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Accelerated atherosclerosis occurs in patients with type III hyperlipoproteinemia and familial hypercholesterolemia. The accumulation of chylomicron remnants of intestinal origin and of VLDL remnants or IDL of hepatic origin observed in type III hyperlipoproteinemia appears to correlate with coronary disease. The presence of defective forms of Apo E prevents normal receptor-mediated catabolism of these lipoproteins. Patients with familial hypercholesterolemia have an elevation of plasma IDL secondary to defective LDL receptors that impair normal catabolism. Familial defective Apo B100 is secondary to an abnormality of Apo B100 that prevents the normal interaction of LDL with the LDL receptor and increases plasma LDL. Macrophages (which are derived from circulating monocytes) have emerged as a key component in atherogenesis because they appear to be progenitors of foam cells in arterial lesions. Macrophages express receptors that recognize chylomicron remnants and VLDL remnants and chemically modified LDL. Thus, in the presence of these specific lipoproteins, macrophages are converted to cells that resemble foam cells.
Macrophage scavenger receptor A (SR-A) is a multifunctional, multiligand pattern recognition receptor with roles in innate immunity, apoptotic cell clearance, and age-related degenerative pathologies, such as atherosclerosis and Alzheimer's disease. Known endogenous SR-A ligands are polyanionic and include modified lipoproteins, advanced glycation end products, and extracellular matrix proteins. No native plasma ligands have been identified, but it is known that SR-A recognition of unidentified serum components mediates integrin-independent macrophage adhesion, which may drive chronic local inflammation. In this study, we used a high-throughput fractionation and screening method to identify novel endogenous SR-A ligands that may mediate macrophage adhesion. SR-A was found to recognize the exchangeable apolipoproteins A-I and E (apo A-I and apo E, respectively) in both lipid-free and lipid-associated form, suggesting the shared amphipathic alpha-helix as a potential recognition motif. Adhesion of RAW 264.7 macrophages to surfaces coated with apo A-I and apo E4 proved to be integrin-independent and could be blocked by anti-SR-A antibodies. The presence of apo A-I and apo E in pathological deposits, such as atherosclerotic lesions and neurotoxic Alzheimer's plaques, suggests a possible contribution of SR-A-dependent adhesion of macrophages to an inflammatory microenvironment.
Several molecules are known to be closely associated with amyloid deposits in human brain. Among these, apolipoproteins such as apolipoproteins E (apo E) and J (apo J) have been found in two neuropathological hallmarks of Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA): senile plaques (SPs) and cerebrovascular amyloid. These apolipoproteins may be implicated in amyloid fibrillogenesis. Apo D is a multiligand-multifunctional glycoprotein present in SPs, as we previously reported. The aim of this work is to study the link between immunolocalization of apo E and apo D in AD and CAA brains. Both apolipoproteins were found in all types of SPs, but apo E was observed more often than apo D in mature plaques. Whereas apo E is always located overlapping the amyloid core, apo D seems to situate preferably around and near the amyloid. Immunohistochemistry revealed that these apolipoproteins behave differently in cerebral vessels. Apo E labeling in vessels appears mainly linked to amyloid deposits, whereas apo D shows a distribution almost opposite to that of apo E. This could be an indication of the different roles that each apolipoprotein plays in the pathogenesis of amyloid deposition.
Nonrheumatic aortic stenosis of trileaflet aortic valves has been considered to be a "degenerative" process, but the early lesion of aortic stenosis contains the chronic inflammatory cells, macrophages and T lymphocytes. Because lipoprotein deposition is prominent in atherosclerosis, another chronic inflammatory process, this study examined whether lipoproteins accumulate in aortic valve lesions. Immunohistochemical studies were performed to detect apolipoprotein (apo) B, apo(a), apoE, macrophages, and alpha-actin-expressing cells on 18 trileaflet aortic valves that ranged from normal to stenotic. All three apolipoproteins were detected in early through end-stage lesions of aortic stenosis but not in histologically normal regions. Comparison with oil red O staining suggested that most of the extracellular neutral lipid in these valves was associated with either plasma-derived or locally produced apolipoproteins. Thus, in early through end-stage aortic valve lesions, apolipoproteins accumulate and are associated with the majority of extracellular valve lipid. These results are consistent with the hypothesis that lipoprotein accumulation in the aortic valve contributes to pathogenesis of aortic stenosis.
Pregnant women with gestational diabetes mellitus (GDM) are at risk of adverse outcomes, including gestational hypertension, pre-eclampsia, and preterm delivery. This study was undertaken to determine if apolipoprotein (apo) levels differed between pregnant women with and without GDM and if they were associated with adverse pregnancy outcome.
