apoA-I Levels Research Articles

Low Serum Paraoxonase-1 Activity Associates with Incident Cardiovascular Disease Risk in Subjects with Concurrently High Levels of High-Density Lipoprotein Cholesterol and C-Reactive Protein.

Paroxonase-1 (PON1) is a key enzyme that inhibits low-density lipoprotein oxidation and consequently atherogenesis. Here, we assessed whether low serum PON1 activity associates with incident cardiovascular disease (CVD) in subjects with high levels of high-density cholesterol (HDL-C) and C-reactive protein (CRP), a marker of low-grade systemic inflammation. Cox proportional-hazards modeling of incident CVD risk (11 years mean follow-up) adjusted for relevant clinical and biomarker covariates was performed on a population-based study (N = 7766) stratified into three groups: low CRP—(LR; event rate 4.9%); low HDL-C/high CRP—(HR1; event rate 14.4%); and high HDL-C/high CRP—(HR2; event rate 7.6%). Modeling results for PON1 activity in HR2 were significant and robust (hazard ratio/SD unit—0.68, 95% CI 0.55–0.83, p = 0.0003), but not so for LR and HR1. Analyses in HR2 of the interaction of PON1 with HDL-C, apoA-I, apoA-II, and apoE levels were significant only for PON1 with apoE (hazard ratio—1.77, 95% CI 1.29–2.41, p = 0.0003). Subsequent subgroup analysis revealed inverse risk dependence for apoE at low PON1 levels. In conclusion, in a population-based study of subjects with concurrently high HDL-C and CRP levels, low serum PON1 activity associates with incident CVD risk with risk accentuated at low apoE levels.

Cholesterol and neurodegeneration: longitudinal changes in serum cholesterol biomarkers are associated with new lesions and gray matter atrophy in multiple sclerosis over 5 years of follow-up.

Cholesterol is an important structural component of myelin and essential for brain homeostasis. Our objective was to investigate whether longitudinal changes in cholesterol biomarkers are associated with neurodegeneration in multiple sclerosis (MS). This prospective, longitudinal study (n=154) included 41 healthy controls, 76 relapsing-remitting MS subjects and 37 progressive MS subjects. Neurological examination, brain magnetic resonance imaging and blood samples were obtained at baseline and at 5-year follow-up visits. Cholesterol biomarkers measured included plasma total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol and the apolipoproteins ApoA-I, Apo-II, ApoB, ApoC-II and ApoE. Key cholesterol pathway single nucleotide polymorphisms were genotyped. Greater percentage increases in HDL-C and ApoA-I levels were associated with a lower rate of gray matter and cortical volume loss. Greater percentage increases in low-density lipoprotein cholesterol were associated with increases in new T2 lesions. The percentage increases in HDL-C (P=0.032) and ApoA-I (P=0.007) were smaller in patients with relapsing-remitting MS at baseline who converted to secondary progressive MS during the 5-year follow-up period. Changes in HDL-C and ApoA-I were associated with lipoprotein lipase rs328 genotype status. Increases in HDL-C and ApoA-I have protective associations with magnetic resonance imaging measures of neurodegeneration in MS.

ABCA1- and ABCG1-mediated cholesterol efflux capacity of cerebrospinal fluid is impaired in Alzheimer's disease

HDL-like particles in human cerebrospinal fluid (CSF) promote the efflux of cholesterol from astrocytes toward the neurons that rely on this supply for their functions. We evaluated whether cell cholesterol efflux capacity of CSF (CSF-CEC) is impaired in Alzheimer's disease (AD) by analyzing AD (n = 37) patients, non-AD dementia (non-AD DEM; n = 16) patients, and control subjects (n = 39). As expected, AD patients showed reduced CSF Aβ 1-42, increased total and phosphorylated tau, and a higher frequency of the apoε4 genotype. ABCA1- and ABCG1-mediated CSF-CEC was markedly reduced in AD (-73% and -33%, respectively) but not in non-AD DEM patients, in which a reduced passive diffusion CEC (-40%) was observed. Non-AD DEM patients displayed lower CSF apoE concentrations (-24%) compared with controls, while apoA-I levels were similar among groups. No differences in CSF-CEC were found by stratifying subjects for apoε4 status. ABCG1 CSF-CEC positively correlated with Aβ 1-42 (r = 0.305, P = 0.025), while ABCA1 CSF-CEC inversely correlated with total and phosphorylated tau (r = -0.348, P = 0.018 and r = -0.294, P = 0.048, respectively). The CSF-CEC impairment and the correlation with the neurobiochemical markers suggest a pathophysiological link between CSF HDL-like particle dysfunction and neurodegeneration in AD.

