apoA-I Levels Research Articles

Abstract 24: Abca1 Agonist Cs6253 Reverses Apoe4-Driven Alzheimer’s Disease With Concomitant Changes in Plasma and Brain Apoe And Apoj

Background: Apolipoprotein E4 (apoE4) is associated with perturbed lipid metabolism and elevated risk for CVD and Alzheimer’s disease (AD). Data suggests impact of both non-brain and brain apoE on risk to develop AD. Homozygosity for apoE4 increases AD risk approximately 10-fold. Brain apoE4particles are smaller and less lipidated than brain apoE2 or apoE3. ApoE is lipidated by ATP Binding Cassette A1 (ABCA1) and both proteins are synthesized predominantly in astrocytes. We hypothesized that enhancing apoE4 lipidation by an ABCA1 agonist, CS6253, would have AD therapeutic actions. Methods and Results: Astrocyte cholesterol efflux is highly responsive to stimulation by exogenous CS6253 peptide. Time-course showed that basal [3H]cholesterol efflux from cells to serum-free medium was compromised in apoE4 astrocytes. Incubating with peptide CS6253 (10 μg/mL) showed 6-fold improvement in [3H] cholesterol efflux to serum-free medium containing either apoE4 or E3 astrocytes. CS6253 crossed the BBB and was found to co-localize with astrocytes in hippocampus. CS6253 i.p. injection (20 mg/kg/48h for 6 weeks) in apoE4 Targeted Replacement mice significantly lowered apoJ in plasma and the brain. The distribution of serum apoE4 on HPLC to smaller lipoproteins was seen rendering similar profile to apoE3. Plasma apoA-I levels, cholesterol and triglyceride levels were unchanged. Lipidation of apoE in brain was compromised in apoE4 compared to apoE3 mice and CS6253 treatment increased apoE4 lipidation. CS6253 treatment prevented cognition decline and development of the brain AD pathological phenotype. CS6253 treatment decreased Aβ42 and P-tau and increased levels of VGluT1 and apoER2. Cognitive decline was fully prevented in apoE4 mice by CS6253 treatment as assessed by novel object recognition and Morris water maze. Conclusion: ABCA1 agonist treatment by CS653 resulted in improved apoE4 lipidation in cells and in mice. Six weeks treatment counteracted apoE4 driven AD with regard to phenotype and cognition. The data point to the potential therapeutic utility of CS6253 in apoE4 AD.

Low apoA-I is associated with insulin resistance in patients with impaired glucose tolerance: a cross-sectional study

BackgroundLow apolipoprotein A-I (apoA-I) is an independent risk factor for atherosclerotic cardiovascular diseases. Insulin resistance predicts the progression of abnormal glucose metabolism, which is the main cause of atherosclerotic cardiovascular disease. In this study, we assessed the potential association between apoA-I levels and insulin resistance in patients with impaired glucose tolerance (IGT) and the possible link between apoA-I and IGT.MethodsThis study evaluated a cross-sectional study of 108 participants with impaired glucose tolerance (IGT group) and 84 controls (control group). ApoA-I and clinical characteristics were measured, and a homeostasis model assessment of insulin resistance (HOMA-IR) was calculated.ResultsThe IGT group exhibited significantly lower apoA-I and higher HOMA-IR levels than the control group (apoA-I: 1.37 ± 0.36 vs 1.57 ± 0.39 g/L; HOMA-IR: 4.21 ± 1.56 vs 2.15 ± 0.99; P < 0.001 for both). ApoA-I was negatively correlated with HOMA-IR in both the IGT and control groups (IGT group: r = −0.269, P = 0.005; control group: r = −0.262, P = 0.016). Multiple stepwise regression analysis showed that low apoA-I levels (β = −1.470, P = 0.002) were independently correlated with high HOMA-IR levels in the IGT group. Moreover, logistic regression analysis identified that low apoA-I was an independent influencing factor for IGT (β = −1.170, OR = 0.310, P = 0.007).ConclusionsApoA-I is inversely associated with insulin resistance in patients with impaired glucose tolerance, and low apoA-I is an independent risk factor for impaired glucose tolerance. These results indicate that apoA-I plays an important role in regulating insulin sensitivity and glucose metabolism in patients with IGT.

