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Atherosclerosis May 2022Epidemiological studies investigating the association between a biomarker and a disease have many limitations. The most prominent among these is that we cannot impute... (Review)
Review
Epidemiological studies investigating the association between a biomarker and a disease have many limitations. The most prominent among these is that we cannot impute causality purely from a statistical association. If we observe an association, the biomarker might really be causal for the development of the disease, the association might be caused by a confounding variable or by reverse causation. With Mendelian Randomization (MR) methods, we have a potent tool at hand to derive evidence for a direct causal relationship. One of the core assumptions of MR studies is that genetic variants can be identified, which are strongly associated with the biomarker of interest, and can serve as an instrument indicating lifetime exposure. Since Lp(a) is primarily genetically determined by KIV-2 repeats, that in turn determine apo(a) isoform size, and by numerous single nucleotide polymorphisms (SNPs) and SNP-scores, this assumption is definitely fulfilled and it is probably one of the best phenotypes to be studied with Mendelian Randomization methods. The first studies evaluating the causal role of Lp(a) for cardiovascular diseases were performed in the early 1990s and more recently gained interest after several Lp(a)-increasing SNPs were identified in genome wide association studies. In this review, the principles behind MR methods are explained, together with their important role for Lp(a) research, particularly reconsidered in their historic context. MR methods have also been used to estimate the extent of Lp(a) reduction that would be required to yield a clinically meaningful reduction in outcomes in clinical intervention trials.
Topics: Apolipoproteins A; Apoprotein(a); Biomarkers; Genome-Wide Association Study; Lipoprotein(a); Mendelian Randomization Analysis; Polymorphism, Single Nucleotide
PubMed: 35606074
DOI: 10.1016/j.atherosclerosis.2022.04.013 -
Circulation Research Jun 2016Lipoprotein(a) [Lp(a)] is a highly atherogenic low-density lipoprotein-like particle characterized by the presence of apoprotein(a) [apo(a)] bound to apolipoprotein B....
RATIONALE
Lipoprotein(a) [Lp(a)] is a highly atherogenic low-density lipoprotein-like particle characterized by the presence of apoprotein(a) [apo(a)] bound to apolipoprotein B. Proprotein convertase subtilisin/kexin type 9 (PCSK9) selectively binds low-density lipoprotein; we hypothesized that it can also be associated with Lp(a) in plasma.
OBJECTIVE
Characterize the association of PCSK9 and Lp(a) in 39 subjects with high Lp(a) levels (range 39-320 mg/dL) and in transgenic mice expressing either human apo(a) only or human Lp(a) (via coexpression of human apo(a) and human apolipoprotein B).
METHODS AND RESULTS
We show that PCSK9 is physically associated with Lp(a) in vivo using 3 different approaches: (1) analysis of Lp(a) fractions isolated by ultracentrifugation; (2) immunoprecipitation of plasma using antibodies to PCSK9 and immunodetection of apo(a); (3) ELISA quantification of Lp(a)-associated PCSK9. Plasma PCSK9 levels correlated with Lp(a) levels, but not with the number of kringle IV-2 repeats. PCSK9 did not bind to apo(a) only, and the association of PCSK9 with Lp(a) was not affected by the loss of the apo(a) region responsible for binding oxidized phospholipids. Preferential association of PCSK9 with Lp(a) versus low-density lipoprotein (1.7-fold increase) was seen in subjects with high Lp(a) and normal low-density lipoprotein. Finally, Lp(a)-associated PCSK9 levels directly correlated with plasma Lp(a) levels but not with total plasma PCSK9 levels.
CONCLUSIONS
Our results show, for the first time, that plasma PCSK9 is found in association with Lp(a) particles in humans with high Lp(a) levels and in mice carrying human Lp(a). Lp(a)-bound PCSK9 may be pursued as a biomarker for cardiovascular risk.
