Structures of Angptl3 and Angptl4, modulators of triglyceride levels and coronary artery disease.
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ABSTRACT:
SUBMITTER: Biterova E
PROVIDER: S-EPMC5928061 | biostudies-literature | 2018 Apr
REPOSITORIES: biostudies-literature
Publications
Structures of Angptl3 and Angptl4, modulators of triglyceride levels and coronary artery disease.
Biterova Ekaterina E Esmaeeli Mariam M Alanen Heli I HI Saaranen Mirva M Ruddock Lloyd W LW
Scientific reports 20180430 1
Coronary artery disease is the most common cause of death globally and is linked to a number of risk factors including serum low density lipoprotein, high density lipoprotein, triglycerides and lipoprotein(a). Recently two proteins, angiopoietin-like protein 3 and 4, have emerged from genetic studies as being factors that significantly modulate plasma triglyceride levels and coronary artery disease. The exact function and mechanism of action of both proteins remains to be elucidated, however, mu ...[more]
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Project description:BackgroundWe investigated the role of ANGPTL3 and ANGPTL4 in atherosclerosis development and determined whether plasma concentrations of ANGPTL3 and ANGPTL4 are related to the degree of coronary stenosis.MethodsA total of 305 consecutive patients with angina who underwent diagnostic coronary angiography were enrolled in the study between August 2017 and August 2018. The levels of ANGPTL3 and ANGPTL4 were measured by using competitive ELISA kits.ResultsAccording to the degree of coronary artery stenosis, patients were classified into four types: coronary artery stenosis of < 10%, 10-50%, 50-75, and > 75%. The plasma ANGPTL3 level was higher (51.71 ± 52.67 vs. 24.65 ± 10.32 ng/mL, P < 0.001) and that of ANGPTL4 was lower (454.66 ± 269.05 vs. 875.49 ± 961.15 ng/mL, P < 0.001) in the coronary artery stenosis ≥ 10% group than in the < 10% group. ANGPTL3 and ANGPTL4 levels were significantly associated with the severity of coronary vascular stenosis. ROC curve analyses indicated that ANGPTL3 concentrations above 30.5 ng/mL can predict atherosclerosis with a sensitivity of 71.2% and specificity of 75.3%, and that ANGPTL4 levels below 497.5 ng/mL can predict atherosclerosis with a sensitivity of 63.9% and specificity of 74.5%. ANGPTL3 and ANGPTL4 were determined to be independent risk factors for coronary atherosclerosis with odds ratios (ORs) of 0.189 (95% CI 0.097-0.368, P < 0.001) and 3.625 (95% CI 1.873-7.016, P < 0.001), respectively.ConclusionsIncreased ANGPTL3 or decreased ANGPTL4 shows an association with coronary atherosclerosis and, may become a predictor of coronary atherosclerosis in the future.
| S-EPMC8571829 | biostudies-literature
Project description:BackgroundFamilial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown.ObjectivesThe study goal was to leverage 3 distinct lines of evidence-a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)-to test whether ANGPTL3 deficiency is associated with lower risk for CAD.MethodsWe assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects.ResultsThe 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001).ConclusionsANGPTL3 deficiency is associated with protection from CAD.
| S-EPMC5404817 | biostudies-literature
Project description:Higher-than-normal levels of circulating triglycerides are a risk factor for ischemic cardiovascular disease. Activation of lipoprotein lipase, an enzyme that is inhibited by angiopoietin-like 4 (ANGPTL4), has been shown to reduce levels of circulating triglycerides.We sequenced the exons of ANGPTL4 in samples obtain from 42,930 participants of predominantly European ancestry in the DiscovEHR human genetics study. We performed tests of association between lipid levels and the missense E40K variant (which has been associated with reduced plasma triglyceride levels) and other inactivating mutations. We then tested for associations between coronary artery disease and the E40K variant and other inactivating mutations in 10,552 participants with coronary artery disease and 29,223 controls. We also tested the effect of a human monoclonal antibody against ANGPTL4 on lipid levels in mice and monkeys.We identified 1661 heterozygotes and 17 homozygotes for the E40K variant and 75 participants who had 13 other monoallelic inactivating mutations in ANGPTL4. The levels of triglycerides were 13% lower and the levels of high-density lipoprotein (HDL) cholesterol were 7% higher among carriers of the E40K variant than among noncarriers. Carriers of the E40K variant were also significantly less likely than noncarriers to have coronary artery disease (odds ratio, 0.81; 95% confidence interval, 0.70 to 0.92; P=0.002). K40 homozygotes had markedly lower levels of triglycerides and higher levels of HDL cholesterol than did heterozygotes. Carriers of other inactivating mutations also had lower triglyceride levels and higher HDL cholesterol levels and were less likely to have coronary artery disease than were noncarriers. Monoclonal antibody inhibition of Angptl4 in mice and monkeys reduced triglyceride levels.Carriers of E40K and other inactivating mutations in ANGPTL4 had lower levels of triglycerides and a lower risk of coronary artery disease than did noncarriers. The inhibition of Angptl4 in mice and monkeys also resulted in corresponding reductions in these values. (Funded by Regeneron Pharmaceuticals.).