The HDL cholesterol/apolipoprotein A-I ratio: an indicator of cardiovascular disease.

In multiple studies, the HDL cholesterol (HDL-C) concentration has been shown to be inversely associated with cardiovascular disease (CVD) and CVD risk. Based on this observation, increasing the plasma HDL-C concentration is thought to be a desirable strategy, in the 21st century, for decreasing the burden of CVD. Recent studies have shown that powerful HDL-C concentration-increasing drugs are ineffective for decreasing CVD. Increasing evidence now shows that HDL is an unstable and heterogeneous particle, and that 'HDL particle functionality' is far more important in atheroprotection than is the HDL-C level, alone. Apolipoprotein A-I (apoA-I) is the major protein component of HDL, and increasing evidence suggests that the ratio of HDL-C to apoA-I may give additional insight as a risk marker not just for CVD but also for all-cause and cancer mortality. In this review, we discuss the importance of HDL composition, apoA-I levels, and the HDL-C/apoA-I ratio for predicting CVD and mortality outcomes.

Molecular effect of fenofibrate on PBMC gene transcription related to lipid metabolism in patients with metabolic syndrome.

Both fasting and postprandial hypertriglyceridaemia are considered independent risk factors for atherosclerosis. Treatment of hypertriglyceridaemia is based on fibrates, which activate the peroxisome proliferator-activated receptor alpha (PPARα). However, the metabolic pathways that activate or inhibit fibrates, and how the postprandial triglyceride levels are modified, have not yet been fully described. Accordingly, the aim of this study was to determine the feasibility of peripheral blood mononuclear cells (PBMC) to study the effects of fenofibrate in patients with the metabolic syndrome. A fat overload was given to 50 patients before and after treatment with fenofibrate for 3 months. Anthropometric and biochemical variables as well as gene expression in PBMC were analysed. After treatment with fenofibrate, we observed a decrease in both baseline and postprandial (3 h after the fat overload) levels of serum triglycerides, cholesterol and uric acid and an increase in HDL cholesterol and apolipoprotein AI levels. After treatment, there was also a rise in PPARα and RXRα expression and changes in genes regulated by PPARα, both baseline and postprandial. Furthermore, in vitro experiments showed that a PPARα agonist changed the expression of genes related with lipid metabolism. Treatment with fenofibrate reduced fasting and postprandial serum triglyceride levels, possibly through a mechanism related with an increase in the expression of RXRα and PPARα, by activating the pathways involved in the uptake and degradation of triglycerides and increasing the synthesis of apolipoprotein. These results suggest that PBMC may be useful for the easy study of fenofibrate actions.

Abstract P120: Relationship of Lipoproteins With Cardiovascular Disease in Persons With Chronic Kidney Disease

Introduction: Chronic kidney disease (CKD) is associated with dyslipidemia (particularly elevated triglycerides [TG] and reduced HDL-cholesterol [HDL-C]) and increased risk of atherosclerotic cardiovascular disease (CVD). However, the association between lipoprotein measures and CVD events in CKD is not well defined. Hypothesis: We hypothesize that high TG and low HDL-C are associated with increased risk for CVD (myocardial infarction [MI] and ischemic stroke) in CKD. Methods: The Chronic Renal Insufficiency Cohort (CRIC) is a prospective study of adults with CKD. We compared tertiles of TG, total cholesterol (TC), VLDL-cholesterol (VLDL-C), LDL-cholesterol (LDL-C), HDL-C, apolipoprotein B (apoB), and apolipoprotein A-I (apoA-I) with risk for MI and ischemic stroke using Fine and Gray methods with death as a competing risk. The lowest tertile was used as the reference category except for HDL-C and apoA-I, in which the highest tertile was used. In secondary analyses, we excluded participants with previous MI or stroke. Results: Among 3811 participants (55% men, 42% Caucasian) with mean age 57.7±11.0 years, 351 had an MI, 132 had an ischemic stroke, and 963 died over a median follow-up of 7.9 years. After adjusting for potential confounders, the hazard ratio (HR, 95% CI) for CVD was 1.04 (0.80-1.34) for high LDL-C, 1.31 (1.01-1.69) for high TG, 1.33 (1.04-1.70) for high VLDL-C, 1.30 (1.01-1.68) for high apoB, 1.65 (1.25-2.17) for low HDL-C, and 1.31 (1.01-1.70) for low apoA-I. In secondary analyses of 2751 participants with no CVD history, high TG (HR 1.46, 1.02-2.10), high VLDL-C (HR 1.56, 1.08-2.25), low HDL-C (HR 2.11, 1.40-3.16) and low apoA-I (HR 2.28, 1.54-3.37) were significantly associated with incident CVD. Conclusions: While high LDL-C is associated with increased CVD risk in the general population, we found no such association in CKD. Instead, high TG, high VLDL-C, low HDL-C and low apoA-I levels show strong associations with increased CVD risk and incident CVD events in CKD.

