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Nature Reviews. Cardiology Mar 2024Prolonged or excessive exposure to oxidized phospholipids (OxPLs) generates chronic inflammation. OxPLs are present in atherosclerotic lesions and can be detected in... (Review)
Review
Prolonged or excessive exposure to oxidized phospholipids (OxPLs) generates chronic inflammation. OxPLs are present in atherosclerotic lesions and can be detected in plasma on apolipoprotein B (apoB)-containing lipoproteins. When initially conceptualized, OxPL-apoB measurement in plasma was expected to reflect the concentration of minimally oxidized LDL, but, surprisingly, it correlated more strongly with plasma lipoprotein(a) (Lp(a)) levels. Indeed, experimental and clinical studies show that Lp(a) particles carry the largest fraction of OxPLs among apoB-containing lipoproteins. Plasma OxPL-apoB levels provide diagnostic information on the presence and extent of atherosclerosis and improve the prognostication of peripheral artery disease and first and recurrent myocardial infarction and stroke. The addition of OxPL-apoB measurements to traditional cardiovascular risk factors improves risk reclassification, particularly in patients in intermediate risk categories, for whom improving decision-making is most impactful. Moreover, plasma OxPL-apoB levels predict cardiovascular events with similar or greater accuracy than plasma Lp(a) levels, probably because this measurement reflects both the genetics of elevated Lp(a) levels and the generalized or localized oxidation that modifies apoB-containing lipoproteins and leads to inflammation. Plasma OxPL-apoB levels are reduced by Lp(a)-lowering therapy with antisense oligonucleotides and by lipoprotein apheresis, niacin therapy and bariatric surgery. In this Review, we discuss the role of role OxPLs in the pathophysiology of atherosclerosis and Lp(a) atherogenicity, and the use of OxPL-apoB measurement for improving prognosis, risk reclassification and therapeutic interventions.
Topics: Humans; Cardiovascular Diseases; Phospholipids; Apolipoproteins B; Atherosclerosis; Lipoprotein(a); Inflammation
PubMed: 37848630
DOI: 10.1038/s41569-023-00937-4 -
Journal of Atherosclerosis and... May 2022Familial hypercholesterolemia (FH) is underdiagnosed in most countries. The genetic heterogeneity of FH requires an algorithm to efficiently integrate genetic testing...
AIM
Familial hypercholesterolemia (FH) is underdiagnosed in most countries. The genetic heterogeneity of FH requires an algorithm to efficiently integrate genetic testing into clinical practice. We aimed to report the spectrum of genetic mutations from patients with clinically diagnosed FH in Taiwan.
METHODS
Patients with LDL-C>190 mg/dL or those with probable or definite FH according to the Taiwan Lipid Guidelines underwent genetic testing. Samples from 750 index patients from the Taiwan FH registry were screened using custom-made mass spectrometry, followed by targeted next generation sequencing (NGS) and/or multiplex ligation-dependent probe amplification (MLPA) if found negative.
RESULTS
The mean age of the patients was 52.4±15.1 years and 40.9% were male. Mutations were detected in 445 patients (59.3%). The distribution of mutations was as follows: LDLR (n=395), APOB (n=58), PCSK9 (n=0), and ABCG5 (n=3). The most common mutations were APOB c.10579 C>T (p.R3527W) (12.6%), LDLR c.986 G>A (p.C329Y) (11.5%), and LDLR c.1747 C>T (p.H583Y) (10.8%). LDLR c.1187-10 G>A (IVS 8-10) and APOB c.10580 G>A (p.R3527Q) were detected using targeted NGS in Taiwan for the first time. Four novel mutations were identified, including LDLR c.1060+2 T>C (IVS 7+2), LDLR c.1139 A>C (p.E380A), LDLR c.1322 T>C (p.A431T)+c.1867 A>G (p.I623V), and ABCG5 c.1337 G>A (p.R447Q).
CONCLUSION
LDLR and APOB, but not PCSK9, mutations were the major genetic causes of FH. Four novel mutations in LDLR or ABCG5 were identified. This genetic screening method using mass spectrometry, targeted NGS, and MLPA analysis provided an efficient algorithm for genetic testing for clinically diagnosed FH in Taiwan.
