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Endocrinology and Metabolism Clinics of... Sep 2022The exogenous lipoprotein pathway starts with the incorporation of dietary lipids into chylomicrons in the intestine. Chylomicron triglycerides are metabolized in muscle... (Review)
Review
The exogenous lipoprotein pathway starts with the incorporation of dietary lipids into chylomicrons in the intestine. Chylomicron triglycerides are metabolized in muscle and adipose tissue and chylomicron remnants are formed, which are removed by the liver. The endogenous lipoprotein pathway begins in the liver with the formation of very low-density lipoprotein particles (VLDL). VLDL triglycerides are metabolized in muscle and adipose tissue forming intermediate-density lipoprotein (IDL), which may be taken up by the liver or further metabolized to low-density lipoprotein (LDL). Reverse cholesterol transport begins with the formation of nascent high-density lipoprotein (HDL) by the liver and intestine that acquire cholesterol from cells resulting in mature HDL. The HDL then transports the cholesterol to the liver either directly or indirectly by transferring the cholesterol to VLDL or LDL.
Topics: Cholesterol; Humans; Lipoproteins; Lipoproteins, LDL; Triglycerides
PubMed: 35963623
DOI: 10.1016/j.ecl.2022.02.008 -
Oxidative Medicine and Cellular... 2020Dyslipidaemia has a prominent role in the onset of notorious atherosclerosis, a disease of medium to large arteries. Atherosclerosis is the prime root of cardiovascular... (Review)
Review
Dyslipidaemia has a prominent role in the onset of notorious atherosclerosis, a disease of medium to large arteries. Atherosclerosis is the prime root of cardiovascular events contributing to the most considerable number of morbidity and mortality worldwide. Factors like cellular senescence, genetics, clonal haematopoiesis, sedentary lifestyle-induced obesity, or diabetes mellitus upsurge the tendency of atherosclerosis and are foremost pioneers to definitive transience. Accumulation of oxidized low-density lipoproteins (Ox-LDLs) in the tunica intima triggers the onset of this disease. In the later period of progression, the build-up plaques rupture ensuing thrombosis (completely blocking the blood flow), causing myocardial infarction, stroke, and heart attack, all of which are common atherosclerotic cardiovascular events today. The underlying mechanism is very well elucidated in literature but the therapeutic measures remains to be unleashed. Researchers tussle to demonstrate a clear understanding of treating mechanisms. A century of research suggests that lowering LDL, statin-mediated treatment, HDL, and lipid-profile management should be of prime interest to retard atherosclerosis-induced deaths. We shall brief the Ox-LDL-induced atherogenic mechanism and the treating measures in line to impede the development and progression of atherosclerosis.
Topics: Antioxidants; Atherosclerosis; Endothelium; Humans; Lipoproteins, LDL; Macrophages; Oxidative Stress; Reactive Oxygen Species; Risk Factors
PubMed: 33014272
DOI: 10.1155/2020/5245308 -
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 the American College of... Jan 2023It is unclear whether elevated low-density lipoprotein (LDL) triglycerides are associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD).
BACKGROUND
It is unclear whether elevated low-density lipoprotein (LDL) triglycerides are associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD).
OBJECTIVES
This study tested the hypothesis that elevated LDL triglycerides are associated with an increased risk of ASCVD and of each ASCVD component individually.
METHODS
The study investigators used the Copenhagen General Population Study, which measured LDL triglycerides in 38,081 individuals with a direct automated assay (direct LDL triglycerides) and in another 30,208 individuals with nuclear magnetic resonance (NMR) spectroscopy (NMR LDL triglycerides). Meta-analyses aggregated the present findings with previously reported results.