Apolipoproten B, LDL Cholesterol and apoB/apoA-I Ratio in Patients With Stable Angina

Aim: To acknowledge the nature of correlation between apolipoprotein B concentrations and LDL cholesterol levels in patients with stable angina pectoris and also to show that the ratio of apoB/apoA-I may be a promising predictor for the risk of cardiovascular disease.Methods: This is an observational study with cross-sectional approach of 34 patients with stable angina pectoris. Prior to the study, patients were advised to fast for 10-12 hours and must complete the informed consent. Patients underwent physical examination and anthropometric measurements (height, body weight, waist circumference), blood test, and ECG check.Results: From 34 patients, the prevalence of high levels of total cholesterol (&gt;200 mg/dl) in men and women are 45.5% and 47.8%, respectively; and 90.9% men and 87% women with increased LDL-C (?100 mg/dl). Low value of apoA-I was determined in 5 men (45.5%) and 4 women (17.4%); and high value of apoB was found in 7 men (63.6%) and 11 women (47.8%), whereas 13 subjects with unfavorable apoB/apoA-I ratio. Six subjects had low levels of apoA-I along with high levels of apoB. ApoB/apoA-I ratio above 0.9 was found in 6 or 11 men (54.5%) and 7 of 23 women (30.4%).Conclusion: We found that in 34 patients with stable angina, 18 of them (52.9%) showed high plasma apoB concentration. This is parallel to 30 subjects (88.2%) with high LDL cholesterol levels, and also 13 subjects (38.2%) with high apoB/apoA-I ratio. It can be concluded the higher the ratio of apoB to apoA-I, the greater the risk of cardiovascular disease. Lifestyle management and pharmacological intervention in dyslipidemia is important in reduction of cardiovascular events.

High-Carbohydrate/Low-Fat Diet-Induced Gender-Specific Serum Lipid Profile Changes Are Associated with LEPR Polymorphisms in Chinese Youth

Background/Aims: The study aimed to investigate the interactions of genetic variants in the leptin receptor (LEPR) gene with lipid profile changes following a high-carbohydrate/low-fat (HC/LF) diet in a Chinese Han population. Methods: Fifty-six healthy young subjects were given washout diets, followed by HC/LF diets consisting of 15% fat and 70% carbohydrate for 6 days. Serum lipid profiles and insulin levels before and after HC/LF diets were analyzed. Results: Statistically elevated high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-1 (apoA-I), and insulin levels were only observed in the GG genotype of LEPR Lys109Arg but not in the A carriers after HC/LF diet. When gender was taken into account, significantly increased HDL-C, apoA-I, and insulin levels were found in women with the GG genotype. Moreover, lower low-density lipoprotein cholesterol (LDL-C) and higher insulin levels were only observed in subjects with the GG genotype of LEPR Gln223Arg, while higher HDL-C and apoA-I were only found in the A allele carriers. Additionally, the lower LDL-C and body mass index (BMI), and higher HDL-C and insulin levels were only observed in subjects with the GG genotype of LEPR Lys656Asn. Conclusions:LEPR polymorphisms contribute to the heterogeneities in BMI, LDL-C, and HDL-C responsiveness that are induced by a HC/LF diet in healthy young Chinese adults.

Effects of blood lipid stability on progression of carotid atherosclerosis.