Topics: Adult; Aged; Apolipoproteins B; DNA Mutational Analysis; Female; Genetic Testing; Humans; Hyperlipoproteinemia Type II; Male; Middle Aged; Mutation; Phenotype; Proprotein Convertase 9; Receptors, LDL
PubMed: 33994402
DOI: 10.5551/jat.62773 -
Lipids in Health and Disease Jul 2023Apolipoproteins and lipoprotein(a) are associated with various cardiometabolic diseases, including insulin resistance, diabetes mellitus, hypertension, dyslipidemia,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND & AIMS
Apolipoproteins and lipoprotein(a) are associated with various cardiometabolic diseases, including insulin resistance, diabetes mellitus, hypertension, dyslipidemia, among others. This systematic review and meta-analysis was conducted to evaluate the association of these markers with metabolic syndrome (MetS).
METHODS
We ran a systematic search through PubMed, Scopus, Embase, Ovid/Medline, and Web of Science on March 15, 2023. No language or date restrictions were applied. The only synthesised effect measure reported was the odds ratio (OR) with its corresponding 95% confidence interval (95% CI). We utilised the random-effects model for the quantitative synthesis.
RESULTS
We analysed 50 studies (n = 150 519) with different definitions for MetS. Increased ApoB values were associated with MetS (OR = 2.8; 95% CI: 2.44-3.22; p < 0.01, I = 99%). Decreased ApoA1 values were associated with MetS (OR = 0.42; 95% CI: 0.38-0.47; p < 0.01, I = 99%). Increased values of the ApoB/ApoA1 ratio were associated with MetS (OR = 4.97; 95% CI: 3.83-6.44; p < 0.01, I = 97%). Decreased values of Lp(a) were associated with MetS (OR = 0.89; 95% CI: 0.82-0.96; p < 0.01; I = 92%).
CONCLUSIONS
Increased values of ApoB and ApoB/ApoA1 ratio are associated with MetS, while decreased values of ApoA1 and Lp(a) are associated with MetS. These findings suggest that these lipid markers may serve as potential indicators for identifying subjects at risk of developing MetS. However, further research is required to elucidate the underlying mechanisms of these associations.
Topics: Humans; Metabolic Syndrome; Lipoprotein(a); Apolipoproteins; Apolipoproteins B; Insulin Resistance
PubMed: 37420190
DOI: 10.1186/s12944-023-01860-w -
Expert Review of Endocrinology &... May 2023Hypocholesterolemia results from genetic - both monogenic and polygenic - and non-genetic causes and can sometimes be a source of clinical concern. We review etiologies... (Review)
Review
INTRODUCTION
Hypocholesterolemia results from genetic - both monogenic and polygenic - and non-genetic causes and can sometimes be a source of clinical concern. We review etiologies and sequelae of hypocholesterolemia and therapeutics inspired from genetic hypocholesterolemia.
AREAS COVERED
Monogenic hypocholesterolemia disorders caused by the complete absence of apolipoprotein (apo) B-containing lipoproteins (abetalipoproteinemia and homozygous hypobetalipoproteinemia) or an isolated absence of apo B-48 lipoproteinemia (chylomicron retention disease) lead to clinical sequelae. These include gastrointestinal disturbances and severe vitamin deficiencies that affect multiple body systems, i.e. neurological, musculoskeletal, ophthalmological, and hematological. Monogenic hypocholesterolemia disorders with reduced but not absent levels of apo B lipoproteins have a milder clinical presentation and patients are protected against atherosclerotic cardiovascular disease. Patients with heterozygous hypobetalipoproteinemia have somewhat increased risk of hepatic disease, while patients with PCSK9 deficiency, ANGPTL3 deficiency, and polygenic hypocholesterolemia typically have anunremarkable clinical presentation.
EXPERT OPINION
In patients with severe monogenic hypocholesterolemia, early initiation of high-dose vitamin therapy and a low-fat diet are essential for optimal prognosis. The molecular basis of monogenic hypocholesterolemia has inspired novel therapeutics to help patients with the opposite phenotype - i.e. elevated apo B-containing lipoproteins. In particular, inhibitors of PCSK9 and ANGPTL3 show important clinical impact.
