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The American Journal of Clinical... Apr 2024Apolipoproteins (APOs) have emerged as significant players in lipid metabolism that affects the risk of chronic disease. However, the impact of circulating APO...
BACKGROUND
Apolipoproteins (APOs) have emerged as significant players in lipid metabolism that affects the risk of chronic disease. However, the impact of circulating APO concentrations on premature death remains undetermined.
OBJECTIVES
This study aimed to investigate the associations of serum APOs with all-cause, cardiovascular disease (CVD)-related, and cancer-related mortality.
METHODS
We included 340,737 participants who had serum APO measurements from the UK Biobank. Restricted cubic splines and multivariable Cox regression models were used to assess the associations between APOs and all-cause and cause-specific mortality by computing hazard ratios (HRs) and 95% confidence intervals (CIs). Based on 1-sample Mendelian randomization (MR) design, including 398,457 participants of White ancestry who had genotyping data from the UK Biobank, we performed instrumental variable analysis with 2-stage least squares regression to assess the association between genetically predicted APOs and mortality.
RESULTS
After adjusting for potential confounders including high-density and low-density lipoprotein particles, we observed nonlinear inverse relationships of APOA1 with all-cause, CVD-related, and cancer-related mortality (P-nonlinear < 0.001). By contrast, positive relationships were observed for APOB and all-cause (P-nonlinear < 0.001), CVD-related (P-linear < 0.001), and cancer-related (P-linear = 0.03) mortality. MR analysis showed consistent results, except that the association between APOB and cancer mortality was null. Furthermore, both observational and MR analyses found an inverse association between APOA1 and lung cancer-related mortality (HR comparing extreme deciles: 0.46; 95% CI: 0.26, 0.80; and HR: 0.78; 95% CI: 0.63, 0.97, respectively).
CONCLUSIONS
Our findings indicate that circulating APOA1 has potential beneficial effects on all-cause, CVD-related, and lung cancer-related death risk, whereas APOB may confer detrimental effects on all-cause and CVD-related death risk.
Topics: Humans; Mendelian Randomization Analysis; Risk Factors; Apolipoproteins; Cardiovascular Diseases; Apolipoproteins B; Lung Neoplasms
PubMed: 38211689
DOI: 10.1016/j.ajcnut.2024.01.002 -
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 -
Chembiochem : a European Journal of... Jun 2016Small interfering RNA (siRNA)-mediated silencing requires siRNA loading into the RNA-induced silencing complex (RISC). Presence of 5'-phosphate (5'-P) is reported to be...
Small interfering RNA (siRNA)-mediated silencing requires siRNA loading into the RNA-induced silencing complex (RISC). Presence of 5'-phosphate (5'-P) is reported to be critical for efficient RISC loading of the antisense strand (AS) by anchoring it to the mid-domain of the Argonaute2 (Ago2) protein. Phosphorylation of exogenous duplex siRNAs is thought to be accomplished by cytosolic Clp1 kinase. However, although extensive chemical modifications are essential for siRNA-GalNAc conjugate activity, they can significantly impair Clp1 kinase activity. Here, we further elucidated the effect of 5'-P on the activity of siRNA-GalNAc conjugates. Our results demonstrate that a subset of sequences benefit from the presence of exogenous 5'-P. For those that do, incorporation of 5'-(E)-vinylphosphonate (5'-VP), a metabolically stable phosphate mimic, results in up to 20-fold improved in vitro potency and up to a threefold benefit in in vivo activity by promoting Ago2 loading and enhancing metabolic stability.
Topics: Acetylgalactosamine; Animals; Apolipoproteins B; Argonaute Proteins; Cells, Cultured; Factor IX; Hepatocytes; Humans; Lipoproteins, LDL; Mice; Mice, Inbred C57BL; Organophosphonates; RNA Interference; RNA, Small Interfering; RNA-Binding Proteins; RNA-Induced Silencing Complex; Transcription Factors; Vinyl Compounds
PubMed: 27121751
DOI: 10.1002/cbic.201600130 -
Frontiers in Endocrinology 2023To investigate the relationship between function of thyroid, lipids, and cholelithiasis and to identify whether lipids mediate the causal relationship between function...