Objective:To evaluate the effects of blood lipid stability on progression of carotid atherosclerosis.Methods:A total of 416 patients who had physical examination in our hospital annually from January 2010 to December 2015 were selected and divided into a progression group (n=216) and a non-progression group (n=200) according to the intima-media thickness measured by carotid ultrasound. The levels of lipid-related parameters within five years were retrospectively analyzed to calculate the smoothness index (SI = x±/s).Results:The cross-sectional TG, HDL-C, ApoAI, ApoB, ApoE and Lpa levels were similar in the two groups (p>0.05). The non-progression group had significantly higher TC ((4.15±0.82 vs. 4.50±1.04) mmol/L) and LDL-C ((2.53±0.76 vs. 2.99±1.03) mmol/L) levels than those of the progression group (p<0.05). The progression group had significantly lower TC SI (5.29±1.28 vs. 5.65±1.76), TG SI (2.13±0.71 vs. 2.79±0.82), LDL-C SI (3.66±1.17 vs. 4.36±1.58), ApoB SI (3.37±0.88 vs. 3.62±0.95) and Lpa SI (1.53±0.49 vs. 1.62±0.43) than those of the non-progression group (p<0.05).Conclusion:Compared with cross-sectional results, SI was better correlated with the progression of atherosclerosis. The progression group had lower SI values.

Differential Effects of apoE4 and Activation of ABCA1 on Brain and Plasma Lipoproteins.

Apolipoprotein E4 (apoE4), the leading genetic risk factor for Alzheimer's disease (AD), is less lipidated compared to the most common and AD-benign allele, apoE3. We have recently shown that i.p. injections of the ATP-binding cassette A1 (ABCA1) agonist peptide CS-6253 to apoE mice reverse the hypolipidation of apoE4 and the associated brain pathology and behavioral deficits. While in the brain apoE is the main cholesterol transporter, in the periphery apoE and apoA-I both serve as the major cholesterol transporters. We presently investigated the extent to which apoE genotype and CS-6253 treatment to apoE3 and apoE4-targeted replacement mice affects the plasma levels and lipid particle distribution of apoE, and those of plasma and brain apoA-I and apoJ. This revealed that plasma levels of apoE4 were lower and eluted faster following FPLC than plasma apoE3. Treatment with CS-6253 increased the levels of plasma apoE4 and rendered the elution profile of apoE4 similar to that of apoE3. Similarly, the levels of plasma apoA-I were lower in the apoE4 mice compared to apoE3 mice, and this effect was partially reversed by CS-6253. Conversely, the levels of apoA-I in the brain which were higher in the apoE4 mice, were unaffected by CS-6253. The plasma levels of apoJ were higher in apoE4 mice than apoE3 mice and this effect was abolished by CS-6253. Similar but less pronounced effects were obtained in the brain. In conclusion, these results suggest that apoE4 affects the levels of apoA-I and apoJ and that the anti-apoE4 beneficial effects of CS-6253 may be related to both central and peripheral mechanisms.

Circulating Apolipoprotein A-IV presurgical levels are associated with improvement in insulin sensitivity after Roux-en-Y gastric bypass surgery

BackgroundApolipoprotein A-IV (ApoA-IV) has been shown to be involved in obesity and diabetes pathogenesis in animal studies, but its role in humans is uncertain. ObjectivesThe objective of this study was to determine the relation of ApoA-IV with changes in glucose metabolism and weight after bariatric surgery. SettingUniversity Hospital. MethodsThe patients (n = 49) included lean controls (n = 8) and patients before and after a mean of 7 months after laparoscopic adjustable gastric banding (LAGB, n = 12), laparoscopic Roux-en-Y gastric bypass (RYGB, n = 22), or laparoscopic sleeve gastrectomy (SG, n = 11). ApoA-IV and other hormone assays were performed in the fasting and the postprandial state. Pearson’s correlation analyses controlled for baseline BMI and percent excess weight loss (EWL) were used to determine relationships between ApoA-IV levels and insulin resistance (HOMA-IR). ResultsWith all bariatric procedures combined, the change in ApoA-IV [533 versus 518 microg/L, P = .813] or ApoA-IV area under the curve (AUC - 1072 versus 1042, P = .939) was not significant. None of the surgeries individually affected levels of fasting or ApoA-IV AUC. Bariatric surgery resulted in a decrease in HOMA-IR (5.3 versus 2.0, P<.001). In the RYGB group, higher baseline ApoA-IV levels correlated with decrease in HOMA-IR [r = -.6, P = .008]. This relationship was independent of EWL and was not observed in the LAGB or SG group. There was no association of ApoA-IV levels with EWL, insulin secretion, Peptide-YY, or leptin levels. ConclusionPreoperative ApoA-IV levels, rather than changes in levels, positively correlate with improvements in insulin sensitivity independent of weight loss after RYGB.

