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Cardiovascular disease (CVD) is an evolving process that begins in the early stages of chronic kidney disease (CKD) in children. Several surrogate markers, such as ambulatory blood pressure monitoring (ABPM), left ventricular (LV) mass, and arterial stiffness assessment, allow for the early detection of subclinical CVD in pediatric CKD. Four groups of plasma samples (n = 3/group) from congenital anomalies of the kidney and urinary tract (CAKUT), as well as non-CAKUT patients with or without BP abnormalities, were studied to screen differentially expressed proteins using isobaric tags for relative and absolute protein quantification (iTRAQ)-based proteomics. As a result, 20 differentially expressed proteins associated with hypertension in children with CKD were discovered. Among them, apolipoprotein C-II (apoC-II) was found to have the highest abundance among the CKD patients with hypertension. As such, we hypothesized that apoC-II and apolipoprotein C-III (apoC-III) levels were related to BP abnormalities and CVD in children suffering from mild-to-moderate CKD. We examined their associations with surrogate markers of CV risk in 88 pediatric patients with CKD stages G1-G4. Children with CKD stages G2-G4 had a higher plasma apoC-II level than G1 patients (6.35 vs. 5.05 mg/dl, p < 0.05). We observed that ABPM abnormalities, LV mass, and arterial stiffness parameters were greater in CKD children who had stages G2-G4 than in those who had stage G1 (all p < 0.05). Plasma levels of apoC-II and apoC-III were positively correlated with total cholesterol, triglyceride, and low-density lipoprotein (LDL) (all p < 0.001). In multivariate linear regression analyses, apoC-II was correlated with a high LV mass index and an abnormal ABPM profile, and apoC-III was correlated with 24-h hypertension (r = 0.303, p = 0.003) and asleep hypertension (r = 0.379, p < 0.001). Early evaluations of apoC-II and apoC-III, ABPM, and surrogate markers of CV risk will aid in early preventative interventions to reduce the risk of CV in youths suffering from CKD.
Abstract Apolipoprotein C-III (apoC-III) is not only predominantly synthesized by the liver but also by the small intestine. Because apoC-III is secreted from the intestine on the chylomicron along with lipid absorption, we questioned whether apoC-III might play a role in intestinal lipid absorption and/or transport. Using both wild-type (WT) and apoC-III transgenic (apoC-III Tg) mice, we showed that apoC-III Tg mice have decreased lymphatic lipid transport compared with WT mice in response to an intraduodenal infusion of radiolabeled lipid. This is associated with accumulation of radiolabeled lipids in the luminal compartment of the apoC-III Tg mice, indicating delayed lipid uptake from the lumen. The total amount of radioactive lipids in the mucosal compartment did not differ between apoC-III Tg and WT mice, but the lipid distribution analysis indicated a predominance of free fatty acids and monoacylglycerol in the mucosa of apoC-III Tg mice, implying impaired esterification capacity. Thus, the mechanisms underlying the reduced lymphatic lipid transport in apoC-III Tg mice involve both a delayed lipid uptake into enterocytes, as well as impaired esterification to form triglyceride in the mucosa. These data document a novel role for apoC-III in the uptake, re-esterification, and lymphatic transport of dietary lipids in the intestine.
Apolipoproteins C-I, C-II, and C-III interact with ApoE to regulate lipoprotein metabolism and contribute to Alzheimer's disease pathophysiology. In plasma, apoC-I and C-II exist as truncated isoforms, while apoC-III exhibits multiple glycoforms. This study aimed to 1) delineate apoC-I, C-II, and C-III isoform profiles in cerebrospinal fluid (CSF) and plasma in a cohort of nondemented older individuals (n = 61), and 2) examine the effect of APOE4 on these isoforms and their correlation with CSF Aβ42, a surrogate of brain amyloid accumulation. The isoforms of the apoCs were immunoaffinity enriched and measured with MALDI-TOF mass spectrometry, revealing a significantly higher percentage of truncated apoC-I and apoC-II in CSF compared with matched plasma, with positive correlation between CSF and plasma. A greater percentage of monosialylated and disialylated apoC-III isoforms was detected in CSF, accompanied by a lower percentage of the two nonsialylated apoC-III isoforms, with significant linear correlations between CSF and plasma. Furthermore, a greater percentage of truncated apoC-I in CSF and apoC-II in plasma and CSF was observed in individuals carrying at least one APOE Ɛ4 allele. Increased apoC-I and apoC-II truncations were associated with lower CSF Aβ42. Finally, monosialylated apoC-III was lower, and disialylated apoC-III greater in the CSF of Ɛ4 carriers. Together, these results reveal distinct patterns of the apoCs isoforms in CSF, implying CSF-specific apoCs processing. These patterns were accentuated in APOE Ɛ4 allele carriers, suggesting an association between APOE4 genotype and Alzheimer's disease pathology with apoCs processing and function in the brain.