OBJECTIVE
To investigate the relationship between function of thyroid, lipids, and cholelithiasis and to identify whether lipids mediate the causal relationship between function of thyroid and cholelithiasis.
METHODS
A Mendelian randomization (MR) study of two samples was performed to determine the association of thyroid function with cholelithiasis. A two-step MR was also performed to identify whether lipid metabolism traits mediate the effects of thyroid function on cholelithiasis. A method of inverse variance weighted (IVW), weighted median method, maximum likelihood, MR-Egger, MR-robust adjusted profile score (MR-RAPS) method, and MR pleiotropy residual sum and outlier test (MR-PRESSO) methods were utilized to obtain MR estimates.
RESULTS
The IVW method revealed that FT4 levels were correlated with an elevated risk of cholelithiasis (OR: 1.149, 95% CI: 1.082-1.283, = 0.014). Apolipoprotein B (OR: 1.255, 95% CI: 1.027-1.535, = 0.027) and low-density lipoprotein cholesterol (LDL-C) (OR: 1.354, 95% CI: 1.060-1.731, = 0.016) were also correlated with an elevated risk of cholelithiasis. The IVW method demonstrated that FT4 levels were correlated with the elevated risk of apolipoprotein B (OR: 1.087, 95% CI: 1.019-1.159, = 0.015) and LDL-C (OR: 1.084, 95% CI: 1.018-1.153, = 0.012). Thyroid function and the risk of cholelithiasis are mediated by LDL-C and apolipoprotein B. LDL-C and apolipoprotein B had 17.4% and 13.5% of the mediatory effects, respectively.
CONCLUSIONS
We demonstrated that FT4, LDL-C, and apolipoprotein B had significant causal effects on cholelithiasis, with evidence that LDL-C and apolipoprotein B mediated the effects of FT4 on cholelithiasis risk. Patients with high FT4 levels should be given special attention because they may delay or limit the long-term impact on cholelithiasis risk.
Topics: Humans; Mendelian Randomization Analysis; Cholesterol, LDL; Thyroid Gland; Apolipoproteins B; Causality
PubMed: 37065749
DOI: 10.3389/fendo.2023.1166740 -
Journal of Medical Primatology Dec 2022Owl monkeys (Aotus infulatus) are frequently affected by heart diseases and, as in humans, dyslipidemia is one of the predisposing factors for adverse cardiovascular...
BACKGROUND
Owl monkeys (Aotus infulatus) are frequently affected by heart diseases and, as in humans, dyslipidemia is one of the predisposing factors for adverse cardiovascular events. In view of this, the study of the lipid profile and plasma apolipoproteins can contribute to the clinical management of this neotropical primate species.
METHODS
Lipid profile as well as A-1 and B apolipoprotein values were analyzed in 60 owl monkeys, studying their relationship with body biometry and the presence of cardiac alterations.
RESULTS
Animals suspected of having heart disease did not show significant differences (p < .05) in terms of biometry or in relation to lipid profile and apolipoproteins A-1 and B values; however, higher values of LDL and ApoB and ApoB/ApoA-1 were observed in this group.
CONCLUSIONS
This study is the first to describe the lipid profile and apolipoprotein values in owl monkeys, and further work will be needed to better elucidate the worthiness of LDL, ApoB, and the ApoB/ApoA-1 ratio in this primate species.
Topics: Animals; Aotidae; Apolipoprotein A-I; Apolipoproteins; Apolipoproteins B
PubMed: 35916434
DOI: 10.1111/jmp.12607 -
Free Radical Biology & Medicine Oct 20174-hydroxy-2-nonenal (HNE) is a α,β-unsaturated hydroxyalkenal generated by peroxidation of n-6 polyunsaturated fatty acid. This reactive carbonyl compound exhibits a... (Review)
Review
4-hydroxy-2-nonenal (HNE) is a α,β-unsaturated hydroxyalkenal generated by peroxidation of n-6 polyunsaturated fatty acid. This reactive carbonyl compound exhibits a huge number of biological properties that result mainly from the formation of HNE-adducts on free amino groups and thiol groups in proteins. In the vascular system, HNE adduct accumulation progressively leads to cellular dysfunction and tissue damages that are involved in the progression of atherosclerosis and related diseases. HNE contributes to the atherogenicity of oxidized LDL, by forming HNE-apoB adducts that deviate the LDL metabolism to the scavenger receptor pathway of macrophagic cells, and lead to the formation of foam cells. HNE activates transcription factors (Nrf2, NF-kappaB) that (dys)regulate various cellular responses ranging from hormetic and survival signaling at very low concentrations, to inflammatory and apoptotic effects at higher concentrations. Among a variety of cellular targets, HNE can modify signaling proteins involved in atherosclerotic plaque remodeling, particularly growth factor receptors (PDGFR, EGFR), cell cycle proteins, mitochondrial and endoplasmic reticulum components or extracellular matrix proteins, which progressively alters smooth muscle cell proliferation, angiogenesis and induces apoptosis. HNE adducts accumulate in the lipidic necrotic core of advanced atherosclerotic lesions, and may locally contribute to macrophage and smooth muscle cell apoptosis, which may induce plaque destabilization and rupture, thereby increasing the risk of athero-thrombotic events.