| S-EPMC4900689 | biostudies-literature
Project description:It is well-established that there exists an inverse relationship between high-density lipoprotein (HDL) cholesterol and triglyceride (TG) levels in the plasma. However, information is lacking on the impact of post-prandial triglyceride-rich lipoproteins (TRLs) on the structure of HDL subclasses in patients with coronary artery disease (CAD). In this study, the data of 49 patients with CAD were analyzed to evaluate dynamic alterations in post-prandial lipid profiles using nuclear magnetic resonance-based methods. An enzyme-linked immunosorbent assay was used to quantify the serum angiopoietin-like protein 3 (ANGPTL3). After glucose supplementation, the expression of hepatic ANGPTL3 was evaluated both in vitro and in vivo. Compared to fasting levels, the post-prandial serum TG level of all participants was considerably increased. Although post-prandial total cholesterol in HDL (HDL-C) remained unchanged, free cholesterol in HDL particles (HDL-FC) was significantly reduced after a meal. Furthermore, the post-prandial decrease in the HDL-FC level corresponded to the increase in remnant cholesterol (RC), indicating the possible exchange of free cholesterol between HDL and TRLs after a meal. Moreover, CAD patients with exaggerated TG response to diet, defined as TG increase >30%, tend to have a greater post-prandial increase of RC and decrease of HDL-FC compared to those with TG increase ≤30%. Mechanistically, the fasting and post-prandial serum ANGPTL3 levels were significantly lower in those with TG increase ≤30% than those with TG increase >30%, suggesting that ANGPTL3, the key lipolysis regulator, may be responsible for the different post-prandial responses of TG, RC, and HDL-FC.
| S-EPMC9276986 | biostudies-literature
Project description:BackgroundLittle is known about the association of the dedicator of cytokinesis 7 (DOCK7 rs1748195) and angiopoietin like 3 (ANGPTL3 rs12563308) single nucleotide polymorphisms (SNPs) and their haplotypes with serum lipid levels and the risk of coronary artery disease (CAD) and ischemic stroke (IS) in the Chinese populations. This study aimed to detect such association in a Southern Chinese Han population.MethodsThis study included 1728 subjects (CAD, 568; IS, 539; and controls, 621). Genotypes of the two SNPs were determined by the Snapshot technology.ResultsThe genotypic and allelic frequencies of the rs1748195 SNP were different between CAD patients and controls (P < 0.05 for each), the rs1748195G allele frequency was higher in CAD patients than in controls (27.6% vs. 23.6%, P = 0.024). The genotypic frequencies of the rs12563308 SNP were also different between CAD patients and controls (P = 0.021). The rs1748195 SNP was associated with an increased risk of CAD after controlling for potential confounders and Bonferroni correction (P < 0.025 considered statistically significant; Recessive: OR = 1.79, 95% CI = 1.04-3.06, P = 0.017; Log-additive: OR = 1.27, 95% CI = 1.02-1.57, P = 0.014), whereas the rs12563308 SNP was associated with a decreased risk of CAD (Dominant: OR = 0.69, 95% CI = 0.45-0.94, P = 0.011; Log-additive: OR = 0.73, 95% CI = 0.49-0.89, P = 0.009). The rs1748195 SNP was also associated with an increased risk of severity to coronary artery atherosclerosis (Dominant: OR = 1.45, 95% CI = 1.07-2.11, P = 0.017; Log-additive: OR = 1.35, 95% CI = 1.09-1.82, P = 0.013). The interactions of SNP-environment on serum lipid levels and the risk of severity to coronary artery atherosclerosis, CAD and IS were noted. The rs1748195G-rs12563308T haplotype was associated with an increased angiographic severity to coronary artery atherosclerosis (OR = 1.46, 95% CI = 1.05-2.03), and the risk of CAD (OR = 1.37, 95% CI = 1.08-1.74). The interactions of haplotype-hypertension on the risk of CAD and haplotype-drinking on the risk of CAD/IS were observed.ConclusionsThese results suggest that the DOCK-ANGPTL3 SNPs and their haplotypes were associated with the angiographic severity to coronary artery atherosclerosis and the risk of CAD and IS in the Southern Chinese Han population.
