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Arteriosclerosis, Thrombosis, and... May 2024Zebrafish have become a powerful model of mammalian lipoprotein metabolism and lipid cell biology. Most key proteins involved in lipid metabolism, including cholesteryl... (Review)
Review
Zebrafish have become a powerful model of mammalian lipoprotein metabolism and lipid cell biology. Most key proteins involved in lipid metabolism, including cholesteryl ester transfer protein, are conserved in zebrafish. Consequently, zebrafish exhibit a human-like lipoprotein profile. Zebrafish with mutations in genes linked to human metabolic diseases often mimic the human phenotype. Zebrafish larvae develop rapidly and externally around the maternally deposited yolk. Recent work revealed that any disturbance of lipoprotein formation leads to the accumulation of cytoplasmic lipid droplets and an opaque yolk, providing a visible phenotype to investigate disturbances of the lipoprotein pathway, already leading to discoveries in MTTP (microsomal triglyceride transfer protein) and ApoB (apolipoprotein B). By 5 days of development, the digestive system is functional, making it possible to study fluorescently labeled lipid uptake in the transparent larvae. These and other approaches enabled the first in vivo description of the STAB (stabilin) receptors, showing lipoprotein uptake in endothelial cells. Various zebrafish models have been developed to mimic human diseases by mutating genes known to influence lipoproteins (eg, , ). This review aims to discuss the most recent research in the zebrafish ApoB-containing lipoprotein and lipid metabolism field. We also summarize new insights into lipid processing within the yolk cell and how changes in lipid flux alter yolk opacity. This curious new finding, coupled with the development of several techniques, can be deployed to identify new players in lipoprotein research directly relevant to human disease.
Topics: Zebrafish; Animals; Lipid Metabolism; Apolipoproteins B; Humans; Disease Models, Animal; Phenotype; Zebrafish Proteins; Mutation
PubMed: 38482694
DOI: 10.1161/ATVBAHA.123.318287 -
Communications Biology Feb 2024Apolipoprotein B-100 (APOB) is a component of fat- and cholesterol-transporting molecules in the bloodstream. It is the main lipoprotein in low-density lipoprotein...
Apolipoprotein B-100 (APOB) is a component of fat- and cholesterol-transporting molecules in the bloodstream. It is the main lipoprotein in low-density lipoprotein cholesterol (LDL) and has been implicated in conditions that end healthspan (the interval between birth and onset of chronic disease). However, APOB's direct relationship with healthspan remains uncertain. With Mendelian randomization, we show that higher levels of APOB and LDL shorten healthspan in humans. Multivariable Mendelian randomization of APOB and LDL on healthspan suggests that the predominant trait accounting for the relationship is APOB. In addition, we provide preliminary evidence that APOB increases risk for Alzheimer's disease, a condition that ends healthspan. If these relationships are causal, they suggest that interventions to improve healthspan in aging populations could include strategies targeting APOB. Ultimately, given that more than 44 million people currently suffer from Alzheimer's disease worldwide, such interventions are needed.
Topics: Humans; Alzheimer Disease; Mendelian Randomization Analysis; Apolipoproteins B; Cholesterol, LDL; Phenotype
PubMed: 38402277
DOI: 10.1038/s42003-024-05887-2 -
Journal of Lipid Research Sep 2017Lipoprotein (a) [Lp(a)] is characterized by apolipoprotein (a) [apo(a)] covalently bound to apolipoprotein B 100. It was described in human plasma by Berg et al. in 1963... (Review)
Review
Lipoprotein (a) [Lp(a)] is characterized by apolipoprotein (a) [apo(a)] covalently bound to apolipoprotein B 100. It was described in human plasma by Berg et al. in 1963 and the gene encoding apo(a) () was cloned in 1987 by Lawn and colleagues. Epidemiologic and genetic studies demonstrate that increases in Lp(a) plasma levels increase the risk of atherosclerotic cardiovascular disease. Novel Lp(a) lowering treatments highlight the need to understand the regulation of plasma levels of this atherogenic lipoprotein. Despite years of research, significant uncertainty remains about the assembly, secretion, and clearance of Lp(a). Specifically, there is ongoing controversy about where apo(a) and apoB-100 bind to form Lp(a); which apoB-100 lipoproteins bind to apo(a) to create Lp(a); whether binding of apo(a) is reversible, allowing apo(a) to bind to more than one apoB-100 lipoprotein during its lifespan in the circulation; and how Lp(a) or apo(a) leave the circulation. In this review, we highlight past and recent data from stable isotope studies of Lp(a) metabolism, highlighting the critical metabolic uncertainties that exist. We present kinetic models to describe results of published studies using stable isotopes and suggest what future studies are required to improve our understanding of Lp(a) metabolism.