RESULTS
During a median follow-up of 3.0 and 9.2 years, respectively, 872 and 5,766 individuals in the 2 cohorts received a diagnosis of ASCVD. Per 0.1 mmol/L (9 mg/dL) higher direct LDL triglycerides, HRs were 1.26 (95% CI: 1.17-1.35) for ASCVD, 1.27 (95% CI: 1.16-1.39) for ischemic heart disease, 1.28 (95% CI: 1.11-1.48) for myocardial infarction, 1.22 (95% CI: 1.08-1.38) for ischemic stroke, and 1.38 (95% CI: 1.21-1.58) for peripheral artery disease. Corresponding HRs for NMR LDL triglycerides were 1.26 (95% CI: 1.20-1.33), 1.33 (95% CI: 1.25-1.41), 1.41 (95% CI: 1.31-1.52), 1.13 (95% CI: 1.05-1.23), and 1.26 (95% CI: 1.10-1.43), respectively. The foregoing results were not entirely statistically explained by apolipoprotein B levels. In meta-analyses for the highest quartile vs the lowest quartile of LDL triglycerides, random-effects risk ratios were 1.50 (95% CI: 1.35-1.66) for ASCVD (4 studies; 71,526 individuals; 8,576 events), 1.62 (95% CI: 1.37-1.93) for ischemic heart disease (6 studies; 107,538 individuals; 9,734 events), 1.30 (95% CI: 1.13-1.49) for ischemic stroke (4 studies; 78,026 individuals; 4,273 events), and 1.53 (95% CI: 1.29-1.81) for peripheral artery disease (4 studies; 107,511 individuals; 1,848 events).
CONCLUSIONS
Elevated LDL triglycerides were robustly associated with an increased risk of ASCVD and of each ASCVD component individually in 2 prospective cohort studies and in meta-analyses of previous and present studies combined.
Topics: Humans; Atherosclerosis; Cholesterol, LDL; Hypertriglyceridemia; Ischemic Stroke; Myocardial Ischemia; Peripheral Arterial Disease; Prospective Studies; Risk Factors; Triglycerides; Lipoproteins, LDL
PubMed: 36631208
DOI: 10.1016/j.jacc.2022.10.019 -
European Journal of Pharmacology Jul 2020The clinical benefit of lipid-lowering therapies is to reduce circulating levels of atherogenic particles and to ameliorate the risk of atherosclerotic cardiovascular... (Review)
Review
The clinical benefit of lipid-lowering therapies is to reduce circulating levels of atherogenic particles and to ameliorate the risk of atherosclerotic cardiovascular disease (ASCVD). The completion of two major clinical trials on PCSK9 inhibitors (PCSK9i), the FOURIER and the ODYSSEY outcome trials, has marked the beginning of a new era of lipid-lowering drugs. PCSK9i, evolocumab and alirocumab, are monoclonal antibodies that inactivate the liver proprotein convertase subtilisin kexin 9 (PCSK9). Inhibition of PCSK9 increases the number of low-density lipoprotein (LDL) receptors available leading to a profound reduction in circulating LDL particles. By preventing LDL receptor destruction, PCSK9i as adjunct to statin therapy can reduce LDL-C by 50-60% above that achieved by statin therapy alone. In addition, PCSK9i in combination with high-dose statins may reduce cardiovascular events and all-cause mortality in patients with clinical ASCVD. Based on evidence from clinical trials, the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines for the management of dyslipidemias now include the use of PCSK9i to very high-risk ASCVD patients who are not achieving treatment goals on a maximum tolerated dose of a statin and ezetimibe. However, the cost-effectiveness of PCSK9i therapy is limited to secondary prevention in high-risk patients. This review outlines the main clinical trials leading to a change in the guidelines, clinical practice as well as the future challenges of PCSK9i therapy.
Topics: Antibodies, Monoclonal, Humanized; Anticholesteremic Agents; Carotid Artery Diseases; Cholesterol, LDL; Dose-Response Relationship, Drug; Drug Therapy, Combination; Dyslipidemias; Ezetimibe; Guidelines as Topic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipoproteins, LDL; PCSK9 Inhibitors; Receptors, LDL; Risk Factors; Serine Proteinase Inhibitors; Treatment Outcome
PubMed: 32302598
DOI: 10.1016/j.ejphar.2020.173114 -
Nature Communications May 2023Lipid nanoparticles have demonstrated utility in hepatic delivery of a range of therapeutic modalities and typically deliver their cargo via low-density lipoprotein...
