein B (apoB) is adequately standardized, and therefore, whether apoB should be applied widely in clinical care. This concern is misplaced. Our objective is to explain why and what the term "standardization" means. To produce clinically valid results, a test must accurately, precisely, and selectively measure the marker of interest. That is, it must be standardized. Accuracy refers to how closely the result obtained with 1 method corresponds to the result obtained with the standard method, precision to how reproducible the result is on repeated testing, and selectivity to how susceptible the method is to error by inclusion of other classes of lipoprotein particles. Multiple expert groups have determined that the measurement of apoB is adequately standardized for clinical care, and that apoB can be measured inexpensively, using widely available automated methods, more accurately, precisely, and selectively than low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol. ApoB is a standard superior to low-density lipoprotein cholesterol and high-density lipoprotein cholesterol because it is a defined molecule, whereas the cholesterol markers are the mass of cholesterol within lipoprotein particles defined by their density, not by their molecular structure. Nevertheless, the standardization of apoB is being further improved by the application of mass spectrophotometric methods, whereas the limitations in the standardization and, therefore, the accurate, precise, and selective measurement of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol are unlikely to be overcome. We submit that greater accuracy, precision, and selectivity in measurement is a decisive advantage for apoB in the modern era of intensive lipid-lowering therapies.
Topics: Cholesterol, LDL; Cholesterol; Apolipoproteins B; Apolipoprotein B-100; Cholesterol, HDL; Lipoproteins; Apolipoprotein A-I
PubMed: 37489721
DOI: 10.1161/JAHA.123.030405