Effects Of Conserved Proline Apoai Variants On Hdl Structure And Function

Background and Aims: Although plasma high density lipoproteins (HDL) and apolipoprotein (apo) AI levels negatively correlate with atherosclerotic cardiovascular disease (CVD), most HDL-raising interventions do not reduce CVD events. Moreover, other studies show that HDL function, e.g., support of macrophage cholesterol efflux, may be more important than the plasma HDL levels. HDL instability is relevant to the activities of plasma LCAT, CETP, PLTP, SR-BI, and HL. The mechanisms and pathways underlying the HDL biogenesis determine its compositions and ultimately its function in vivo. Alignment of the α-helices of apo AI, reveals highly conserved amino acid residues across 31 species. Moreover, proline-initiated amphipathic a-helices are a conserved structural motif among the exchangeable apos. We tested the hypothesis that highly conserved amino acid residues in apo AI are essential to its structure and function.

Allergic rhinitis is associated with complex alterations in high-density lipoprotein composition and function

Despite strong evidence that high-density lipoproteins (HDLs) modulate the immune response, the role of HDL in allergies is still poorly understood. Many patients with allergic rhinitis (AR) develop a late-phase response, characterized by infiltration of monocytes and eosinophils into the nasal submucosa. Functional impairment of HDL in AR-patients may insufficiently suppress inflammation and cell infiltration, but the effect of AR on the composition and function of HDL is not understood. We used apolipoprotein (apo) B-depleted serum as well as isolated HDL from AR-patients (n = 43) and non-allergic healthy controls (n = 20) for detailed compositional and functional characterization of HDL. Both AR-HDL and apoB-depleted serum of AR-patients showed decreased anti-oxidative capacity and impaired ability to suppress monocyte nuclear factor-κB expression and pro-inflammatory cytokine secretion, such as interleukin (IL)-4, IL-6, IL-8, tumor necrosis factor alpha and IL-1 beta. Sera of AR-patients showed decreased paraoxonase and cholesteryl-ester transfer protein activities, increased lipoprotein-associated phospholipase A2 activity, while lecithin-cholesterol acyltransferase activity and cholesterol efflux capacity were not altered. Surprisingly, apoB-depleted serum and HDL from AR-patients showed an increased ability to suppress eosinophil effector responses upon eotaxin-2/CCL24 stimulation. Mass spectrometry and biochemical analyses showed reduced levels of apoA-I and phosphatidylcholine, but increased levels of apoA-II, triglycerides and lyso-phosphatidylcholine in AR-HDL. The changes in AR-HDL composition were associated with altered functional properties. In conclusion, AR alters HDL composition linked to decreased anti-oxidative and anti-inflammatory properties but improves the ability of HDL to suppress eosinophil effector responses.

Apolipoprotein A-I Protects Against Pregnancy-Induced Insulin Resistance in Rats.

Objective- Insulin resistance and inflammation in pregnancy are risk factors for gestational diabetes mellitus. Increased plasma HDL (high-density lipoprotein) and apo (apolipoprotein) A-I levels have been reported to improve glucose metabolism and inhibit inflammation in animals and humans. This study asks whether increasing plasma apoA-I levels improves insulin sensitivity and reduces inflammation in insulin-resistant pregnant rats. Approach and Results- Insulin-resistant pregnant rats received intravenous infusions of lipid-free apoA-I (8 mg/kg) or saline on days 6, 9, 12, 15, and 18 of pregnancy. The rats were then subjected to a euglycemic-hyperinsulinemic clamp. Glucose uptake was increased in white and brown adipose tissue by 57±13% and 32±10%, respectively ( P<0.05 for both), and in quadriceps and gastrocnemius muscle by 35±9.7% and 47±14%, respectively ( P<0.05 for both), in the apoA-I-treated pregnant rats relative to saline-infused pregnant rats. The pregnant rats that were treated with apoA-I also had reduced plasma TNF-α (tumor necrosis factor-α) levels by 57±8.4%, plasma IL (interleukin)-6 levels by 67±9.5%, and adipose tissue macrophage content by 54±8.2% ( P<0.05 for all) relative to the saline-treated pregnant rats. Conclusions- These studies establish that apoA-I protects against pregnancy-induced insulin resistance in rats by increasing insulin sensitivity in adipose tissue and skeletal muscle and inhibiting inflammation. This identifies apoA-I as a potential target for preventing pregnancy-induced insulin resistance and reducing the incidence of gestational diabetes mellitus.

Atrial fibrillation is associated with alterations in HDL function, metabolism, and particle number.