Lipid nanoparticles have demonstrated utility in hepatic delivery of a range of therapeutic modalities and typically deliver their cargo via low-density lipoprotein receptor-mediated endocytosis. For patients lacking sufficient low-density lipoprotein receptor activity, such as those with homozygous familial hypercholesterolemia, an alternate strategy is needed. Here we show the use of structure-guided rational design in a series of mouse and non-human primate studies to optimize a GalNAc-Lipid nanoparticle that allows for low-density lipoprotein receptor independent delivery. In low-density lipoprotein receptor-deficient non-human primates administered a CRISPR base editing therapy targeting the ANGPTL3 gene, the introduction of an optimized GalNAc-based asialoglycoprotein receptor ligand to the nanoparticle surface increased liver editing from 5% to 61% with minimal editing in nontargeted tissues. Similar editing was noted in wild-type monkeys, with durable blood ANGPTL3 protein reduction up to 89% six months post dosing. These results suggest that GalNAc-Lipid nanoparticles may effectively deliver to both patients with intact low-density lipoprotein receptor activity as well as those afflicted by homozygous familial hypercholesterolemia.
Topics: Animals; Gene Editing; Homozygous Familial Hypercholesterolemia; Clustered Regularly Interspaced Short Palindromic Repeats; Nanoparticles; Liver; Receptors, LDL; Lipoproteins, LDL
PubMed: 37188660
DOI: 10.1038/s41467-023-37465-1 -
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 -
Biological Chemistry Sep 2020Metabolic disorders, including obesity, diabetes, and hyperlipidemia, as well as cardiovascular diseases (CVD), particularly atherosclerosis, are still leading causes of... (Review)
Review
Metabolic disorders, including obesity, diabetes, and hyperlipidemia, as well as cardiovascular diseases (CVD), particularly atherosclerosis, are still leading causes of death worldwide. Plasma levels of low-density lipoprotein (LDL) are currently being considered as a critical risk factor for the diseases mentioned above, especially atherosclerosis. Because of the heterogeneous nature of LDL, many studies have already been conducted on its subclasses, especially small dense LDL (sdLDL). According to available evidence, sdLDL levels can be considered as an ideal alternative to LDL levels for monitoring CVD and early diagnosis of atherosclerosis. Recently, several researchers have focused on factors that are able to decrease sdLDL levels and improve health quality. Therefore, the purpose of this study is to describe the production process of sdLDL particles and review the effects of pharmaceutical and dietary agents as well as lifestyle on sdLDL plasma levels. In brief, their mechanisms of action are discussed. Apparently, cholesterol and LDL-lowering compounds are also effective in the reduction of sdLDL levels. In addition, improving lipid profile, especially the reduction of triglyceride levels, appropriate regimen, and lifestyle can decrease sdLDL levels. Therefore, all the aforementioned parameters should be taken into consideration simultaneously in sdLDL levels reducing strategies.
Topics: Atherosclerosis; Dietary Supplements; Humans; Hypoglycemic Agents; Hypolipidemic Agents; Lipoproteins, LDL; Plants, Medicinal
PubMed: 32427116
DOI: 10.1515/hsz-2019-0426 -
Clinica Chimica Acta; International... Sep 2021The causal relationship between low-density lipoprotein (LDL) and atherosclerotic cardiovascular disease (CVD) has been firmly substantiated. LDL consists of a... (Review)
Review
BACKGROUND
The causal relationship between low-density lipoprotein (LDL) and atherosclerotic cardiovascular disease (CVD) has been firmly substantiated. LDL consists of a heterogeneous group of particles with different physicochemical and metabolic properties. Among them, small dense LDL (sdLDL) particles are considered an emerging CVD risk factor and a promising CVD risk biomarker. This paper reviews published analytical and calculation-based methods for sdLDL determination in plasma, present their principles, strengths, and weaknesses, and examine the challenges arising from method comparison.