Topics: Animals; Apolipoproteins A; Apolipoproteins B; Biomarkers; Humans; Lipoprotein(a); Mice; Proprotein Convertase 9; Protein Binding
PubMed: 27121620
DOI: 10.1161/CIRCRESAHA.116.308811 -
Molecules (Basel, Switzerland) Mar 2021Membrane-scaffolding proteins (MSPs) derived from apolipoprotein A-1 have become a versatile tool in generating nano-sized discoidal membrane mimetics (nanodiscs) for...
Membrane-scaffolding proteins (MSPs) derived from apolipoprotein A-1 have become a versatile tool in generating nano-sized discoidal membrane mimetics (nanodiscs) for membrane protein research. Recent efforts have aimed at exploiting their controlled lipid protein ratio and size distribution to arrange membrane proteins in regular supramolecular structures for diffraction studies. Thereby, direct membrane protein crystallization, which has remained the limiting factor in structure determination of membrane proteins, would be circumvented. We describe here the formation of multimers of membrane-scaffolding protein MSP1D1-bounded nanodiscs using the thiol reactivity of engineered cysteines. The mutated positions N42 and K163 in MSP1D1 were chosen to support chemical modification as evidenced by fluorescent labeling with pyrene. Minimal interference with the nanodisc formation and structure was demonstrated by circular dichroism spectroscopy, differential light scattering and size exclusion chromatography. The direct disulphide bond formation of nanodiscs formed by the MSP1D1_N42C variant led to dimers and trimers with low yield. In contrast, transmission electron microscopy revealed that the attachment of oligonucleotides to the engineered cysteines of MSP1D1 allowed the growth of submicron-sized tracts of stacked nanodiscs through the hybridization of nanodisc populations carrying complementary strands and a flexible spacer.
Topics: Amino Acid Sequence; Apolipoprotein A-I; DNA; Lipid Bilayers; Membrane Proteins; Microscopy, Electron, Transmission; Nanostructures; Phospholipids
PubMed: 33809519
DOI: 10.3390/molecules26061647 -
Best Practice & Research. Clinical... Jul 2023COVID-19 infections decrease total cholesterol, LDL-C, HDL-C, and apolipoprotein A-I, A-II, and B levels while triglyceride levels may be increased or inappropriately... (Review)
Review
COVID-19 infections decrease total cholesterol, LDL-C, HDL-C, and apolipoprotein A-I, A-II, and B levels while triglyceride levels may be increased or inappropriately normal for the poor nutritional status. The degree of reduction in total cholesterol, LDL-C, HDL-C, and apolipoprotein A-I are predictive of mortality. With recovery lipid/lipoprotein levels return towards pre-infection levels and studies have even suggested an increased risk of dyslipidemia post-COVID-19 infection. The potential mechanisms for these changes in lipid and lipoprotein levels are discussed. Decreased HDL-C and apolipoprotein A-I levels measured many years prior to COVID-19 infections are associated with an increased risk of severe COVID-19 infections while LDL-C, apolipoprotein B, Lp (a), and triglyceride levels were not consistently associated with an increased risk. Finally, data suggest that omega-3-fatty acids and PCSK9 inhibitors may reduce the severity of COVID-19 infections. Thus, COVID-19 infections alter lipid/lipoprotein levels and HDL-C levels may affect the risk of developing COVID-19 infections.
Topics: Humans; Proprotein Convertase 9; Triglycerides; Apolipoprotein A-I; Cholesterol, LDL; COVID-19; Lipoproteins; Cholesterol, HDL
PubMed: 36894344
DOI: 10.1016/j.beem.2023.101751 -
International Journal of Molecular... Nov 2023Preeclampsia (PE) is one of the pregnancy complications, leading to major maternal and fetal morbidity and mortality; however, the underlying mechanisms of PE still...