Increased morbidity and mortality in atrial fibrillation (AF) are related to the pro-fibrotic, pro-thrombotic, and pro-inflammatory processes that underpin the disease. High-density lipoproteins (HDL) have anti-inflammatory, anti-oxidative, and anti-thrombotic properties. Functional impairment of HDL may, therefore, associate with AF initiation or progression. We studied indices of HDL quality and quantity of AF patients and healthy controls, including HDL-particle number, HDL cholesterol, apolipoprotein (apo) A-I levels, serum amyloid A (SAA) content and HDL-cholesterol efflux capacity, and paraoxonase activity of apoB-depleted serum. Serum samples were collected from AF patients (n = 91) before catheter ablation and from age- and sex-matched control subjects (n = 54). HDL-cholesterol efflux capacity was assessed in a validated assay using [3H]-cholesterol-labeled J774 macrophages. Lecithin-cholesterol acyltransferase (LCAT) and paraoxonase activities were assessed using fluorometric assays, SAA levels were determined by ELISA, and total and subclass HDL-particle number was assessed by nuclear magnetic resonance spectroscopy. ApoA-I levels were determined by immunoturbidimetry. HDL-cholesterol efflux capacity, HDL-particle number, apoA-I levels, and LCAT activity were markedly reduced in AF patients when compared to healthy individuals (all p < 0.001), whereas HDL-associated paraoxonase activity and SAA content were not altered (p = 0.578, p = 0.681). Notably, cholesterol efflux capacity, HDL-particle number, apoA-I levels as well as LCAT activity recovered following restoration of sinus rhythm (all p < 0.001). We identified marked alterations in HDL function, HDL maturation, and HDL-particle number in AF patients. Assessing HDL-particle number and function in AF may be used as a surrogate marker of AF onset and progression and may help identifying patients at high risk.

Astaxanthin exerts protective effects similar to bexarotene in Alzheimer's disease by modulating amyloid-beta and cholesterol homeostasis in blood-brain barrier endothelial cells

The pathogenesis of Alzheimer's disease (AD) is characterized by overproduction, impaired clearance, and deposition of amyloid-β peptides (Aβ) and connected to cholesterol homeostasis. Since the blood-brain barrier (BBB) is involved in these processes, we investigated effects of the retinoid X receptor agonist, bexarotene (Bex), and the peroxisome proliferator-activated receptor α agonist and antioxidant, astaxanthin (Asx), on pathways of cellular cholesterol metabolism, amyloid precursor protein processing/Aβ production and transfer at the BBB in vitro using primary porcine brain capillary endothelial cells (pBCEC), and in 3xTg AD mice. Asx/Bex downregulated transcription/activity of amyloidogenic BACE1 and reduced Aβ oligomers and ~80 kDa intracellular 6E10-reactive APP/Aβ species, while upregulating non-amyloidogenic ADAM10 and soluble (s)APPα production in pBCEC. Asx/Bex enhanced Aβ clearance to the apical/plasma compartment of the in vitro BBB model. Asx/Bex increased expression levels of ABCA1, LRP1, and/or APOA-I. Asx/Bex promoted cholesterol efflux, partly via PPARα/RXR activation, while cholesterol biosynthesis/esterification was suppressed. Silencing of LRP-1 or inhibition of ABCA1 by probucol reversed Asx/Bex-mediated effects on levels of APP/Aβ species in pBCEC. Murine (m)BCEC isolated from 3xTg AD mice treated with Bex revealed elevated expression of APOE and ABCA1. Asx/Bex reduced BACE1 and increased LRP-1 expression in mBCEC from 3xTg AD mice when compared to vehicle-treated or non-Tg treated mice. In parallel, Asx/Bex reduced levels of Aβ oligomers in mBCEC and Aβ species in brain soluble and insoluble fractions of 3xTg AD mice. Our results suggest that both agonists exert beneficial effects at the BBB by balancing cholesterol homeostasis and enhancing clearance of Aβ from cerebrovascular endothelial cells.

Relationship between serum levels of osteoproteins, inflammatory cytokines and coronary heart disease and disease severity