White (WAT) and brown (BAT) adipose tissue, the two main types of adipose organ, are responsible for lipid storage and non-shivering thermogenesis, respectively. Thermogenesis is a process mediated by mitochondrial uncoupling protein 1 (UCP1) which uncouples oxidative phosphorylation from ATP production, leading to the conversion of free fatty acids to heat. This process can be triggered by exposure to low ambient temperatures, caloric excess, and the immune system. Recently mitochondrial thermogenesis has also been associated with plasma lipoprotein transport system. Specifically, apolipoprotein (APO) E3 is shown to have a bimodal effect on WAT thermogenesis that is highly dependent on its site of expression. Similarly, APOE2 and APOE4 differentially affect BAT and WAT mitochondrial metabolic activity in processes highly modulated by APOA1. Furthermore, the absence of classical APOA1 containing HDL (APOA1-HDL), is associated with no measurable non-shivering thermogenesis in WAT of mice fed high fat diet. Based on these previous observations which indicate important regulatory roles for both APOA1 and APOE in adipose tissue mitochondrial metabolic activity, here we sought to investigate the potential roles of these apolipoproteins in BAT and WAT metabolic activation in mice, following stimulation by cold exposure (7 °C). Our data indicate that APOA1-HDL promotes metabolic activation of BAT only in the presence of very low levels (virtually undetectable) of APOE3-containing HDL (APOE3-HDL), which acts as an inhibitor in this process. In contrast, induction of WAT thermogenesis is subjected to a more complicated regulation which requires the combined presence of both APOA1-HDL and APOE3-HDL.
BackgroundApolipoprotein C-III (apoC-III) is a regulator of triglyceride (TG) metabolism, and due to its association with risk of cardiovascular disease, is an emergent target for pharmacological intervention. The impact of substantially lowering apoC-III on lipoprotein metabolism is not clear.MethodsWe investigated the kinetics of apolipoproteins B48 and B100 (apoB48 and apoB100) in chylomicrons, VLDL1, VLDL2, IDL, and LDL in patients heterozygous for a loss-of-function (LOF) mutation in the APOC3 gene. Studies were conducted in the postprandial state to provide a more comprehensive view of the influence of this protein on TG transport.ResultsCompared with non-LOF variant participants, a genetically determined decrease in apoC-III resulted in marked acceleration of lipolysis of TG-rich lipoproteins (TRLs), increased removal of VLDL remnants from the bloodstream, and substantial decrease in circulating levels of VLDL1, VLDL2, and IDL particles. Production rates for apoB48-containing chylomicrons and apoB100-containing VLDL1 and VLDL2 were not different between LOF carriers and noncarriers. Likewise, the rate of production of LDL was not affected by the lower apoC-III level, nor were the concentration and clearance rate of LDL-apoB100.ConclusionThese findings indicate that apoC-III lowering will have a marked effect on TRL and remnant metabolism, with possibly significant consequences for cardiovascular disease prevention.Trial registrationClinicalTrials.gov NCT04209816 and NCT01445730.FundingSwedish Heart-Lung Foundation, Swedish Research Council, ALF grant from the Sahlgrenska University Hospital, Novo Nordisk Foundation, Sigrid Juselius Foundation, Helsinki University Hospital Government Research funds, Finnish Heart Foundation, and Finnish Diabetes Research Foundation.
Dyslipidemia is a major risk factor for atherosclerotic cardiovascular disease (ASCVD). As key regulators of lipoprotein metabolism, apolipoproteins (apos) are discussed as vascular risk factors. This study aimed to analyze associations of major plasma apos with coronary artery disease (CAD), peripheral artery disease (PAD) and carotid artery plaque (CAP) to elucidate their diagnostic potential in risk assessment.
Epidermal-fatty acid-binding protein (E-FABP) is a marker of transiently amplifying cells which are formed from stem cells in epidermis. Their role is an uptake of fatty acids and metabolism. Psoriatic keratinocytes overexpress E-FABPs, which leads to acanthosis and may explain the lipid's disturbances in psoriasis.
The gut microbiota has been linked to blood lipids. However, the relationship between the gut microbiome and other lipid markers like apolipoproteins A1 (apoA1) and B (apoB) as well as classical lipid markers in Asians remain unclear. Here, we examined the associations between gut microbial diversity and taxonomic compositions with both apolipoproteins and lipid markers in a large number of Korean patients. The fecal 16S rRNA gene sequencing data from 1141 subjects were analyzed and subjects were categorized into control group (G0) or abnormal group (G1) according to blood lipid measurements. The microbial diversity and several taxa of the gut microbiota were significantly associated with triglyceride, apoA1, and apoB levels, but not with total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels. The alpha diversity of the gut microbiota was inversely associated with high triglyceride level. Interestingly, G1 of apoA1 showed increased microbial richness and distinct microbial community compared with G0 of apoA1. A high abundance of Fusobacteria and low abundance of Oscillospira were found in the hypertriglyceridemia group. In this large-scale study, we identified associations of gut microbiota with apolipoproteins and classical lipid markers, indicating that the gut microbiota may be an important target for regulating blood lipids.