| S-EPMC5816384 | biostudies-literature
Project description:BACKGROUND:The role of triglyceride (TG) in secondary prevention of patients with coronary artery disease (CAD) was debated. In the present study, we assessed the association between admission TG levels and long-term mortality risk in CAD patients. METHODS:A retrospective analysis was conducted from a single registered database. 3061 consecutive patients with CAD confirmed by coronary angiography were enrolled and were grouped into 3 categories by the tertiles of admission serum TG levels. The primary end point in this study was all-cause mortality and the secondary end point was cardiovascular mortality. RESULTS:The mean follow-up time was 26.9?±?13.6?months and death events occurred in 258 cases and cardiovascular death events occurred in 146 cases. Cumulative survival curves indicated that the risk of all-cause death decreased with increasing TG level (Tertile 1 vs. Tertile 2 vs. Tertile 3?=?10.3% vs. 8.6% vs. 6.3%, log rank test for overall p?=?0.001). Cox regression analysis showed an independent correlation between TG level and risk of all-cause mortality [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.58-0.86] and cardiovascular mortality (HR 0.67, 95% CI 0.51-0.89) in total patients with CAD. Subgroup analysis found the similar results in patients with acute coronary syndrome and acute myocardial infarction. CONCLUSIONS:This study found an inverse association between TG levels and mortality risk in CAD patients, which suggests that the "TG paradox" may exist in CAD patients. TRIAL REGISTRATION:ChiCTR, ChiCTR-OOC-17010433 . Registered 17 February 2017 - Retrospectively registered.
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Project description:Triglyceride (TG) molecules represent the major storage form of fatty acids, and TG metabolism is essential to human health. However, the mechanistic details surrounding TG metabolism are complex and incompletely elucidated. Although it is known that angiopoietin-like protein 8 (ANGPTL8) increases TGs through an ANGPTL3/8 complex that inhibits LPL, the mechanism governing ApoA5, which lowers TGs, has remained elusive. Current hypotheses for how ApoA5 acts include direct stimulation of LPL, facilitation of TG-containing particle uptake, and regulation of hepatic TG secretion. Using immunoprecipitation-MS and Western blotting, biolayer interferometry, functional LPL enzymatic assays, and kinetic analyses of LPL activity, we show that ApoA5 associates with ANGPTL3/8 in human serum and most likely decreases TG by suppressing ANGPTL3/8-mediated LPL inhibition. We also demonstrate that ApoA5 has no direct effect on LPL, nor does it suppress the LPL-inhibitory activities of ANGPTL3, ANGPTL4, or ANGPTL4/8. Importantly, ApoA5 suppression of ANGPTL3/8-mediated LPL inhibition occurred at a molar ratio consistent with the circulating concentrations of ApoA5 and ANGPTL3/8. Because liver X receptor (LXR) agonists decrease ApoA5 expression and cause hypertriglyceridemia, we investigated the effect of the prototypical LXR agonist T0901317 on human primary hepatocytes. We observed that T0901317 modestly stimulated hepatocyte ApoA5 release, but markedly stimulated ANGPTL3/8 secretion. Interestingly, the addition of insulin to T0901317 attenuated ApoA5 secretion, but further increased ANGPTL3/8 secretion. Together, these results reveal a novel intersection of ApoA5 and ANGPTL3/8 in the regulation of TG metabolism and provide a possible explanation for LXR agonist-induced hypertriglyceridemia.