To explore the relationship between serum levels of osteoprotein (OPG), soluble nuclear factor-κB receptor activator ligand (sRANKL), inflammatory factors and coronary heart disease (CHD) and its severity. The patients who underwent coronary angiography (CAG) due to chest pain admitted to department of cardiology of Tianjin Chest Hospital from April 2017 to December 2018 were enrolled, and they were divided into CHD group and non-CHD group according to the CAG results. The gender, age, history of hypertension, smoking history, diabetes, the levels of cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apolipoprotein AI (apoAI), apolipoprotein B (apoB), lipoprotein (a) [Lp (a)], MB isoenzyme of creatine kinase (CK-MB) and other clinical data of patients were collected. The serum levels of OPG, sRANKL, matrix metalloproteinase-9 (MMP-9), monocyte chemotactic protein-1 (MCP-1), insulin-like growth factor-1 (IGF-1) and interleukin-6 (IL-6) were determined by enzyme-linked immunosorbent assay (ELISA). According to the results of CAG, the patients with CHD were divided into single-, double-, triple-branch coronary artery lesion groups, and the relationship between the levels of serum OPG, sRANKL, inflammatory factors and the degree of coronary artery lesions was observed. Multivariate Logistic regression was used to analyze the risk factors of CHD, and receiver operating characteristic (ROC) curve was plotted to analyze the predictive value of main risk factors for CHD. A total of 472 patients were enrolled in the final analysis during the study period, including 264 patients in the CHD group, 208 patients in the non-CHD group, 79 patients in the CHD group with single-branch disease, 75 patients with double-branch disease, and 110 patients with three-branch disease. (1) Compared with the non-CHD group, the CHD group had more older male patients, as well as higher proportion of hypertension and diabetes, the levels of serum Lp (a) and CK-MB were significantly increased, and the levels of serum HDL-C and apoAI were significantly lowered. There was no statistically significant difference in serum TC, LDL-C, or apoB between the two groups. The levels of serum OPG, MMP-9, MCP-1, IGF-1 and IL-6 in the CHD group were significantly higher than those in the non-CHD group [OPG (μg/L): 1.79±0.50 vs. 1.50±0.30, MMP-9 (μg/L): 57.91 (33.50, 130.46) vs. 38.33 (29.43, 109.78), MCP-1 (μg/L): 298.30 (207.96, 537.16) vs. 252.73 (165.22, 476.01), IGF-1 (μg/L): 734.03±486.11 vs. 217.75±126.45, IL-6 (ng/L): 64.76±40.25 vs. 48.60±15.80, all P < 0.05], and the levels of serum sRANKL was significantly lower than that in the non-CHD group (ng/L: 344.31±122.14 vs. 378.74±109.27, P < 0.05). (2) The serum OPG level showed a slight upward tendency with the increase in the number of coronary artery lesions, and the sRANKL level showed a slight downward tendency [OPG (μg/L) in the single-, double-, triple-branch coronary artery lesion groups was 1.74±0.49, 1.76±0.50, 1.85±0.52, and sRANKL (ng/L) was 354.96±116.64, 340.05±124.24, 339.57±125.03, respectively) without statistically significant differences (all P > 0.05). The levels of IGF-1 and IL-6 were increased with the number of coronary artery lesions [IGF-1 (μg/L) in the single-, double- and triple-branch coronary artery lesions groups was 372.13±258.42, 676.06±350.29, 1 033.47±468.06, and IL-6 (ng/L) was 48.87±16.72, 65.36±18.84, 75.76±22.72, respectively], and the differences among different lesion groups were statistically significant (all P < 0.01). Correlation analysis showed that IGF-1 level was significantly positively correlated with the number of coronary artery lesions (r = 0.612, P < 0.01), while IL-6 was not correlated with the number of coronary artery lesions (r = 0.185, P > 0.05). (3) Multivariate Logistic regression analysis showed that elevated serum OPG and IGF-1 levels were risk factors for CHD [OPG: odds ratio (OR) = 1.995, 95% confidence interval (95%CI) = 1.936-2.067, P = 0.012; IGF-1: OR = 1.009, 95%CI = 1.004-1.015, P = 0.001]. (4) ROC curve analysis showed that the area under ROC curve (AUC) of OPG and IGF-1 was 0.716 and 0.867, respectively. When the cut-off value of OPG was 1.13 μg/L, the sensitivity was 81.7%, the specificity was 58.1%; when the cut-off value of sRANKL was 401.20 μg/L, the sensitivity was 69.7%, the specificity was 95.7%. CHD was associated with increased in OPG, related inflammatory cytokines including MMP-9, MCP-1, IGF-1 and IL-6, and decreased in sRANKL. The level of IGF-1 was positively correlated with the severity of CHD. The serum levels of OPG and IGF-1 were risk factors for CHD, which had good predictive value for CHD.