We examined the effects of a fibric acid, clinofibrate, on lipoprotein metabolism in 12 hyperlipidemic patients with uremia treated on continuous ambulatory peritoneal dialysis during a 24 week treatment. Daily dose of clinofibrate was 200 mg for the initial four weeks, 400 mg for the second four weeks, and 600 mg for the subsequent 16 weeks. Serum and very-low density lipoprotein (VLDL) triglyceride were decreased by 36% and 48%, respectively. Neither total cholesterol nor apolipoprotein B changed significantly, whereas cholesterol was decreased in VLDL and increased in low (LDL) and high density lipoprotein (HDL) fractions. Post-heparin plasma lipoprotein lipase (LPL) before treatment was not lower than the normal value, and we found no change in LPL activity following clinofibrate. Hepatic triglyceride lipase also did not change. Apolipoprotein (apo) C-II/C-III ratio was low as compared to the normal value before treatment, and the ratio was increased by 38% after the treatment. Decrease in VLDL triglyceride was associated with increase in apo C-II/C-III ratio in all the cases. Abnormal enrichment with triglyceride of LDL and HDL fractions was improved by clinofibrate. Although one patient had a transient and asymptomatic elevation of serum creatine phosphokinase, no patient had muscle pain. There was no accumulation of the drug in the 24 week trial. These results suggest that clinofibrate is an effective and safe approach to the management of dyslipidemia in CAPD patients.
Apolipoprotein C-III deficiency provides cardiovascular protection, but apolipoprotein C-III is not known to be associated with human amyloidosis. Here we report a form of amyloidosis characterized by renal insufficiency caused by a new apolipoprotein C-III variant, D25V. Despite their uremic state, the D25V-carriers exhibit low triglyceride (TG) and apolipoprotein C-III levels, and low very-low-density lipoprotein (VLDL)/high high-density lipoprotein (HDL) profile. Amyloid fibrils comprise the D25V-variant only, showing that wild-type apolipoprotein C-III does not contribute to amyloid deposition in vivo. The mutation profoundly impacts helical structure stability of D25V-variant, which is remarkably fibrillogenic under physiological conditions in vitro producing typical amyloid fibrils in its lipid-free form. D25V apolipoprotein C-III is a new human amyloidogenic protein and the first conferring cardioprotection even in the unfavourable context of renal failure, extending the evidence for an important cardiovascular protective role of apolipoprotein C-III deficiency. Thus, fibrate therapy, which reduces hepatic APOC3 transcription, may delay amyloid deposition in affected patients.
Hypertriglyceridemia (HTG) is defined as a triglyceride (TG) plasma level exceeding 150 mg/dl and is tightly associated with atherosclerosis, metabolic syndrome, obesity, diabetes and acute pancreatitis. The present study was undertaken to investigate the mitochondrial, sub-mitochondrial and cellular proteomic impact of hypertriglyceridemia in the hepatocytes of hypertriglyceridemic transgenic mice (overexpressing the human apolipoproteinC-III).
High-density lipoprotein (HDL) proteomic study has identified substantial changes associated with various disease states. In the current study, the HDL proteomes in patients with cerebral lacunar infarction (LACI) and control subjects were investigated. A total of 12 LACI patients without evident large vessel occlusions and 12 controls were enrolled in the study. The HDL fraction from each sample was isolated from the plasma by ultracentrifugation. The protemics of the HDL were investigated using nano liquid chromatography coupled to tandem mass spectrometry. There were 55 proteins identified as differentially expressed in the LACI and control groups. Among the 55 proteins, 33 were upregulated and 22 were downregulated in the patients with LACI. The identified proteins were associated with numerous molecular functions, including lipid and cholesterol transport, lipid metabolism, inflammatory response, the complement and coagulation pathway, metal ion metabolism, hemostasis and endopeptidase inhibitory activity. Serum amyloid A, apolipoprotein C (apoC-III) and apolipoprotein A-II (apoA-II) were selected to confirm the proteomics results via western blotting. HDL from the LACI patients exhibited an impaired ability to inhibit the binding of THP-1 cells to endothelial cells compared with the controls (P<0.01). ApoC-III-rich HDL also had a significantly reduced ability to inhibit the binding of THP-1 cells to endothelial cells (P<0.01). The expression of vascular cell adhesion molecule-1 protein by the endothelial cells exhibited a similar pattern of response to the different HDL samples. In conclusion, the present study demonstrates major modifications of the HDL proteome in patients with LACI. The ApoC-III enrichment of the HDL of patients with LACI may cause a reduction in the anti-inflammatory ability of HDL, which may contribute to the progression of the disease.