Topics: Humans; Proprotein Convertase 9; Hypobetalipoproteinemias; Apolipoproteins B; Lipoproteins; Cholesterol; Angiopoietin-Like Protein 3
PubMed: 37089071
DOI: 10.1080/17446651.2023.2204932 -
Current Opinion in Lipidology Dec 2019Determine if evidence supports interventions to prevent development of atherosclerosis and atherosclerotic cardiovascular disease (ASCVD) events and death. (Review)
Review
PURPOSE OF REVIEW
Determine if evidence supports interventions to prevent development of atherosclerosis and atherosclerotic cardiovascular disease (ASCVD) events and death.
RECENT FINDINGS
An extensive body of evidence supports the fundamental causal role of apolipoprotein B lipoproteins in the development of atherosclerosis. Recent epidemiologic studies have shown that LDL-cholesterol (LDL-C) and non-HDL-cholesterol levels in early adults are associated with accelerated subclinical atherosclerosis and an excess of atherosclerotic cardiovascular events later in life. Animal and human data have shown that intensive LDL-C lowering can regress earlier stages of atherosclerosis.
SUMMARY
The next research priority is evaluating the impact of lowering LDL-C earlier in life to regress early atherosclerosis, followed by trials to demonstrate this approach will eradicate later-life ASCVD events and death. This approach of curing atherosclerosis will likely be the most effective strategy for reducing the huge global burden of atherosclerosis.
Topics: Animals; Apolipoproteins B; Atherosclerosis; Cholesterol, LDL; Humans; Lipoproteins, HDL
PubMed: 31592794
DOI: 10.1097/MOL.0000000000000644 -
BMC Musculoskeletal Disorders Nov 2023Lipids are critical in bone metabolism, and several studies have highlighted their importance. This study aimed to investigate the relationship between apolipoprotein B...
BACKGROUND
Lipids are critical in bone metabolism, and several studies have highlighted their importance. This study aimed to investigate the relationship between apolipoprotein B (apo B) and bone mineral density (BMD) at different skeletal sites (lumbar spine, femoral neck, and total femur) and to compare the influence of apo B with other traditional lipid markers.
METHODS
The study included participants from the National Health and Nutrition Examination Survey (NHANES) between 2011 and 2016 who had complete data for apo B and BMD at the three skeletal sites. We used weighted multivariate regression analysis, subgroup analysis, and interaction tests to examine associations. Restricted cubic spline (RCS) was used to examine the non-linear relationship.
RESULTS
A total of 4,258 adults were included in the study. Multivariate linear regression analysis showed that the relationship between apo B and BMD varied by skeletal site: a negative association was found with lumbar spine BMD [β = -0.054, 95%CI: (-0.073, -0.035)]. In contrast, a positive association was found with femoral neck BMD [β = 0.031, 95%CI: (0.011, 0.051)] and no significant association between apo B and total femur BMD.
CONCLUSIONS
Our findings suggest that apo B is associated with BMD in a site-specific manner.
Topics: Adult; Humans; Absorptiometry, Photon; Apolipoproteins B; Bone Density; Femur Neck; Lumbar Vertebrae; Nutrition Surveys
PubMed: 37919727
DOI: 10.1186/s12891-023-06990-x -
Clinica Chimica Acta; International... May 2023Obesity is a state presented by excessive accumulation and abnormal distribution of body fat, with metabolic disorders being one of its distinguishing features. Obesity... (Review)
Review
Obesity is a state presented by excessive accumulation and abnormal distribution of body fat, with metabolic disorders being one of its distinguishing features. Obesity is associated with dyslipidemia and apolipoproteins are important structural components of plasma lipoproteins. Apolipoproteins influence the progression of obesity by a variety of mechanisms including lipid metabolism, energy expenditure and inflammatory response. In this review, we discuss the role of apolipoproteins in obesity, mechanisms of action as well as their potential as new therapeutic targets.
Topics: Humans; Apolipoproteins; Lipoproteins; Obesity; Apolipoproteins E; Apolipoproteins B
PubMed: 37086940
DOI: 10.1016/j.cca.2023.117359 -
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 -
Current Opinion in Lipidology Dec 2023The triglyceride-rich apoB lipoprotein particles make up a minority of the apoB particles in plasma. They vary in size, in lipid, and in protein content. Most are small... (Review)
Review
PURPOSE OF REVIEW
The triglyceride-rich apoB lipoprotein particles make up a minority of the apoB particles in plasma. They vary in size, in lipid, and in protein content. Most are small enough to enter the arterial wall and therefore most are atherogenic. But how important a contribution TRL particles make to the total risk created by the apoB lipoproteins remains controversial. A recent Mendelian randomization analysis determined that the cardiovascular risk related to the cholesterol within these apoB particles--the TRL cholesterol--was greater than--and independent of--the risk related to apoB. If correct, these observations have major clinical significance.