SUN-071 Unexpected Paradoxical Extremely Low of HDL-Cholesterol Level in a Non-Diabetes, Non-CKD Patient after Treatment with Specific Fibrate and Statin and Specific Fibrate Alone

Background: Fibrates are the class of the lipid-modifying agents to treat hypertriglyceridemia with usually increasing HDL that generally reflected by increased plasma levels of apoA-I and apoA-II. Paradoxical decrease in serum HDL level has been rarely reported. This presents a specific use of fibrates and statins therapy lead to markedly low of serum HDL level, in a non-diabetes and non-kidney disease patient. Clinical case: A 50-year-old man, underlying NAFLD, hypertension and dyslipidemia, has been followed up for 11 years. He was a non-smoker, non-drinker and denied to use any herbal supplement. His BMI and renal function were normal. He had a family history of cardiovascular death, including his grandmother (at 63 years old), his father (at 59 years old) and his mother (at 65 years old). Eleven years ago, he was started with simvastatin 10 mg when his presentation fasting serum lipids values were LDL 130 mg/dL, triglyceride 137 mg/dL and HDL 34 mg/dL. Three years later, his lipids showed severe hypertriglyceridemia; 795 mg/dL, LDL 75 mg/dL and HDL 28 mg/dL, he was added gemfibrozil 600 mg and up titrate dose to 900 mg during next two years of follow-up without any adverse event. After that, FDA warning drugs interaction between statins and gemfibrozil, simvastatin 10 mg was changed to ezetimibe 10 mg when his serum lipids were LDL 85 mg/dL, triglyceride 339 mg/dL and HDL 41 mg/dL for the next 3 years. Because his lipids values showed increase LDL to 150 mg/dL, he was changed his medications to ezetimibe/ simvastatin 10/20 with lifestyle modification to maintain normal triglyceride level. One year following, he complained myalgia with mildly elevated of CPK (298 U/L; < 190) together with ALT (86 U/L; < 41). At that time, his serum lipids were LDL 67 mg/dL, triglyceride 318 mg/dL and HDL 32 mg/dL. Ezetimibe/ simvastatin 10/20 was stopped and changed to pravastatin 40 mg due to the lesser side effects on the muscles and liver. In the next six months, his CPK level turned to normal however triglyceride level elevated to 533 mg/dL then fenofibrate 300 mg was added. Four months later, his serum lipids revealed triglyceride 190 mg/dL, LDL 86 mg/dL and HDL 3 mg/dL which pravastatin was stopped alone. During next several visits, serum HDL slightly elevated from 3 to 9 to 11 mg/dL every two months until fenofibrate was decided to stop as the serum HDL level was 8 mg/dL, LDL 126 mg/dL and triglyceride 241 mg/dL. Four months later, his serum HDL returned to 31 mg/dL with ezetimibe 10 mg alone. Concussion: This case presents the paradoxical severe decrease in serum HDL-cholesterol after treatment with specific combination of pravastatin and fenofibrate and fenofibrate alone which did not happen in the longer period use of simvastatin and gemfibrozil or gemfibrozil alone without abnormal renal function or diabetes. Awareness of decline in HDL during treatment with fenofibrate alone or combination with statins should be considered.

Distinct phospholipid and sphingolipid species are linked to altered HDL function in apolipoprotein A-I deficiency

Familial apolipoprotein A-I (apoA-I) deficiency (FAID) involving low levels of both apoA-I and high-density lipoprotein (HDL) cholesterol is associated with accelerated atherosclerosis. The objective of this study was to define distinctive patterns in the lipidome of HDL subpopulations in FAID in relationship to antiatherogenic activities. Five HDL subfractions were isolated by ultracentrifugation from plasma of FAID Caucasian patients (n=5) and age-matched healthy normolipidemic Caucasian controls (n=8), and the HDL lipidome (160 molecular species of 9 classes of phospholipids and sphingolipids) was quantitatively evaluated. Increased concentrations of numerous molecular species of lysophosphatidylcholine (up to 12-fold), ceramides (up to 3-fold), phosphatidylserine (up to 34-fold), phosphatidic acid (up to 71-fold), and phosphatidylglycerol (up to 20-fold) were detected throughout all five HDL subpopulations as compared with their counterparts from controls, whereas concentrations of phosphatidylethanolamine species were decreased (up to 5-fold). Moderately to highly abundant, within their lipid class, species of phosphatidylcholine, sphingomyelin, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine, and ceramide featuring multiple unsaturations were primarily affected by apoA-I deficiency; their HDL content, particularly that of phosphatidylcholine (34:2), was strongly correlated with HDL function, impaired in FAID. Metabolic pathway analysis revealed that sphingolipid, glycerophospholipid, and linoleic acid metabolism was significantly affected by FAID. These data reveal that altered content of specific phospholipid and sphingolipid species is linked to deficient antiatherogenic properties of HDL in FAID.