Topics: Apolipoproteins B; Humans; Kinetics; Lipoprotein(a); Models, Biological
PubMed: 28720561
DOI: 10.1194/jlr.R077693 -
Journal of the American College of... Jan 2024
Topics: Humans; Lipoprotein(a); Apolipoproteins B; Lipoproteins, LDL
PubMed: 38233013
DOI: 10.1016/j.jacc.2023.11.008 -
Arquivos Brasileiros de Cardiologia Jul 2020Excess Weight and Cardiovascular Diseases are health problems with increasing prevalence among children and adolescents, hence the need to investigate the issues related... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Excess Weight and Cardiovascular Diseases are health problems with increasing prevalence among children and adolescents, hence the need to investigate the issues related to them to better deal with the problem.
OBJECTIVE
To investigate the influence of excess adiposity on the levels of apolipoprotein B and A1 in children and adolescents.
METHODS
A systematic search was conducted in the PubMed, Embase, Lilacs, Web of Science, Ovid and Science direct databases, searching for cohort eligible studies and evaluating their results, methodological quality and risk of bias; combinable studies with good quality and low risk of bias were evaluated by meta-analysis. The summary measure used was the weighted mean difference (WMD) with its respective 95% confidence interval.
RESULTS
8 articles attended the eligibility criteria including individuals with age mean varying from 9 to 15.7 years of age. The meta-analysis included 4 articles with a total of 7,974 children and adolescents. It was observed a mean increase of 4,94mg/dL (95%CI: 4,22 to 5,67) in the ApoB levels in individuals with excess of body adiposity. For the ApoA1, we identified a mean reduction of -8,13mg/dL (95%CI: -9,09 to -7,17 mg/dL) in its levels in children and adolescents with higher body adiposity. Beside this, the influence of excess adiposity on the ApoB and ApoA1 levels was higher between adolescents than children.
CONCLUSIONS
The excess of body adiposity influenced both the reduction of ApoA1 values and the increase of ApoB levels, being these changes more relevant among adolescents. (Arq Bras Cardiol. 2020; [online].ahead print, PP.0-0).
Topics: Adiposity; Adolescent; Apolipoproteins B; Child; Humans; Obesity; Prospective Studies
PubMed: 32696854
DOI: 10.36660/abc.20190331 -
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 -
Nutrition, Metabolism, and... Mar 2022While low-density lipoprotein cholesterol (LDL-C) is a good predictor of atherosclerotic cardiovascular disease, apolipoprotein B (ApoB) is superior when the two markers...
BACKGROUND AND AIMS
While low-density lipoprotein cholesterol (LDL-C) is a good predictor of atherosclerotic cardiovascular disease, apolipoprotein B (ApoB) is superior when the two markers are discordant. We aimed to determine the impact of adiposity, diet and inflammation upon ApoB and LDL-C discordance.
METHODS AND RESULTS
Machine learning (ML) and structural equation models (SEMs) were applied to the National Health and Nutrition Examination Survey to investigate cardiometabolic and dietary factors when LDL-C and ApoB are concordant/discordant. Mendelian randomisation (MR) determined whether adiposity and inflammation exposures were causal of elevated/decreased LDL-C and/or ApoB. ML showed body mass index (BMI), dietary saturated fatty acids (SFA), dietary fibre, serum C-reactive protein (CRP) and uric acid were the most strongly associated variables (R = 0.70) in those with low LDL-C and high ApoB. SEMs revealed that fibre (b = -0.42, p = 0.001) and SFA (b = 0.28, p = 0.014) had a significant association with our outcome (joined effect of ApoB and LDL-C). BMI (b = 0.65, p = 0.001), fibre (b = -0.24, p = 0.014) and SFA (b = 0.26, p = 0.032) had significant associations with CRP. MR analysis showed genetically higher body fat percentage had a significant causal effect on ApoB (Inverse variance weighted (IVW) = Beta: 0.172, p = 0.0001) but not LDL-C (IVW = Beta: 0.006, p = 0.845).
CONCLUSION
Our data show increased discordance between ApoB and LDL-C is associated with cardiometabolic, clinical and dietary abnormalities and that body fat percentage is causal of elevated ApoB.