Preeclampsia (PE) is one of the pregnancy complications, leading to major maternal and fetal morbidity and mortality; however, the underlying mechanisms of PE still remain unclear. We aimed to explore the role of apolipoprotein A1 (APOA1) in the pathophysiology of PE. The expression of APOA1 was elevated in both plasma and placental tissues, as detected by Western blotting, immunohistochemistry, and a qRT-PCR assay. Importantly, we detected the concentration of APOA1 using the ELISA assay in normal control women ( = 30) and women with preeclampsia ( = 29) from a prospective cohort study. The concentration of APOA1 was not significantly altered in plasma during early and mid-term gestation of the PE patients compared to the NP patients; however, it was elevated during late gestation. Additionally, the concentration of APOA1 was positively associated with systolic blood pressure during late gestation. The proliferation and invasion of trophoblast were all increased in HTR8/SVneo cells transfected with siRNA and decreased in HTR8/SVneo cells treated with the recombinant human APOA1 protein (rhAPOA1). Additionally, we used public datasets to investigate the downstream genes of APOA1 and qRT-PCR for validation. Furthermore, we explored the transcriptional activity of peroxisome proliferator-activated receptor gamma (PPARγ) in APOA1 by using a luciferase assay, which showed that the promoter was activated by PPARγ. Additionally, the inhibitory effect of rhAPOA1 on the ability of trophoblast invasion and proliferation can be rescued by the PPARγ inhibitor. Our findings suggest the crucial role of APOA1 in PE, which might provide a new strategy for the prevention and treatment of PE.
Topics: Pregnancy; Humans; Female; Placenta; Pre-Eclampsia; Apolipoprotein A-I; PPAR gamma; Prospective Studies; Trophoblasts; Cell Movement; Cell Proliferation
PubMed: 38003549
DOI: 10.3390/ijms242216363 -
Cells Apr 2019Apolipoprotein A-IV (apoA-IV) is a lipid-binding protein, which is primarily synthesized in the small intestine, packaged into chylomicrons, and secreted into intestinal... (Review)
Review
Apolipoprotein A-IV (apoA-IV) is a lipid-binding protein, which is primarily synthesized in the small intestine, packaged into chylomicrons, and secreted into intestinal lymph during fat absorption. In the circulation, apoA-IV is present on chylomicron remnants, high-density lipoproteins, and also in lipid-free form. ApoA-IV is involved in a myriad of physiological processes such as lipid absorption and metabolism, anti-atherosclerosis, platelet aggregation and thrombosis, glucose homeostasis, and food intake. ApoA-IV deficiency is associated with atherosclerosis and diabetes, which renders it as a potential therapeutic target for treatment of these diseases. While much has been learned about the physiological functions of apoA-IV using rodent models, the action of apoA-IV at the cellular and molecular levels is less understood, let alone apoA-IV-interacting partners. In this review, we will summarize the findings on the molecular function of apoA-IV and apoA-IV-interacting proteins. The information will shed light on the discovery of apoA-IV receptors and the understanding of the molecular mechanism underlying its mode of action.
Topics: Animals; Apolipoproteins A; Atherosclerosis; Cholesterol; Diabetes Mellitus; Glucose; Homeostasis; Humans
PubMed: 30959835
DOI: 10.3390/cells8040319 -
Frontiers in Endocrinology 2023This study aims to evaluate the effect of acupuncture on the emotion domain and metabolic parameters of Chinese women with polycystic ovarian syndrome (PCOS) by... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
This study aims to evaluate the effect of acupuncture on the emotion domain and metabolic parameters of Chinese women with polycystic ovarian syndrome (PCOS) by secondary analysis of a randomized clinical trial, conducted from 6 July 2012 to 7 October 2015.
METHOD
In this study, we investigated the effects of acupuncture (458 patients) and sham acupuncture (468 patients) on metabolic parameters, serum ions, and all quality-of-life scale scores related to PCOS. The quality of life of patients was evaluated using five relevant scales, operated by the research assistant, namely, PCOSQ, SF-36, and ChiQOL, as well as Zung-SAS and Zung-SDS. Metabolic parameters and serum ions were measured.
RESULTS
A reduction in acne score, AN, Hcy, and LDL-C, and an increase in the level of lipoprotein α, Apo A1, and Apo A1/Apo B were observed in the acupuncture group after 4 months' intervention after adjusting clomiphene and reproductive outcome (< 0.05). An increase in SF-36 total scores, RP and RE scores, ChiQOL total scores, and emotion domain scores was observed in the acupuncture group after 4 months' intervention, while PF and HT scores were decreased (adjusted < 0.05). Those same changes were observed in sham acupuncture. Meanwhile, the serum levels of Ca, K, and Cl were elevated in the acupuncture group after the interventions (adjusted < 0.005). There were no significant differences in HOMA-IR, MetS, FPG, FINS, HDL-C, TG, Apo B, and level of serum P, Mg, and Na. Also, no changes in BP, GH, VT, SF, physical form domain, and spirit domain were observed after treatment.