Apolipoproteins (Apos) play an important role in regulating plasma lipid concentration. Complex disorders of Apos are highly related with diabetes mellitus, cardiovascular and other diseases. Direct measures of lipoprotein fractions for risk assessment suffer from inaccuracy in the dyslipidemia and pathological states. Therefore, a reliable precise assay will be of high clinical utility. LC-MS/MS methods with multiple reaction monitoring modes have proven suitable for multiplexed quantification. We aimed to develop a simple, cost-effective and amenable LC-MS/MS assay for quantification of ApoA-I, ApoE and ApoJ in human plasma. Standards were constructed from substitute matrix and proteotypic peptides for external calibration and corresponding stable isotope labeled peptides were added as internal standards to remove matrix effects. Analytical validation of the assay included the assessment of linearity, accuracy (RE: -3.02% to 5.32%), intra-assay precision (RSD: 2.50% to 6.56%), inter-assay precision (RSD: 0.78% to 6.68%), spiking recovery rate (accuracy: 87.17% to 112.71%), matrix effect (accuracy: 88.03% to 114.87%), and reproducibility and repeatability of sample preparation (RSD: 1.95% to 7.26%). The performance of proteotypic peptides ApoA-I, ApoE and ApoJ was sufficient for triplex quantitation within a linear range from 16.26 to 1626.41 pmol mL-1, 1.03 to 103.35 pmol mL-1 and 0.86 to 86.46 pmol mL-1 respectively. For all quantified peptides, the determination coefficient (R 2) was >0.997. Besides, the validated LC-MS/MS method has been successfully applied to the quantification of plasma samples in diabetes mellitus and cardiovascular diseases. We anticipate that this assay may provide an alternative method for future clinical applications.
In order to establish a successful infection in the human host, the malaria parasite Plasmodium falciparum must establish interactions with a variety of human proteins on the surface of different cell types, as well as with proteins inside the host cells. To better understand this aspect of malaria pathogenesis, a study was conducted with the goal of identifying interactions between proteins of the parasite and those of its human host.
The substantial link between apolipoprotein E (APOE) ε4 allele and oxidative stress may underlie enhanced Alzheimer's disease (AD) risk. Here, we studied the impact of APOE ε4 on the level of apolipoproteins with antioxidant activities along with oxidative markers in circulating extracellular vesicles (cEVs) and plasma from cognitively impaired-not demented (CIND) individuals converted to AD (CIND-AD).
Adipokines and apolipoproteins are key regulators and potential biomarkers in obesity and associated diseases and their quantitative assessment is crucial for functional analyses to understand disease mechanisms. Compared to routinely used ELISAs, multiple reaction monitoring (MRM)-based mass spectrometry allows multiplexing and detection of proteins for which antibodies are not available. Thus, we established an MRM method to quantify 9 adipokines and 10 apolipoproteins in human serum. We optimized sample preparation by depleting the two most abundant serum proteins for improved detectability of low abundant proteins. Intra-day and inter-day imprecision were below 16.5%, demonstrating a high accuracy. In 50 serum samples from participants with either normal weight or obesity, we quantified 8 adipokines and 10 apolipoproteins. Significantly different abundances were observed for five adipokines (adipsin, adiponectin, chemerin, leptin, vaspin) and four apolipoproteins (apo-B100/-C2/-C4/-D) between the body mass index (BMI) groups. Additionally, we applied our MRM assay to serum samples from normal weight children and human adipocyte cell culture supernatants to proof the feasibility for large cohort studies and distinct biological matrices. In summary, this multiplexed assay facilitated the investigation of relationships between adipokines or apolipoproteins and phenotypes or clinical parameters in large cohorts, which may contribute to disease prediction approaches in the future.