Topics: Adiposity; Apolipoprotein B-100; Apolipoproteins B; Cholesterol, LDL; Diet; Humans; Inflammation; Nutrition Surveys
PubMed: 35123856
DOI: 10.1016/j.numecd.2021.12.004 -
Current Pharmaceutical Design 2018Nonalcoholic fatty liver disease (NAFLD), now the leading cause of liver damage worldwide, is epidemiologically associated with obesity, insulin resistance and type 2... (Review)
Review
Nonalcoholic fatty liver disease (NAFLD), now the leading cause of liver damage worldwide, is epidemiologically associated with obesity, insulin resistance and type 2 diabetes, and is a potentially progressive condition to advanced liver fibrosis and hepatocellular carcinoma. However, there is huge interindividual variability in liver disease susceptibility. Inherited factors also play an important role in determining disease predisposition. During the last years, common variants in PNPLA3, TM6SF2, MBOAT7 and GCKR have been demonstrated to predispose to the full spectrum of NAFLD pathology by facilitating hepatic fat accumulation in the presence of environmental triggers. Other variants regulating inflammation and fibrogenesis then modulate liver disease progression in those at higher risk. Evidence is also accumulating that rare variants are involved in disease predisposition. In the future, evaluation of genetic risk factors may be exploited to stratify the risk of liver-related complications of the disease, and to guide hepatocellular carcinoma surveillance and choose pharmacological therapy.
Topics: Apolipoproteins B; Disease Progression; Gene-Environment Interaction; Humans; Insulin Resistance; Lipase; Liver; Membrane Proteins; Mutation; Non-alcoholic Fatty Liver Disease; Polymorphism, Genetic
PubMed: 30659533
DOI: 10.2174/1381612825666190119113836 -
Annals of Laboratory Medicine May 2023
Topics: Humans; Cholesterol, LDL; Cardiovascular Diseases; Cholesterol; Apolipoproteins B; Atherosclerosis; Risk Assessment; Cholesterol, HDL; Biomarkers; Risk Factors
PubMed: 36544332
DOI: 10.3343/alm.2023.43.3.221 -
Atherosclerosis Mar 2022Large amounts of clot-bound lipoproteins were reported in proteomic analysis of plasma clot but their impact on fibrin clot properties is unknown. We investigated a...
BACKGROUND AND AIMS
Large amounts of clot-bound lipoproteins were reported in proteomic analysis of plasma clot but their impact on fibrin clot properties is unknown. We investigated a contribution of lipid profile and apolipoproteins (apo) to the prothrombotic plasma fibrin clot phenotype in patients with aortic stenosis (AS).
METHODS
In 138 patients with isolated severe AS, we determined serum apoA-I, A-II, B, C-II, C-III, E, oxidized low-density lipoprotein (OxLDL) and lipoprotein(a) concentrations. Plasma fibrin clot permeability (Ks), maximal absorbance (MaxAbs and MaxAbs), and fibrinolytic capacity were studied using 3 plasma-based lysis assays (CLT2018, CLT, and Lys50), and compared with well-matched patients without AS (control group).
RESULTS
After adjustment for confounding factors, including statin use, only low-density lipoprotein cholesterol (LDL-C) and apoB levels were inversely associated with Ks. Triglycerides, apoC-II, and C-III were associated with MaxAbs and MaxAbs, explaining 56-64% of their variability. CLT2018 and CLT showed associations with total cholesterol, LDL-C, triglycerides, and OxLDL as well as with apoB, C-II, C-III, and E. ApoA-I, C-II, and C-III but not serum lipids were associated with Lys50. Only CLT2018 was associated with lipoprotein(a). ApoC-III, B, A-I, and E along with estimated glomerular filtration rate and OxLDL predicted hypofibrinolysis in multiple regression analysis. AS patients had higher lipoprotein(a) (+34.9%) and apoA-I (+25.9%) levels and less compact fibrin clots (-13.3% lower MaxAbs, -53.2% lower MaxAbs, and +28.3% higher Ks) displaying higher susceptibility to lysis (-17.9% lower Lys50) in comparison with control group.
CONCLUSIONS
Apolipoproteins and OxLDL contribute to prothrombotic fibrin clot phenotype in severe AS. Moreover, apolipoproteins better than serum lipids predicted hypofibrinolysis, which provides additional argument for a role of elevated lipoproteins in the prothrombotic state.
Topics: Aortic Valve Stenosis; Apolipoproteins; Apolipoproteins B; Fibrin; Fibrin Clot Lysis Time; Fibrinolysis; Humans; Lipoprotein(a); Proteomics
PubMed: 35134656
DOI: 10.1016/j.atherosclerosis.2022.01.011