CONCLUSION
Acupuncture can improve not only the emotional changes in SF-36 scores and ChiQOL scores, but also lipid metabolism, implying that it may have a correlation between emotional change and lipid metabolism. Furthermore, acupuncture can also regulate the changes of serum Ca, K, and Cl.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, identifier NCT01573858.
Topics: Humans; Female; Apolipoprotein A-I; Polycystic Ovary Syndrome; Quality of Life; Acupuncture Therapy; Apolipoproteins B; Emotions
PubMed: 37711905
DOI: 10.3389/fendo.2023.1237260 -
Arteriosclerosis, Thrombosis, and... Oct 2023High levels of Lp(a) (lipoprotein(a)) are associated with multiple forms of cardiovascular disease. Lp(a) consists of an apoB-containing particle attached to the...
BACKGROUND
High levels of Lp(a) (lipoprotein(a)) are associated with multiple forms of cardiovascular disease. Lp(a) consists of an apoB-containing particle attached to the plasminogen homologue apo(a). The pathways for Lp(a) clearance are not well understood. We previously discovered that the plasminogen receptor PlgRKT (plasminogen receptor with a C-terminal lysine) promoted Lp(a) uptake in liver cells. Here, we aimed to further define the role of PlgRKT and to investigate the role of 2 other plasminogen receptors, annexin A2 and S100A10 (S100 calcium-binding protein A10) in the endocytosis of Lp(a).
METHODS
Human hepatocellular carcinoma (HepG2) cells and haploid human fibroblast-like (HAP1) cells were used for overexpression and knockout of plasminogen receptors. The uptake of Lp(a), LDL (low-density lipoprotein), apo(a), and endocytic cargos was visualized and quantified by confocal microscopy and Western blotting.
RESULTS
The uptake of both Lp(a) and apo(a), but not LDL, was significantly increased in HepG2 and HAP1 cells overexpressing PlgRKT, annexin A2, or S100A10. Conversely, Lp(a) and apo(a), but not LDL, uptake was significantly reduced in HAP1 cells in which PlgRKT and S100A10 were knocked out. Surface binding studies in HepG2 cells showed that overexpression of PlgRKT, but not annexin A2 or S100A10, increased Lp(a) and apo(a) plasma membrane binding. Annexin A2 and S100A10, on the other hand, appeared to regulate macropinocytosis with both proteins significantly increasing the uptake of the macropinocytosis marker dextran when overexpressed in HepG2 and HAP1 cells and knockout of S100A10 significantly reducing dextran uptake. Bringing these observations together, we tested the effect of a PI3K (phosphoinositide-3-kinase) inhibitor, known to inhibit macropinocytosis, on Lp(a) uptake. Results showed a concentration-dependent reduction confirming that Lp(a) uptake was indeed mediated by macropinocytosis.
CONCLUSIONS
These findings uncover a novel pathway for Lp(a) endocytosis involving multiple plasminogen receptors that enhance surface binding and stimulate macropinocytosis of Lp(a). Although the findings were produced in cell culture models that have limitations, they could have clinical relevance since drugs that inhibit macropinocytosis are in clinical use, that is, the PI3K inhibitors for cancer therapy and some antidepressant compounds.
Topics: Humans; Plasminogen; Lipoprotein(a); Annexin A2; Dextrans; Phosphatidylinositol 3-Kinases; Carrier Proteins; Apolipoproteins A
PubMed: 37589135
DOI: 10.1161/ATVBAHA.123.319344 -
Travel Medicine and Infectious Disease 2021Apolipoproteins are predictive biomarkers for cardiovascular, neoplasms and cerebrovascular diseases and are postulated as prognostic biomarkers in infectious diseases,... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Apolipoproteins are predictive biomarkers for cardiovascular, neoplasms and cerebrovascular diseases and are postulated as prognostic biomarkers in infectious diseases, as COVID-19. Thus, we assessed the prognosis value of apolipoproteins for COVID-19 severity and mortality.