Apolipoprotein C-III (Apoc3) is a key component of triglyceride-rich lipoproteins (TRL). The Apoc3-transgenic mice are characterized by high levels of plasma triglyceride and free fatty acids (FFAs). Apoc3 stimulates human monocytes via activation of the NLRP3 inflammasome. Considering the NK cell downregulation in obese individuals and the possible stimulatory-effects of macrophages, variations of NK cell functions and underlying mechanisms were investigated in mice with Apoc3-induced hyperlipidemia.
The impetus for discovery and evaluation of protein biomarkers has been accelerated by recent development of advanced technologies for rapid and broad proteome analyses. Mass spectrometry (MS)-based protein assays hold great potential for in vitro biomarker studies. Described here is the development of a multiplex mass spectrometric immunoassay (MSIA) for quantification of apolipoprotein C-I (apoC-I), apolipoprotein C-II (apoC-II), apolipoprotein C-III (apoC-III) and their proteoforms. The multiplex MSIA assay was fast (∼ 40 min) and high-throughput (96 samples at a time). The assay was applied to a small cohort of human plasma samples, revealing the existence of multiple proteoforms for each apolipoprotein C. The quantitative aspect of the assay enabled determination of the concentration for each proteoform individually. Low-abundance proteoforms, such as fucosylated apoC-III, were detected in less than 20% of the samples. The distribution of apoC-III proteoforms varied among samples with similar total apoC-III concentrations. The multiplex analysis of the three apolipoproteins C and their proteoforms using quantitative MSIA represents a significant step forward toward better understanding of their physiological roles in health and disease.
Background Little is known about plasma apolipoprotein profiles in very preterm-born and term-born preschool children compared with the adult population. This is of particular interest because apolipoprotein composition might contribute to cardiometabolic outcome in later life. Methods and Results Children aged 5 to 7 years born at term or with <32 weeks of gestation were included. Apolipoprotein concentrations were measured in plasma collected after an overnight fast using multiple-reaction monitoring-based mass spectrometry. Twelve apolipoproteins were measured in 26 former term and 38 former very preterm infants. Key findings were confirmed by assessing apolipoprotein levels using antibody-based assays. Comparing children born term and preterm, apolipoprotein A-I, A- IV , C- II , and C- III were significantly higher in the latter group. Term-born children showed plasma levels of apolipoprotein C- II and C- III quantitatively similar to the adult range (Bruneck study). Hierarchical clustering analyses suggested that a higher proportion of apolipoprotein C- III and C- II reside on high-density lipoprotein particles in children than in adults given the marked correlations of apolipoprotein C- III and C- II with high-density lipoprotein cholesterol and apolipoprotein A-I in children but not adults. High-density lipoprotein cholesterol concentrations were similar in children and adults but the pattern of high-density lipoprotein cholesterol-associated apolipoproteins was different (lower apolipoprotein A-I and C-I but higher A- II , A- IV , and M). Conclusions Our study defines apolipoprotein profiles in preschoolers and reports potential effects of prematurity. Further large-scale studies are required to provide evidence whether this apolipoprotein signature of prematurity, including high apolipoprotein C- II and C- III levels, might translate into adverse cardiometabolic outcome in later life.
Inflammatory bowel disease (IBD) has been associated with an abnormal lipid profile. Apolipoprotein C-III (ApoC3) is a key molecule of triglyceride metabolism that is known to be related to inflammation and cardiovascular disease. In this study, we aim to study whether ApoC3 serum levels differ between patients with IBD and controls and whether the hypothetical disturbance of ApoC3 can be explained by IBD characteristics.