Effect of microsomal triglyceride transfer protein gene variants (-493G > T, Q95H and H297Q) on plasma lipid levels in healthy middle-aged UK men.

Microsomal triglyceride transfer protein (MTP) plays a central role in the synthesis of lipoproteins by shuttling lipids between phospholipid membranes to apoB. We have examined the effect of three MTP gene variants, -493G > T, Q95H and H297Q, in 2831 healthy UK middle-aged men. The rare allele frequencies were: 0.25 (95% CI 0.24-0.26) for -493T, 0.054 (95% CI 0.05-0.06) for 95H and 0.32 (95% CI 0.31-0.33) for 297Q. The three variants were in strong allelic association in all pairwise combinations (p < 0.001). None of the variant sites were associated with significant differences in cholesterol, triglyceride, apoB or apoAI levels. When stratified by tertiles of triglycerides for the H297Q variant alone there was a significant effect on apoB levels in men in the top tertile (p = 0.01). Considering the -493G > T and H297Q genotype in combination on baseline levels, individuals with three or four rare alleles had 6.6% higher mean apoB levels compared to the rest (p = 0.007). Therefore, homozygosity for 297Q at higher triglyceride (Tg) levels, or in combination with -493G > T, is associated with a raising effect on apoB levels, suggesting the importance of modest differences in MTP activity in determining hepatic secretion of lipoproteins in healthy men.

Syphilitic dementia and lipid metabolism.

Chronic syphilitic infection may lead to dementia. It is in general paresis (GP), which is the major late form of neurosyphilis, that cognitive impairment frequently occurs. The association between lipid metabolism and GP is unclear. In this study, serum lipids were studied in 188 GP patients, in 241 syphilitic patients without neurosyphilis and in 539 healthy controls. The Mini-Mental State Examination (MMSE) was tested in all GP patients. Thirty-five GP patients had a follow-up evaluation 3 months after penicillin treatment. Significantly lower apolipoprotein A-I (apoA-I) levels were found in GP and in syphilitic patients without neurosyphilis compared to controls. In the 25-44-year-old groups, the male syphilitic patients without neurosyphilis had lower serum apoA-I levels and higher apolipoprotein B (apoB)/apoA-I ratios compared with female patients. A follow-up evaluation of 35 GP patients 3 months after penicillin treatment showed a significant positive correlation between increased apoA-I levels and MMSE scores. Abnormal apoA-I metabolism may be associated with the decline of cognitive performance. Long-term decrease of apoA-I level and higher apoB/apoA-I ratio may be contributing factors in syphilitic dementia. These results suggest a similar overlap between syphilitic dementia and lipid metabolism to that occurring in Alzheimer's disease.

Effects of Carvedilol Compared to Nebivolol on Insulin Resistance and Lipid Profile in Patients With Essential Hypertension.