RECENT FINDINGS
Accordingly, we have analyzed these results in detail. In our view, the independent strength of the association between TRL cholesterol and apoB with cardiovascular risk seems inconsistent with the biological connections between apoB and cholesterol as integral and highly correlated constituents of apoB particles. These results are also inconsistent with other lines of evidence such as the results of the fibrate randomized clinical trials. Moreover, we are also concerned with other aspects of the analysis.
SUMMARY
We do not regard the issue as settled. However, this enquiry has led us to a fuller understanding of the determinants of the cholesterol content of the TRL apoB particles and the complex processing of cholesterol amongst the plasma lipoproteins.
Topics: Humans; Cardiovascular Diseases; Risk Factors; Cholesterol; Lipoproteins; Triglycerides; Apolipoproteins B; Heart Disease Risk Factors
PubMed: 37773930
DOI: 10.1097/MOL.0000000000000905 -
BMC Medicine Jul 2023Asialoglycoprotein receptor 1 (ASGR1) is emerging as a potential drug target to reduce low-density lipoprotein (LDL)-cholesterol and coronary artery disease (CAD) risk....
Genetically mimicked effects of ASGR1 inhibitors on all-cause mortality and health outcomes: a drug-target Mendelian randomization study and a phenome-wide association study.
BACKGROUND
Asialoglycoprotein receptor 1 (ASGR1) is emerging as a potential drug target to reduce low-density lipoprotein (LDL)-cholesterol and coronary artery disease (CAD) risk. Here, we investigated genetically mimicked ASGR1 inhibitors on all-cause mortality and any possible adverse effects.
METHODS
We conducted a drug-target Mendelian randomization study to assess genetically mimicked effects of ASGR1 inhibitors on all-cause mortality and 25 a priori outcomes relevant to lipid traits, CAD, and possible adverse effects, i.e. liver function, cholelithiasis, adiposity and type 2 diabetes. We also performed a phenome-wide association study of 1951 health-related phenotypes to identify any novel effects. Associations found were compared with those for currently used lipid modifiers, assessed using colocalization, and replicated where possible.
RESULTS
Genetically mimicked ASGR1 inhibitors were associated with a longer lifespan (3.31 years per standard deviation reduction in LDL-cholesterol, 95% confidence interval 1.01 to 5.62). Genetically mimicked ASGR1 inhibitors were inversely associated with apolipoprotein B (apoB), triglycerides (TG) and CAD risk. Genetically mimicked ASGR1 inhibitors were positively associated with alkaline phosphatase, gamma glutamyltransferase, erythrocyte traits, insulin-like growth factor 1 (IGF-1) and C-reactive protein (CRP), but were inversely associated with albumin and calcium. Genetically mimicked ASGR1 inhibitors were not associated with cholelithiasis, adiposity or type 2 diabetes. Associations with apoB and TG were stronger for ASGR1 inhibitors compared with currently used lipid modifiers, and most non-lipid effects were specific to ASGR1 inhibitors. The probabilities for colocalization were > 0.80 for most of these associations, but were 0.42 for lifespan and 0.30 for CAD. These associations were replicated using alternative genetic instruments and other publicly available genetic summary statistics.
CONCLUSIONS
Genetically mimicked ASGR1 inhibitors reduced all-cause mortality. Beyond lipid-lowering, genetically mimicked ASGR1 inhibitors increased liver enzymes, erythrocyte traits, IGF-1 and CRP, but decreased albumin and calcium.
Topics: Humans; Apolipoproteins B; Asialoglycoprotein Receptor; Calcium; Cholelithiasis; Coronary Artery Disease; Diabetes Mellitus, Type 2; Genome-Wide Association Study; Insulin-Like Growth Factor I; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide; Risk Factors; Triglycerides
PubMed: 37400795
DOI: 10.1186/s12916-023-02903-w