Apolipoprotein A-I enhances insulin-dependent and insulin-independent glucose uptake by skeletal muscle

Therapeutic interventions that increase plasma high density lipoprotein (HDL) and apolipoprotein (apo) A-I levels have been reported to reduce plasma glucose levels and attenuate insulin resistance. The present study asks if this is a direct effect of increased glucose uptake by skeletal muscle. Incubation of primary human skeletal muscle cells (HSKMCs) with apoA-I increased insulin-dependent and insulin–independent glucose uptake in a time- and concentration-dependent manner. The increased glucose uptake was accompanied by enhanced phosphorylation of the insulin receptor (IR), insulin receptor substrate-1 (IRS-1), the serine/threonine kinase Akt and Akt substrate of 160 kDa (AS160). Cell surface levels of the glucose transporter type 4, GLUT4, were also increased. The apoA-I-mediated increase in glucose uptake by HSKMCs was dependent on phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt, the ATP binding cassette transporter A1 (ABCA1) and scavenger receptor class B type I (SR-B1). Taken together, these results establish that apoA-I increases glucose disposal in skeletal muscle by activating the IR/IRS-1/PI3K/Akt/AS160 signal transduction pathway. The findings suggest that therapeutic agents that increase apoA-I levels may improve glycemic control in people with type 2 diabetes.

A monoclonal antibody to assess oxidized cholesteryl esters associated with apoAI and apoB-100 lipoproteins in human plasma

Atherosclerosis is associated with increased lipid peroxidation, leading to generation of multiple oxidation-specific epitopes (OSEs), contributing to the pathogenesis of atherosclerosis and its clinical manifestation. Oxidized cholesteryl esters (OxCEs) are a major class of OSEs found in human plasma and atherosclerotic tissue. To evaluate OxCEs as a candidate biomarker, we generated a novel mouse monoclonal Ab (mAb) specific to an OxCE modification of proteins. The mAb AG23 (IgG1) was raised in C57BL6 mice immunized with OxCE-modified keyhole limpet hemocyanin, and hybridomas were screened against OxCE-modified BSA. This method ensures mAb specificity to the OxCE modification, independent of a carrier protein. AG23 specifically stained human carotid artery atherosclerotic lesions. An ELISA method, with AG23 as a capture and either anti-apoAI or anti-apoB-100 as the detection Abs, was developed to assay apoAI and apoB-100 lipoproteins that have one or more OxCE epitopes. OxCE-apoA or OxCE-apoB did not correlate with the well-established oxidized phospholipid-apoB biomarker. In a cohort of subjects treated with atorvastatin, OxCE-apoA was significantly lower than in the placebo group, independent of the apoAI levels. These results suggest the potential diagnostic utility of a new biomarker assay to measure OxCE-modified lipoproteins in patients with CVD.

Serum levels of proteins involved in amyloid-β clearance are related to cognitive decline and neuroimaging changes in mild cognitive impairment

IntroductionAmyloid-β (Aβ) clearance is important for damage prevention in Alzheimer's disease. We investigated the utility of Aβ clearance proteins as biomarkers for mild cognitive impairment (MCI). MethodsSerum apolipoprotein (apo) A-I, compliment protein C3 (C3), transthyretin, and cholesterol levels were measured in 273 subjects, and we analyzed the relationship between these levels and brain atrophy and cerebral blood flow in 63 clinically diagnosed mild cognitive impairment, Alzheimer's disease, and nondemented disease control subjects. ResultsApoA-I and transthyretin levels and the active form of C3:native form of C3 ratio achieved an area under the curve of 0.89 (sensitivity: 83%, specificity: 90%) for detecting late mild cognitive impairment. Atrophy was associated with decreased apoA-I and high-density lipoprotein levels. Subjects with reduced cerebral blood flow had lower levels of native form of C3, apoA-I, high-density lipoprotein, and total cholesterol. Low native form of C3 and high active form of C3 levels were found in the hippocampi of patients with Alzheimer's disease. DiscussionAβ clearance proteins in the serum are potential biomarkers for mild cognitive impairment evaluation.

Apolipoprotein C-III Strongly Correlates with Activated Factor VII–Anti-Thrombin Complex: An Additional Link between Plasma Lipids and Coagulation

Activated factor VII-anti-thrombin (FVIIa-AT) complex is a potential biomarker of pro-thrombotic diathesis reflecting FVIIa-tissue factor (TF) interaction and has been associated with mortality in patients with coronary artery disease (CAD). Previous data indicated plasma lipids as predictors of FVIIa-AT variability, and plasma lipoproteins as potential stimulators of the coagulation cascade. Our aim was to evaluate the relationships between FVIIa-AT plasma concentration and a broad apolipoprotein profile (including ApoA-I, ApoB, ApoC-III and ApoE). Within the framework of the observational Verona Heart Study, we selected 666 subjects (131 CAD-free and 535 CAD, 75.4% males, mean age: 61.1 ± 10.9 years) not taking anticoagulant drugs and for whom plasma samples were available for both FVIIa-AT assay and a complete lipid profile. Plasma concentration of FVIIa-AT levels significantly and directly correlated with total and high-density lipoprotein cholesterol, triglycerides, ApoA-I, ApoC-III and ApoE levels. ApoC-III showed the strongest correlation (R = 0.235, p = 7.7 × 10-10), confirmed in all the sub-group analyses (males/females and CAD/CAD-free). Only ApoC-III remained associated with FVIIa-AT plasma concentration, even after adjustment for sex, age, CAD diagnosis, body mass index, renal function, smoking status, lipid-lowering therapies and FVIIa levels. The APOC3 gene locus-tagging polymorphism rs964184, previously linked with cardiovascular risk and plasma lipids by genome-wide association studies, was associated with both ApoC-III and FVIIa-AT plasma concentration. Our results indicate a strong association between ApoC-III and FVIIa-AT levels, thereby suggesting that an increased ApoC-III concentration may identify subjects with a pro-thrombotic diathesis characterized by an enhanced TF-FVIIa interaction and activity.