Beta-blockers have unfavorable effects on metabolic parameters in hypertensive treatment. New generation beta-blockers with vasodilatory capabilities are superior to traditional beta-blockers, but studies examining their effects on metabolic parameters are still lacking. This study aimed to compare the effects of 2 new generation beta-blockers, carvedilol and nebivolol, on insulin resistance (IR) and lipid profiles in patients with essential hypertension. This was a prospective, randomized, open-label, single-center clinical trial. A total of 80 patients were randomized into 2 groups: the carvedilol group (n = 40, 25 mg of carvedilol daily) and the nebivolol group (n = 40, 5 mg of nebivolol daily). Follow-up was performed for 4 months. Fasting plasma glucose, insulin levels, and the lipid profile (high-density lipoprotein [HDL], low-density lipoprotein [LDL], total cholesterol, triglyceride, apolipoprotein AI, and apolipoprotein B levels) were measured and IR was calculated by the homeostasis model assessment (HOMA) index. These variables were compared before and 4 months after treatment. Blood pressure and heart rate were significantly and similarly reduced in the carvedilol and nebivolol groups after treatment compared to those before treatment (both P < .001). Serum glucose ( P < .001), insulin ( P < .01), HOMA-IR (P < .01), HDL ( P < .001), LDL ( P < .001), total cholesterol ( P < .001), and apolipoprotein B ( P < .05) levels decreased in a similar manner in the carvedilol and nebivolol groups after treatment compared to those before treatment. Serum triglyceride and apolipoprotein AI levels did not change after treatment with both drugs. New generation beta-blockers, carvedilol and nebivolol, efficiently and similarly decrease blood pressure. They have similar favorable effects on glucose, insulin, IR, and the lipid profile.

Ratios of leptin to insulin and adiponectin to endothelin are sex-dependently associated with extent of coronary atherosclerosis

Objective: Noninvasive diagnostics of early stages of coronary artery disease and discrimination between various extents of vascular lesions in patients is an important clinical problem especially considering wide spread use of cholesterol lowering drugs that affect lipid and lipoprotein profiling. The main goal of our study was to evaluate applicability of new combinations of noninvasive biomarkers such as leptin to insulin and adiponectin to endothelin ratios, for detection of early stages of coronary atherosclerosis versus later stages of the disease.Patients and methods: A number of previously validated serum biomarkers were tested in a group of 500 patients with coronary artery disease and examined for their association with severity of coronary lesion according to Gensini score determined by coronary angiography.Results: Lowest extent of coronary lesions was associated with significant increase in apoA-I levels and with significantly increased ratios of adiponectin to endothelin and leptin to insulin. In male but not in female patients, adiponectin to endothelin ratio below 7.0 was associated with Gensini score representing early to high coronary lesions (p = 0.02). In female but not in male patients, leptin to insulin ratio below 3.5 was associated with Gensini score representing early to high coronary lesions (p = 0.013).Conclusion: Leptin to insulin and adiponectin to endothelin ratios are novel derived biomarkers useful for noninvasive diagnostics of initial stages of coronary lesions in patients with coronary artery disease.

Evaluation of Serum Apo B and A-I as Cardiac Biomarkers in Young Adult Population

Clinically normal young adults with no well-known risk factors may present with metabolic syndrome, hypertension, atherogenic dyslipidemia and type-II diabetes. Age and sex are two non-modifiable risk factors for developing cardiovascular disturbances which may affect the levels of apolipoprotein B and apolipoprotein A-I. The objective is to study serum apo B and A-I levels in association with the conventional lipid profile parameters in atherogenic dyslipidemia. In this hospital-based prospective study, clinically normal males (n=172) and females (n=188), aged between 20-39 years, divided into two age groups: group-I (20-29 years) and group-II (30-39 years), subjected to overnight fasting had their lipid profile parameters (enzymatic colorimetric assay) along with the serum levels of apoB and apoA-I (immunoturbidimetry method) estimated. Subjects with body mass index (BMI) >30 were excluded from the study. Data was statistically analysed using Chi-square test and ROC curves. ApoB levels showed continuous increase with age in both sexes with males having significantly raised (p<0.01) levels in both groups compared to females. ApoA-I levels declined with increasing age in both sexes and this decline was relatively earlier in males. Within each group females were having relatively raised (p<0.05) apoA-I levels than males. Moderate to strong correlations were observed between serum apoA-I and HDL-C concentrations (p<0.0001) and between serum apoB and LDL-C concentrations (p<0.0001), respectively. ApoB may be a more sensitive measure of atherogenic dyslipidemia than LDL-C and a better index for assessing cardiovascular risk, whereas apoA-I did not add significantly to the estimation of future atherosclerotic vascular risk.