METHODS
We conducted a systematic review and meta-analysis using observational studies that reported the association between apolipoproteins and severity or mortality in COVID-19 patients. Newcastle-Ottawa was used for the quality assessment of included studies. Effects measurements were shown as odds ratios (ORs) with 95% confidence intervals (CIs), and Egger-test was developed for assessing the risk of bias publication.
RESULTS
We analyzed 12 cohort studies (n = 3580). Patients with low ApoliproteinA1 (ApoA1) (OR 0.35; 95%CI 0.24 to 0.49; P < 0.001) and ApoliproteinB (ApoB) (OR = 0.78; 95%CI 0.69 to 0.87; P < 0.001) values had a higher risk of developing severe disease. ApoB/ApoA1 ratio showed no statistically significant association with higher odds of severity. Low ApoA1 levels were associated with higher odds of all-cause mortality (OR = 0.34; 95%CI 0.20 to 0.57; P < 0.001). ApoB values showed no statistically significant association with a high risk of all-cause mortality.
CONCLUSION
We suggest that adequate levels of ApoA1 and ApoB can be a protective factor for severity in COVID-19, and ApoB/ApoA1 ratio did not show predictive utility for severity.
Topics: Apolipoprotein A-I; Apolipoproteins; COVID-19; Humans; Prognosis; Risk Factors; SARS-CoV-2
PubMed: 34752921
DOI: 10.1016/j.tmaid.2021.102200 -
The Journal of Clinical Investigation Sep 2023BACKGROUNDCellular cholesterol efflux capacity (CEC) is a better predictor of cardiovascular disease (CVD) events than HDL-cholesterol (HDL-C) but is not suitable as a...
BACKGROUNDCellular cholesterol efflux capacity (CEC) is a better predictor of cardiovascular disease (CVD) events than HDL-cholesterol (HDL-C) but is not suitable as a routine clinical assay.METHODSWe developed an HDL-specific phospholipid efflux (HDL-SPE) assay to assess HDL functionality based on whole plasma HDL apolipoprotein-mediated solubilization of fluorescent phosphatidylethanolamine from artificial lipid donor particles. We first assessed the association of HDL-SPE with prevalent coronary artery disease (CAD): study I included NIH severe-CAD (n = 50) and non-CAD (n = 50) participants, who were frequency matched for sex, BMI, type 2 diabetes mellitus, and smoking; study II included Japanese CAD (n = 70) and non-CAD (n = 154) participants. We also examined the association of HDL-SPE with incident CVD events in the Prevention of Renal and Vascular End-stage Disease (PREVEND) study comparing 340 patients with 340 controls individually matched for age, sex, smoking, and HDL-C levels.RESULTSReceiver operating characteristic curves revealed stronger associations of HDL-SPE with prevalent CAD. The AUCs in study I were as follows: HDL-SPE, 0.68; apolipoprotein A-I (apoA-I), 0.62; HDL-C, 0.63; and CEC, 0.52. The AUCs in study II were as follows: HDL-SPE, 0.83; apoA-I, 0.64; and HDL-C, 0.53. Also longitudinally, HDL-SPE was significantly associated with incident CVD events independent of traditional risk factors with ORs below 0.2 per SD increment in the PREVEND study (P < 0.001).CONCLUSIONHDL-SPE could serve as a routine clinical assay for improving CVD risk assessment and drug discovery.TRIAL REGISTRATIONClinicalTrials.gov NCT01621594.FUNDINGNHLBI Intramural Research Program, NIH (HL006095-06).
Topics: Humans; Lipoproteins, HDL; Cardiovascular Diseases; Apolipoprotein A-I; Diabetes Mellitus, Type 2; Coronary Artery Disease; Cholesterol, HDL; Phospholipids
PubMed: 37471145
DOI: 10.1172/JCI165370