Blood lipids are important cardiovascular disease (CVD) risk factors with both genetic and environmental determinants. The Whitehall II study (n=5592) was genotyped with the gene-centric HumanCVD BeadChip (Illumina). We identified 195 SNPs in 16 genes/regions associated with 3 major lipid fractions and 2 apolipoprotein components at p<10(-5), with the associations being broadly concordant with prior genome-wide analysis. SNPs associated with LDL cholesterol and apolipoprotein B were located in LDLR, PCSK9, APOB, CELSR2, HMGCR, CETP, the TOMM40-APOE-C1-C2-C4 cluster, and the APOA5-A4-C3-A1 cluster; SNPs associated with HDL cholesterol and apolipoprotein AI were in CETP, LPL, LIPC, APOA5-A4-C3-A1, and ABCA1; and SNPs associated with triglycerides in GCKR, BAZ1B, MLXIPL, LPL, and APOA5-A4-C3-A1. For 48 SNPs in previously unreported loci that were significant at p<10(-4) in Whitehall II, in silico analysis including the British Women's Heart and Health Study, BRIGHT, ASCOT, and NORDIL studies (total n>12,500) revealed previously unreported associations of SH2B3 (p<2.2x10(-6)), BMPR2 (p<2.3x10(-7)), BCL3/PVRL2 (flanking APOE; p<4.4x10(-8)), and SMARCA4 (flanking LDLR; p<2.5x10(-7)) with LDL cholesterol. Common alleles in these genes explained 6.1%-14.7% of the variance in the five lipid-related traits, and individuals at opposite tails of the additive allele score exhibited substantial differences in trait levels (e.g., >1 mmol/L in LDL cholesterol [approximately 1 SD of the trait distribution]). These data suggest that multiple common alleles of small effect can make important contributions to individual differences in blood lipids potentially relevant to the assessment of CVD risk. These genes provide further insights into lipid metabolism and the likely effects of modifying the encoded targets therapeutically.
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).
Plasma lipids, lipoproteins, and apolipoproteins were assessed in three groups of Nigerians at increased risk for atherosclerotic heart disease. The three patient groups, diabetes mellitus (n = 15), essential hypertension (n = 12), and hypertensive-diabetes mellitus (n = 11), were compared with age-matched, apparently healthy controls (n = 14). In subjects with diabetes mellitus, triglyceride and its related apolipoproteins CIII and CIII:NonB were significantly higher than controls. High-density lipoprotein cholesterol (HDL-C) was significantly lower; its related ratios, total/HDL-C and low-density lipoprotein cholesterol (LDL-C)/HDL-C were significantly higher than those for controls. Subjects with hypertension and hypertensive-diabetes mellitus had significantly higher values than controls for those lipids and lipid fractions considered atherogenic (total cholesterol, LDL-C, triglyceride, and the total/HDL-C and LDL-C/HDL-C ratios) as well as apolipoproteins B, CIII, and lipoprotein particles Lp(a) and CIII:NonB. Only hypertensive-diabetes mellitus subjects had lower HDL-C levels, while hypertension patients had significantly higher apolipoprotein AI and LpAI concentrations than controls. Subjects with hypertensive-diabetes mellitus had significantly worse lipid, lipoprotein, and apolipoprotein profiles both in terms of increased atherogenic and reduced anti-atherogenic parameters compared with subjects with diabetes mellitus or hypertension only. These studies suggest that Nigerians with diabetes, hypertension, and especially both hypertension and diabetes need to be fully evaluated from a lipid and lipoprotein standpoint, and any abnormalities detected need to be taken into consideration during therapy of this group of high-risk patients.
ATP-binding cassette transporter A1 (ABCA1) mediates the lipidation of exchangeable apolipoproteins, the rate-limiting step in the formation of high density lipoproteins (HDL). We previously demonstrated that HDL oxidized ex vivo by peroxidase-generated tyrosyl radical (tyrosylated HDL, tyrHDL) increases the availability of cellular cholesterol for efflux and reduces the development of atherosclerosis when administered to apolipoprotein E-deficient mice as compared to treatment with control HDL.
Apolipoprotein B (ApoB) and ApoE have been shown to participate in the particle formation and the tissue tropism of hepatitis C virus (HCV), but their precise roles remain uncertain. Here we show that amphipathic α-helices in the apolipoproteins participate in the HCV particle formation by using zinc finger nucleases-mediated apolipoprotein B (ApoB) and/or ApoE gene knockout Huh7 cells. Although Huh7 cells deficient in either ApoB or ApoE gene exhibited slight reduction of particles formation, knockout of both ApoB and ApoE genes in Huh7 (DKO) cells severely impaired the formation of infectious HCV particles, suggesting that ApoB and ApoE have redundant roles in the formation of infectious HCV particles. cDNA microarray analyses revealed that ApoB and ApoE are dominantly expressed in Huh7 cells, in contrast to the high level expression of all of the exchangeable apolipoproteins, including ApoA1, ApoA2, ApoC1, ApoC2 and ApoC3 in human liver tissues. The exogenous expression of not only ApoE, but also other exchangeable apolipoproteins rescued the infectious particle formation of HCV in DKO cells. In addition, expression of these apolipoproteins facilitated the formation of infectious particles of genotype 1b and 3a chimeric viruses. Furthermore, expression of amphipathic α-helices in the exchangeable apolipoproteins facilitated the particle formation in DKO cells through an interaction with viral particles. These results suggest that amphipathic α-helices in the exchangeable apolipoproteins play crucial roles in the infectious particle formation of HCV and provide clues to the understanding of life cycle of HCV and the development of novel anti-HCV therapeutics targeting for viral assembly.
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