The A’s Have It: Developing Apolipoprotein A-I Mimetic Peptides Into a Novel Treatment for Asthma

New treatments are needed for patients with asthma who are refractory to standard therapies, such as individuals with a phenotype of "type 2-low" inflammation. This important clinical problem could potentially be addressed by the development of apolipoprotein A-I (apoA-I) mimetic peptides. ApoA-I interacts with its cellular receptor, the ATP-binding cassette subfamily A, member 1 (ABCA1), to facilitate cholesterol efflux out of cells to form nascent high-density lipoprotein particles. The ability of the apoA-I/ABCA1 pathway to promote cholesterol efflux from cells that mediate adaptive immunity, such as antigen-presenting cells, can attenuate their function. Data from experimental murine models have shown that the apoA-I/ABCA1 pathway can reduce neutrophilic airway inflammation, primarily by suppressing the production of granulocyte-colony stimulating factor. Furthermore, administration of apoA-I mimetic peptides to experimental murine models of allergic asthma has decreased both neutrophilic and eosinophilic airway inflammation, as well as airway hyperresponsiveness and mucous cell metaplasia. Higher serum levels of apoA-I have also been associated with less severe airflow obstruction in patients with asthma. Collectively, these results suggest that the apoA-I/ABCA1 pathway may have a protective effect in asthma, and support the concept of advancing inhaled apoA-I mimetic peptides to clinical trials that can assess their safety and effectiveness. Thus, we propose that the development of inhaled apoA-I mimetic peptides as a new treatment could represent a clinical advance for patients with severe asthma who are unresponsive to other therapies.

Predictive value of chemotherapy-related high-density lipoprotein cholesterol (HDL) elevation in patients with colorectal cancer receiving adjuvant chemotherapy: an exploratory analysis of 851 cases

BackgroundThe phenomenon of chemotherapy-related lipid alterations has been reported based on a small number of patients and varies among different cancers. However, little is known about these alterations in colorectal cancer (CRC) patients.ResultsPatients in cohort 1, but not in cohort 2, exhibited significantly increased cholesterol, triglyceride, HDL-C, and ApoA-I levels, and decreased LDL-C and ApoB levels after adjuvant chemotherapy. Patients with chemotherapy-related HDL-C elevation exhibited better 3-year DFS (84.5% vs. 73%, P = 0.001) and 7-year OS (82% vs. 70%, P = 0.002) than those without. Similarly, the 3-year DFS (83.3% vs. 77.6%, P = 0.008) and 7-year OS (81% vs. 74.6%, P = 0.040) were superior in chemotherapy-related ApoA-I elevation patients. However, only HDL-C elevation remained an independent prognostic value in the multivariate Cox model.MethodsEight hundred fifty-one CRC patients with curative-intent resection were retrospectively analyzed. Six hundred sixty-seven receiving fluoropyrimidine-based adjuvant chemotherapy for more than 3 months were enrolled in cohort 1. The lipid alterations before and after chemotherapy were studied. Simultaneously, 184 patients not treated with chemotherapy (cohort 2) were included as a control for the comparisons of lipids alterations within 1 month after resection and at half-year follow-up. Furthermore, these significant alterations were investigated with respect to the prognostic value of disease-free survival (DFS) and overall survival (OS). An internal validation was performed.ConclusionWe observed significant changes in the levels of various lipids in CRC patients receiving adjuvant chemotherapy. Furthermore, chemotherapy-related HDL-C elevation was determined to be an independent prognostic indicator for superior DFS and OS.

Impaired HDL cholesterol efflux in metabolic syndrome is unrelated to glucose tolerance status: the CODAM study

Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) increase atherosclerotic cardiovascular disease risk. Cholesterol efflux capacity (CEC) is a key metric of the anti-atherosclerotic functionality of high-density lipoproteins (HDL). The present study aimed to delineate if T2DM and MetS cross-sectionally associate with altered CEC in a large high cardiometabolic risk population. CEC was determined from THP-1 macrophage foam cells towards apolipoprotein B-depleted plasma from 552 subjects of the CODAM cohort (288 controls, 126 impaired glucose metabolism [IGM], 138 T2DM). MetS was present in 297 participants. CEC was not different between different glucose tolerance categories but was lower in MetS (P < 0.001), at least partly attributable to lower HDL cholesterol (HDL-C) and apoA-I levels (P < 0.001 for each). Low grade inflammation was increased in IGM, T2DM and MetS as determined by a score comprising 8 different biomarkers (P < 0.05-< 0.001; n = 547). CEC inversely associated with low-grade inflammation taking account of HDL-C or apoA-I in MetS (P < 0.02), but not in subjects without MetS (interaction: P = 0.015). This study demonstrates that IGM and T2DM do not impact the HDL CEC function, while efflux is lower in MetS, partly dependent on plasma HDL-C levels. Enhanced low-grade inflammation in MetS may conceivably impair CEC even independent of HDL-C and apoA-I.