Topics: Aldehydes; Animals; Aorta; Apolipoproteins B; Atherosclerosis; Endothelium, Vascular; Gene Expression Regulation; Humans; Lipid Peroxidation; Lipoproteins, LDL; Macrophages; NF-E2-Related Factor 2; NF-kappa B; Neovascularization, Pathologic; Signal Transduction
PubMed: 28040472
DOI: 10.1016/j.freeradbiomed.2016.12.038 -
Journal of Diabetes Research 2019Nontraditional cardiovascular risk factors as apolipoprotein A (ApoA), apolipoprotein B (ApoB), and the proprotein convertase subtilisin/kexin type 9 (PCSK9) increase... (Review)
Review
PURPOSE
Nontraditional cardiovascular risk factors as apolipoprotein A (ApoA), apolipoprotein B (ApoB), and the proprotein convertase subtilisin/kexin type 9 (PCSK9) increase the prevalence of cardiovascular mortality in chronic kidney disease (CKD) or in end-stage renal disease (ESRD) through quantitative alterations. This review is aimed at establishing the biomarker (ApoA, ApoB, and PCSK9) level variations in uremic patients, to identify the studies showing the association between these biomarkers and the development of cardiovascular events and to depict the therapeutic options to reduce cardiovascular risk in CKD and ESRD patients.
METHODS
We searched the electronic database of PubMed, Scopus, EBSCO, and Cochrane CENTRAL for studies evaluating apolipoproteins and PCSK9 in CKD and ESRD. Randomized controlled trials, observational studies (including case-control, prospective or retrospective cohort), and reviews/meta-analysis were included if reference was made to those keys and cardiovascular outcomes in CKD/ESRD.
RESULTS
18 studies met inclusion criteria. Serum ApoA-I has been significantly associated with the development of new cardiovascular event and with cardiovascular mortality in ESRD patients. ApoA-IV level was independently associated with maximum carotid intima-media thickness (cIMT) and was a predictor for sudden cardiac death. The ApoB/ApoA-I ratio represents a strong predictor for coronary artery calcifications, cardiovascular mortality, and myocardial infarction in CKD/ESRD. Plasma levels of PCSK9 were not associated with cardiovascular events in CKD patients.
CONCLUSIONS
Although the "dyslipidemic status" in CKD/ESRD is not clearly depicted, due to different research findings, ApoA-I, ApoA-IV, and ApoB/ApoA-I ratio could be predictors of cardiovascular risk. Serum PCSK9 levels were not associated with the cardiovascular events in patients with CKD/ESRD. Probably in the future, the treatment of dyslipidemia in CKD/ESRD will be aimed at discovering new effective therapies on the action of these biomarkers.
Topics: Apolipoproteins A; Apolipoproteins B; Cardiovascular Diseases; Humans; Kidney Failure, Chronic; Proprotein Convertase 9; Renal Insufficiency, Chronic; Risk Factors
PubMed: 31915710
DOI: 10.1155/2019/6906278 -
Circulation Research Feb 2023Recognition of the importance of conventional lipid measures and the advent of novel lipid-lowering medications have prompted the need for more comprehensive lipid...