Prognostic value of serum apolipoprotein A-I in locally advanced cervical squamous cell carcinoma treated with radical chemoradiotherapy

Background: Distant metastasis (DM) remains the major cause of death from locally advanced cervical squamous cell carcinoma (CSCC). This study aimed to evaluate the predictive value of pretreatment serum lipids on DM and death, in patients with locally advanced CSCC. Methods: In this study, a total of 331 consecutive patients with stages IIB–IVA CSCC and completed record of radical concurrent chemoradiotherapy (CCRT) were involved between January 2011 and June 2013. Pretreatment serum lipid indexes including total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), apolipoprotein A-I (apoAI) and apolipoprotein B (apoB) were analyzed for their association with the overall survival (OS), the local-recurrence-free survival (RFS), the distant-metastasis-free survival (MFS) and the disease-free survival (DFS), together with clinical features [age, stage, parametrial invasion, tumor diameter, lymph node metastasis, hemoglobin, squamous cell carcinoma (SCC) antigen and carbohydrate antigen 125 (CA125)]. Results: After univariate and multivariate analysis, serum apoAI level (≥1.2 vs . Conclusions: For locally advanced CSCC treated with CCRT, low pretreatment level of serum apoAI could predict high risk of DM and poor prognosis. This finding might help clinicians to direct therapy for eradicating DM and conduct clinical trials on apoAI-targeting anti-tumor therapies.

Interrelationships Among Apolipoprotein B/Apolipoprotein A-I Ratio, Insulin Resistance and Obstructive Sleep Apnea: A Large-Scale Observational Study

Background: The apolipoprotein B/apolipoprotein A-I (ApoB/ApoA-I) ratio has been recognized as a new predictor of cardiovascular diseases (CVD). However, the interrelationships between the ApoB/ApoA-I ratio and common CVD risk factor [insulin resistance, obstructive sleep apnea (OSA)] remain unclear. Methods: A total of 6,433 suspected OSA consecutively admitted to our sleep center were screened and 4,813 were included. Anthropometric, fasting biochemical, and polysomnographic parameters were collected. The relationships between insulin resistance, OSA risk, and the ApoB/ApoA-I ratio were evaluated through logistic regressions analysis and restricted cubic spline (RCS) analysis. Mediation analyses were qualified to assess the interrelationships. Results: Patients with OSA had a lower level of ApoA-I and a higher ApoB and ApoB/ApoA-I ratio. The fully adjusted odds ratios (95% confidence intervals) for both OSA [1 (reference), 1.406 (1.129-1.751), 1.556 (1.236-1.958), and 1.943 (1.508-2.505)] and insulin resistance [1 (reference), 1.424 (1.176-1.725), 1.948 (1.359-1.998), 2.019(1.658-2.459)] increased from the first to the fourth quartiles of the ApoB/ApoA-I ratio. Finally, the RCS mapped a nonlinear dose-effect relationship between the ApoB/ApoA-I ratio and risk of insulin resistance and OSA. OSA was also independently associated with insulin resistance. Mediation analyses showed insulin resistance explain 7.4%, 3.6% and 10.8% of the association between apnea-hypopnea index, oxygen desaturation index, micro-arousal index and ApoB/ApoA-I ratio, respectively. Conclusions: Our study revealed that ApoB/ApoA-I ratio was positively associated with an increased risk for insulin resistance and OSA severity. Insulin resistance may serve as a potential mediator in OSA-related lipoprotein disorders and further increase CVD risk. Funding Statement: This study was supported by grants-in-aid from National Key R&D Program of China (2017YFC0112500), National Natural Science Foundation of China (81770987), Shanghai Sailing Program (17YF1414300), multi-center clinical research project from school of medicine, Shanghai Jiao Tong University (DLY201502) and Shanghai Shen-Kang Hospital Management Center Project of Shanghai (SHDC12015101). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The ethics committee of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital approved this study according to Helsinki Declaration II. All the participants have given the informed consent before taking part in the study.