ApoL1 levels in high density lipoprotein and cardiovascular event presentation in patients with familial hypercholesterolemia

HDL composition rather than HDL-cholesterol (HDL-C) levels seems to be a key determinant of HDL-induced atheroprotection. Heterozygous familial hypercholesterolemia (FH) patients, with lifelong exposure to high LDL levels, show a high prevalence of premature coronary artery disease. We hypothesized that HDL of FH patients might have a modified protein composition and investigated the proteomic signature of HDL obtained from FH patients and their unaffected relatives. HDLs were characterized by 2D electrophoresis/MS in 10 families from the SAFEHEART cohort (3 individuals/family: 2 with genetic FH diagnosis and 1 non-FH relative) clinically characterized and treated as per guidelines. FH patients had lower apoA-I levels and a differential HDL distribution profile of apoL1 and apoA-IV. ELISA validation revealed decreased apoL1 serum levels in FH patients. ApoL1 levels were able to predict presentation of an ischemic cardiac event, and apoL1/HDL-C ratio was associated with the survival rate after the event. FH patients who died because of a fatal cardiac event had lower apoL1 and LCAT content in HDL3 an average of 3.5 years before the event than those who survived. Changes in HDL protein composition could affect patients' prognosis. The proteomic profile of apoL1 is modified in HDLs of high cardiovascular risk patients, and apoL1 plasma levels are significantly lower in serum and in HDL3 of patients that will suffer an adverse cardiac event within 3 years.

HDL mimetic CER-001 targets atherosclerotic plaques in patients

Background and aimsInfusion of high-density lipoprotein (HDL) mimetics aimed at reducing atherosclerotic burden has led to equivocal results, which may relate in part to the inability of HDL mimetics to adequately reach atherosclerotic lesions in humans. This study evaluated delivery of recombinant human apolipoprotein A-I (apoA-I) containing HDL mimetic CER-001 in carotid plaques in patients. MethodsCER-001 was radiolabeled with the long-lived positron emitter zirconium-89 (89Zr) to enable positron emission tomography with computed tomography (PET/CT) imaging. Eight patients with atherosclerotic carotid artery disease (>50% stenosis) received a single infusion of unlabeled CER-001 (3 mg/kg), co-administered with 10 mg of 89Zr-labeled CER-001 (18 MBq). Serial PET/CT imaging and contrast enhanced-magnetic resonance imaging (CE-MRI) were performed to evaluate targeted delivery of CER-001. ResultsOne hour after infusion, mean plasma apoA-I levels increased by 9.9 mg/dL (p = 0.026), with a concomitant relative increase in the plasma cholesterol efflux capacity of 13.8% (p < 0.001). Using serial PET/CT imaging, we showed that arterial uptake of CER-001 expressed as target-to-background ratio (TBRmax) increased significantly 24 h after infusion, and remained increased up to 48 h (TBRmax t = 10 min: 0.98; t = 24 h: 1.14 (p = 0.001); t = 48 h: 1.12 (p = 0.007)). TBRmax was higher in plaque compared with non-plaque segments (1.18 vs. 1.05; p < 0.001). Plaque TBRmax correlated with local plaque contrast enhancement (r = 0.56; p = 0.019) as assessed by CE-MRI. ConclusionsInfusion of HDL mimetic CER-001 increases plasma apoA-I concentration and plasma cholesterol efflux capacity. Our data support the concept that CER-001 targets plaque regions in patients, which correlates with plaque contrast enhancement. These clinical findings may also guide future nanomedicine development using HDL particles for drug delivery in atherosclerosis. Clinical trial registrationNetherlands Trial Registry – NTR5178.http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=5178.