BACKGROUND
Recognition of the importance of conventional lipid measures and the advent of novel lipid-lowering medications have prompted the need for more comprehensive lipid panels to guide use of emerging treatments for the prevention of coronary heart disease (CHD). This report assessed the relevance of 13 apolipoproteins measured using a single mass-spectrometry assay for risk of CHD in the PROCARDIS case-control study of CHD (941 cases/975 controls).
METHODS
The associations of apolipoproteins with CHD were assessed after adjustment for established risk factors and correction for statin use. Apolipoproteins were grouped into 4 lipid-related classes [lipoprotein(a), low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides] and their associations with CHD were adjusted for established CHD risk factors and conventional lipids. Analyses of these apolipoproteins in a subset of the ASCOT trial (Anglo-Scandinavian Cardiac Outcomes Trial) were used to assess their within-person variability and to estimate a correction for statin use. The findings in the PROCARDIS study were compared with those for incident cardiovascular disease in the Bruneck prospective study (n=688), including new measurements of Apo(a).
RESULTS
Triglyceride-carrying apolipoproteins (ApoC1, ApoC3, and ApoE) were most strongly associated with the risk of CHD (2- to 3-fold higher odds ratios for top versus bottom quintile) independent of conventional lipid measures. Likewise, ApoB was independently associated with a 2-fold higher odds ratios of CHD. Lipoprotein(a) was measured using peptides from the Apo(a)-kringle repeat and Apo(a)-constant regions, but neither of these associations differed from the association with conventionally measured lipoprotein(a). Among HDL-related apolipoproteins, ApoA4 and ApoM were inversely related to CHD, independent of conventional lipid measures. The disease associations with all apolipoproteins were directionally consistent in the PROCARDIS and Bruneck studies, with the exception of ApoM.
CONCLUSIONS
Apolipoproteins were associated with CHD independent of conventional risk factors and lipids, suggesting apolipoproteins could help to identify patients with residual lipid-related risk and guide personalized approaches to CHD risk reduction.
Topics: Humans; Prospective Studies; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Case-Control Studies; Proteomics; Apolipoproteins; Risk Factors; Coronary Disease; Triglycerides; Cholesterol, HDL; Lipoprotein(a); Apolipoproteins B; Apolipoprotein A-I
PubMed: 36691918
DOI: 10.1161/CIRCRESAHA.122.321690 -
Biological & Pharmaceutical Bulletin 2016Increased levels of apolipoprotein B (apoB)-containing lipoproteins, such as low density lipoproteins (LDL) and chylomicron remnants, are associated with the development... (Review)
Review
Increased levels of apolipoprotein B (apoB)-containing lipoproteins, such as low density lipoproteins (LDL) and chylomicron remnants, are associated with the development of atherosclerosis. Chylomicrons containing apoB-48 are secreted from the intestine during the postprandial state, whereas very low density lipoproteins (VLDL) containing apoB-100 are constitutively formed in the liver. Chylomicron remnants and VLDL remnants are produced by the lipoprotein lipase-mediated lipolysis of triglycerides, which is activated by apolipoprotein C-II bound on the particle surfaces. The hepatic uptake of these remnants is facilitated by apolipoprotein E (apoE), but is inhibited by apolipoproteins C-I, C-II and C-III. In the plasma, VLDL remnants are further converted into LDL by the hydrolysis of triglycerides. ApoB-100 is responsible for the hepatic uptake of LDL. LDL receptor, LDL receptor-related protein and heparan sulfate proteoglycans are involved in the hepatic clearance of lipoproteins containing apoB-100 and/or apoE. The subendothelial retention and modification of apoB-containing lipoproteins are crucial events in the initiation of atherosclerosis. In the subendothelium, the uptake of modified lipoproteins by macrophages leads to the formation of foam cells storing excess amounts of cholesteryl esters and subsequently to apoptosis. This review describes the current knowledge about the metabolism and modification of apoB-containing lipoproteins involved in dyslipidemia and atherogenesis. In particular, I focus on the effects of apolipoproteins, lipid composition and particle size on lipoprotein metabolism and on the roles of cholesterol, sphingomyelinase and apoB denaturation in macrophage foam cell formation and apoptosis. A detailed understanding of these mechanisms will help to develop new therapeutic strategies.
Topics: Apolipoproteins B; Atherosclerosis; Dyslipidemias; Humans
PubMed: 26725424
DOI: 10.1248/bpb.b15-00716