Cholesterol efflux responds to viral load and CD4 counts in HIV+ patients and is dampened in HIV exposed

Cholesterol efflux (CE) capacity has been inversely associated with atherosclerosis and may provide an insight on inflammation occurring in human immunodeficiency virus (HIV) individuals. We address this by studying CE in HIV patients at different stages of HIV disease progression. In this cross-sectional study, CE from ApoB-depleted plasma, lipids levels, viral load (VL), CD4+/CD8+ T-cells, high-sensitive C-reactive protein (hsCRP), and lipoprotein (a) were evaluated in untreated HIV-infected patients (UHIVs; n = 43), elite controllers (ECs; n = 8), HIV-exposed seronegative individuals (HESNs; n = 32), and healthy controls (HCs; n = 14). Among UHIVs, those with CD4+ <500 cells/mm3 presented the lowest significant CE, HDL cholesterol (HDL-C), and ApoAI levels. ECs showed similar HDL-C, ApoAI, and CE compared with HCs. Among UHIVs, CE positively correlated with CD4+ T-cell counts (Beta: 1.05; 95% CI: 1.02; 1.07), and for VL higher than 3.8 log, CE was inversely associated with VL (Beta: 0.70; 95% CI: 0.51; 0.95). Remarkably, HESNs presented higher CE (0.78 ± 0.14) than UHIVs (0.65 ± 0.17; P = 0.0005), but lower than HCs (0.90 ± 0.13; P = 0.009). hsCRP levels were highest in the UHIV group (0.45 ± 0.49). CE was sensitive to HIV disease progression. Low CE in HIV patients was associated with lower CD4+ T-cells and higher VL and hsCRP. CE was also lower in HESNs compared with HCs. Our results suggest that immune status secondary to HIV progression and exposure influence plasma HDL-CE capacity.

Impaired HDL (High-Density Lipoprotein)-Mediated Macrophage Cholesterol Efflux in Patients With Abdominal Aortic Aneurysm-Brief Report.

Objective- The ability of HDL (high-density lipoprotein) to promote macrophage cholesterol efflux is considered the main HDL cardioprotective function. Abdominal aortic aneurysm (AAA) is usually characterized by cholesterol accumulation and macrophage infiltration in the aortic wall. Here, we aim to evaluate the composition of circulating HDL particles and their potential for promoting macrophage cholesterol efflux in AAA subjects. Approach and Results- First, we randomly selected AAA and control subjects from Spain. The AAA patients in the Spanish cohort showed lower plasma apoA-I levels concomitantly associated with low levels of plasma HDL cholesterol and the amount of preβ-HDL particles. We determined macrophage cholesterol efflux to apoB-depleted plasma, which contains mature HDL, preβ-HDL particles and HDL regulatory proteins. ApoB-depleted plasma from AAA patients displayed an impaired ability to promote macrophage cholesterol efflux. Next, we replicated the experiments with AAA and control subjects derived from Danish cohort. Danish AAA patients also showed lower apoA-I levels and a defective HDL-mediated macrophage cholesterol efflux. Conclusions- AAA patients show impaired HDL-facilitated cholesterol removal from macrophages, which could be mechanistically linked to AAA.

Metabolic disorders and inflammation are associated with familial combined hyperlipemia

BackgroundFamilial Combined Hyperlipidemia (FCH) is related to different metabolic disorders. The objective of this study was to evaluate the presence of alterations of hydrocarbonated metabolism and lipid profile together with inflammatory and adhesion molecules in subjects with FCH compared to controls. Methods75 HFC patients and 75 healthy individuals were studied. Glucose, insulin, HOMA-IR index and lipid parameters, in addition to anti-oxidized LDL antibodies (Anti ox-LDL), small and dense LDL (sdLDL) and HDL subfractions, proinflammatory cytokines and adhesion molecules were measured. ResultsFCH patients showed higher levels of hydrocarbonated metabolism parameters, total cholesterol, triglycerides, LDLc, Apolipoprotein B and non-HDLc (p < .001), and lower levels of HDLc (p < .001) and Apolipoprotein AI (p < .05) than controls. In addition, the inflammatory markers hsCRP, IL-6, IL-8, P-selectin, E-selectin and ICAM were all higher with (p < .05) respect to controls. The increase of sdLDL was correlated with the presence of IR and IL-6 levels. Significant differences in diameter and percentage of phenotype B LDL, small HDL subfractions and Anti ox-LDL were also detected between patients and controls. ConclusionsThe lipid characteristics of FCH are confirmed by IR and a low grade inflammatory state in patients, and are associated with the predominance of sdLDL and Anti ox-LDL.