| S-EPMC8079461 | biostudies-literature
Project description:SubjectThe Angiopoietin-like 3 (ANGPTL3) gene has been reported to be associated with cardiovascular risk. This study is designed to compare the genetic variant (rs1748195) of the ANGPTL3 gene and the presence of a coronary artery occlusion of >50% in Iranian nation.MethodIn this study, 184 patients underwent angiography and 317 healthy individuals were evaluated for polymorphism of rs1748195 the ANGPTL3 gene using Tetra-ARMs PCR. Coronary patients who experience angiography were categorized into two groups: 54 patients who had an angiography indication for the first time and coronary occlusion was <50% (Angio-) and 134 patients who formerly underwent coronary stent implanting at least 1 month before with coronary occlusion of ≥50% that again have an angiography indication (Angio+). In addition, individuals with angio+ are categorized in two groups: (1) non-in-stent restenosis (NISR); patient with a patent stent (N = 92). (2) in-stent restenosis (ISR); in-stent stenosis >50% (N = 42).ResultThe fundamental of characteristics of our study design population was categorized based on undergoing angiography or not. In the present study, we investigated that the CC genotype, and also the A allele corresponding to rs1748195 at the ANGPTL3 gene loci, was associated with negative angiogram and directly related to the risk of coronary occlusion >50%. In contrast, this result was not significant in genotypes of ANGPTL3 between non-ISR and ISR groups.ConclusionThe outcomes of this study showed that rs1748195 polymorphism at the ANGPTL3 gene loci is associated with an elevated risk for the existence of a coronary occlusion of >50%.
| S-EPMC10009914 | biostudies-literature
Project description:Background:This study aimed to assess the association between the angiopoietin-like protein 4 gene (ANGPTL4) single nucleotide polymorphisms (SNPs) and serum lipid levels, the risk of coronary artery disease (CAD) and ischemic stroke (IS), and response to atorvastatin therapy in a Southern Chinese Han population. Methods:Genotypes of the ANGPTL4 rs4076317, rs7255436, rs1044250 and rs2967605 SNPs in 1,654 unrelated subjects (CAD, 568; IS, 537; and controls, 549) were determined by the Snapshot technology. Another group of 724 hyperlipidemic patients was selected and treated with atorvastatin calcium tablet 20 mg/day for 8 weeks. Results:The rs2967605 CT/TT genotypes were associated with a decreased risk of CAD (adjusted OR = 0.68, 95% CI = 0.47-0.99, P = 0.043 for CT/TT vs. CC) and IS (adjusted OR = 0.55, 95% CI = 0.38-0.80, P = 0.020 for CT/TT vs. CC). There was no significant association between the four SNPs and angiographic severity of CAD. The subjects with the rs4076317 CG/CC genotypes in controls had higher total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels than the subjects with the GG genotype (P < 0.001; a P < 0.0018 was regarded statistically significant by the Bonferroni correction). The subjects with rs4076317CG/GG genotypes had lower TC and LDL-C levels than the subjects with CC genotype after atorvastatin treatment (P < 0.001). Conclusions:The observed associations suggest that the ANGPTL4 variants have a potential role on serum lipid levels and atherosclerosis-related diseases in the Chinese Han population, especially the ANGPTL4 rs4076317 and rs2967605 SNPs.
| S-EPMC6173870 | biostudies-literature
Project description:The correlation between diabetes and coronary artery disease (CAD) is well established. Insulin resistance (IR) is considered a primary contributor to elevated CAD risk in diabetic individuals. The triglyceride-glucose (TyG) index serves as a straightforward surrogate marker for insulin resistance. However, few studies have explored their correlations with myocardial infarction and CAD severity. Therefore, our study aimed to investigate the association between the TyG index and the occurrence of myocardial infarction, as well as the severity of coronary artery disease. We conducted a retrospective study involving 3865 consecutive patients who underwent coronary angiography at the First Affiliated Hospital of Zhejiang University, School of Medicine. Of these, 1724 patients were diagnosed with coronary artery disease. Demographic, biochemical, clinical, and angiographic data were gathered. A robust correlation exists between the TyG index and CAD subtypes, suggesting its potential as an independent clinical diagnostic marker. Moreover, the TyG index exhibited a significant positive correlation with disease severity, as assessed by the Gensini score. Elevated TyG index was associated with an increased predisposition to severe CAD, as indicated by the Gensini score, and myocardial infarction, even after adjusting for well-established cardiovascular risk factors.
| S-EPMC11369095 | biostudies-literature