METHODS
A literature survey was conducted using the PubMed database. Subject headings and keywords facilitated the search strategy. Titles and abstracts were initially assessed, and the full-text article of the pre-selected ones was reviewed.
RESULTS
A range of methods is currently available for the analysis of LDL subfractions and the measurement of sdLDL particle size, number, and cholesterol concentration. Ultracentrifugation (UC), vertical auto profile, gradient gel electrophoresis (GGE), nuclear magnetic resonance (NMR) spectroscopy, high-performance liquid chromatography, ion mobility analysis, and a homogeneous assay are the most prevalent. To date, there is no "gold standard". UC and GGE are the most established techniques, albeit significantly sophisticated. NMR and the homogeneous assay are options with potential clinical use as they yield results rapidly and can be high-throughput. None of the proposed equations for the calculated sdLDL determination has been sufficiently validated to serve as a clinical tool.
CONCLUSIONS
Many analytical procedures have been developed for the study of sdLDL particles. Their use remains largely restricted to research laboratories since their analytical and clinical performance, along with the clinical- and cost-effectiveness of sdLDL determination have not been fully established.
Topics: Atherosclerosis; Biomarkers; Electrophoresis; Humans; Lipoproteins, LDL; Ultracentrifugation
PubMed: 34118239
DOI: 10.1016/j.cca.2021.06.012 -
Cell Death & Disease Sep 2022Oxidative stress is a vital contributor to the development and progression of diabetes-accelerated atherosclerosis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is...
Oxidative stress is a vital contributor to the development and progression of diabetes-accelerated atherosclerosis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known molecule that participates in cellular defense against oxidative stress. Utilizing luciferase reporter assay from 379 natural products, we reported here that Ginsenoside Rb1 played a dual role in inhibiting Kelch-like ECH-associated protein 1 (Keap1) and p47 luciferase reporter activities. In endothelial cells (ECs), Rb1 pretreatment enhanced cell viability, reduced oxidative stress, inflammation, endothelial-mesenchymal transition (EndMT), and apoptosis, as well as ameliorated mitochondrial quality following oxidized low-density lipoprotein (ox-LDL) plus high glucose (HG) challenge. Rb1 directly bound to Keap1 and promoted its ubiquitination and proteasomal degradation dependent on lysine residues (K108, K323, and K551) by recruiting the E3 ligase synovial apoptosis inhibitor 1 (SYVN1), leading to Nrf2 dissociation from Keap1, Nrf2 nuclear translocation, Nrf2/PGC-1α complex formation. We further identified that Rb1 could bind to p47 and reduce its phosphorylation and membrane translocation, thereby disrupting the assembly of the NOX2 complex. Importantly, Rb1-mediated preservation of cytoplasmic p47 stabilized and contributed to Nrf2 activation. Additionally, we revealed that Rb1 reduced aortic atherosclerotic plaque formation along with reductions in oxidative stress and inflammatory response in streptozotocin (STZ)-induced ApoE mice, but not in ApoE mice with deficiency of Nrf2 and PGC-1α. Collectively, we demonstrated that Rb1, which directly targeted Keap1 and p47 in ECs, may be an attractive candidate for the treatment of atherosclerosis in diabetes.
Topics: Animals; Mice; Apolipoproteins E; Atherosclerosis; Biological Products; Diabetes Mellitus; Endothelial Cells; Ginsenosides; Glucose; Kelch-Like ECH-Associated Protein 1; Lipoproteins, LDL; Luciferases; Lysine; NF-E2-Related Factor 2; Oxidative Stress; Streptozocin; Ubiquitin-Protein Ligases
PubMed: 36163178
DOI: 10.1038/s41419-022-05274-x