Apolipoprotein (apo) E plays a key role in lipoprotein metabolism and has been proposed to modulate triglyceride (TG) lipolysis. However, no systematic investigation on lipolysis using all 3 isoforms of apoE has been performed. To clarify the role of common human apoE isoforms in the lipolysis of very low-density lipoprotein (VLDL) TGs, we overexpressed human apoE isoforms in apoE and low-density lipoprotein receptor-deficient mice using adenoviral-mediated gene transfer and used VLDL particles obtained from these mice for in vitro lipolysis assay. Overexpression of apoE, regardless of its isoforms, increased the TG content of VLDL in mice in vivo. In vitro analysis of the effect of apoE on lipolysis revealed that irrespective of its isoforms, apoE did inhibit TG lipolysis at every concentration of apoE examined, and this inhibitory effect became more pronounced as the apoE content of VLDL increased. No difference was observed in TG lipolysis activity among isoforms at low apoE/TG ratio; however, intermediate ratios of apoE/TG, which reflect physiologic VLDL apoE/TG ratios, demonstrated a significantly greater level of lipolysis inhibition in apoE2, but less so in apoE4 compared with other isoforms. This differential effect by apoE isoforms on lipolysis was attenuated at higher apoE/TG ratios; nevertheless, apoE2 still inhibited lipolysis significantly more than did apoE4. Enrichment of VLDL with apoE decreased both the apoC contents and apoC-II/C-III ratios of VLDL, contributing, at least in part, to the inhibitory function of apoE on lipolysis. The present study clarifies the differential lipolysis-modulating effect of apoE isoforms, which would help explain the difference in pre- and postprandial TG levels among humans carrying different apoE isoforms.
Apolipoprotein C-III (apoC-III) is a critical regulator of triglyceride metabolism and correlates positively with hypertriglyceridemia and cardiovascular disease (CVD). It remains unclear if therapeutic apoC-III lowering reduces CVD risk and if the CVD correlation depends on the lipid-lowering or antiinflammatory properties. We determined the impact of interventional apoC-III lowering on atherogenesis using an apoC-III antisense oligonucleotide (ASO) in 2 hypertriglyceridemic mouse models where the intervention lowers plasma triglycerides and in a third lipid-refractory model. On a high-cholesterol Western diet apoC-III ASO treatment did not alter atherosclerotic lesion size but did attenuate advanced and unstable plaque development in the triglyceride-responsive mouse models. No lesion size or composition improvement was observed with apoC-III ASO in the lipid-refractory mice. To circumvent confounding effects of continuous high-cholesterol feeding, we tested the impact of interventional apoC-III lowering when switching to a cholesterol-poor diet after 12 weeks of Western diet. In this diet switch regimen, apoC-III ASO treatment significantly reduced plasma triglycerides, atherosclerotic lesion progression, and necrotic core area and increased fibrous cap thickness in lipid-responsive mice. Again, apoC-III ASO treatment did not alter triglyceride levels, lesion development, and lesion composition in lipid-refractory mice after the diet switch. Our findings suggest that interventional apoC-III lowering might be an effective strategy to reduce atherosclerosis lesion size and improve plaque stability when lipid lowering is achieved.
Protease inhibitors (PIs) are associated with hypertriglyceridemia and atherogenic dyslipidemia. Identifying HIV-1-infected individuals who are at increased risk of PI-related dyslipidemia will facilitate therapeutic choices that maintain viral suppression while reducing risk of atherosclerotic diseases. Apolipoprotein C-III (apoC-III) gene variants, which vary by race/ethnicity, have been associated with a lipid profile that resembles PI-induced dyslipidemia. However, the association of race/ethnicity, or candidate gene effects across race/ethnicity, with plasma lipid levels in HIV-1-infected individuals, has not been reported.
Although emerging evidence has suggested that apolipoprotein C-III (APOC-III) is involved in the pathogenesis of Alzheimer's disease (AD), the association of APOC-III with longitudinal changes in cerebrospinal fluid (CSF) AD pathologies (β-amyloid (Aβ42) and tau proteins) is not clear. In the present study, we aimed to examine whether plasma APOC-III levels are associated with longitudinal changes in CSF Aβ42, total-tau (t-tau), and phosphorylated-tau (p-tau) levels among older individuals without dementia.
The functionality of high-density lipoproteins (HDL) is a better cardiovascular risk predictor than HDL concentrations. One of the key elements of HDL functionality is its apolipoprotein composition. Lecithin-cholesterol acyl transferase (LCAT) and cholesterol-ester transfer protein (CETP) are enzymes involved in HDL-mediated reverse cholesterol transport. This study assessed the concentration and activity of LCAT and CETP in HDL subspecies defined by their content of apolipoproteins E (apoE) and C-III (apoC-III) in humans.
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