High-density lipoproteins (HDL) are considered atheroprotective in contrast to low-density lipoproteins (LDL), which are atherogenic in their oxidized form. A growing body of evidence suggests that HDL exert part of their antiatherogenic effect by counteracting LDL oxidation as well as their proinflammatory effect. However, a number of studies, carried over the past 30 years, have shown that cholesterol efflux plays a major role in the atheroprotective effects of HDL and cholesterol homeostasis. These studies have further identified the scavenger receptor type B-I (SR-BI), the adenosine triphosphate (ATP)-binding cassette transporters ATP-binding cassette subfamily A1 (ABCA1), ATP-binding cassette subfamily G1 (ABCG1) and ABCG4, the liver X receptor/retinoid X receptor (LXR/RXR) and peroxisome proliferator-activated receptorgamma(PPAR gamma) transcription factors, the HDL components apolipoprotein A-I (apoA-I), lecithin-cholesterol acyltransferase (LCAT), and phospholipids as additional mediators of cholesterol transport. Cholesterol efflux occurs via three independent pathways: (1) aqueous diffusion, (2) nonspecific efflux via SR-BI receptors, and (3) specific efflux via cholesterol-responsive members of the ABC superfamily. Whereas aqueous diffusion and scavenger receptor class B, type I (SR-BI)-mediated efflux transport free cholesterol to a wide variety of cholesterol acceptors (particles containing phospholipids, HDL, and lipidated apo-lipoproteins; LDL, etc), the ABCA1 pathway mediates the transport of cholesterol in a unidirectional manner, mainly to lipid-poor apoA-I. In contrast, the ABCG1 pathway is responsible for the transport of cholesterol to all the subfamily members of HDL. Although HDL-mediated cholesterol efflux is apoA-I-dependent, recent studies have suggested an involvement of the enzyme paraoxonase 1 (PON1). Cholesterol efflux is carried on by a number of factors such as genetic mutations, smoking, stress, and high-fat diets. It is attenuated with aging due to changes in the composition and structure of HDL, especially the phosphatidylcholine/sphingomyelin ratio, the fluidity of the phospholipidic layer, the concentration of apoA-I, and the activity of PON1. This review summarizes the findings that cholesterol homeostasis is disrupted with aging as a consequence of dysfunctional cholesterol efflux and the impairment of physiological functions.

This study aimed to detect the association between the MLX interacting protein-like (MLXIPL), BUD13 homolog (BUD13) and zinc finger protein 259 (ZNF259) single nucleotide polymorphisms (SNPs) and serum lipid levels in the Chinese Mulao and Han populations. Genotyping of 9 SNPs was performed in 825 Mulao and 781 Han participants. The genotype and allele frequencies of ZNF259 rs2075290 and rs964184, and BUD13 rs10790162 SNPs were different between the Mulao and Han populations (P < 0.001). The SNPs of ZNF259 rs2075290 and BUD13 rs10790162 were associated with serum total cholesterol levels; ZNF259 rs2075290 and rs964184, BUD13 rs10790162, and MLXIPL rs3812316 and rs13235543 were associated with triglyceride (TG); and MLXIPL rs35332062 was associated with apolipoprotein (Apo) A1 in the Mulaos (P < 0.006-0.001). However, in the Hans, the SNPs of ZNF259 rs2075290 and BUD13 rs10790162 were associated with serum TG levels; ZNF259 rs2075290 was associated with low-density lipoprotein cholesterol and the ApoA1/ApoB ratio (P < 0.006-0.001). Significant linkage disequilibria were noted among ZNF259 rs2075290 and rs964184 and BUD13 rs10790162, and between MLXIPL rs3812316 and rs13235543 (r(2)>> 0.05, P < 0.001). The haplotypes of A-C-G-A-C (rs2075290A-rs964184C-rs10790162G-rs17119975A-rs11556024C) and C-C-C-C (rs799161C-rs35332062C-rs3812316C-rs13235543C) accounted for over half of the % haplotype of each ethnic group.

OBJECTIVE

Diets high in nuts reduce cholesterol, probably due to their favorable lipid profile and other bioactive substances. However, the physical form of the nut may be important as the cell wall of intact nuts may limit the hypocholesterolemic effect of nuts by reducing lipid bioavailability. Therefore, we investigated the effects on blood lipids of incorporating three different forms of hazelnuts (ground, sliced and whole) into the usual diet.

METHODS

In a randomized crossover study with three phases, 48 mildly hypercholesterolemic participants were asked to consume 30 g of ground, sliced or whole hazelnuts for 4 weeks. Body weight, plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triacylglycerol (TAG), apolipoprotein (apo) A1, apo B100 and α-tocopherol were measured at baseline and at the end of each dietary phase.

RESULTS

There were no significant differences in any outcome variable between the different forms of nuts (all P ≥ 0.159). However, compared with baseline, mean values at the end of each hazelnut intervention were significantly higher for HDL-C (P = 0.023) and α-tocopherol (P = 0.005), and significantly lower for TC (P < 0.001), LDL-C (P < 0.001), TC:HDL-C ratio (P <0 .001), apo B100 (P = 0.002) and apo B100:apo A1 ratio (P < 0.001), with no significant difference in body weight (P = 0.813).

CONCLUSIONS

The ingestion of three different forms of hazelnuts equally improved the lipoprotein profile and α-tocopherol concentrations in mildly hypercholesterolemic individuals. Hazelnuts can therefore be incorporated into the usual diet as a means of reducing cardiovascular disease risk.

The present study reports results from two investigations to determine effects of a 6-week period of moderate n-3 fatty acid supplementation (2.7 g/d) on fasting and on postprandial triacylglycerol and metabolic hormone concentrations in response to standard test meals. In the first study postprandial responses were followed for 210 min after an early morning test meal challenge; in the second study responses to an evening test meal were followed during the evening and overnight for a total period of 12 h. In both studies postprandial triacylglycerol responses to the test meals were significantly reduced after compared with before fish-oil supplementation. In the second study the triacylglycerol peak response seen between 200 and 400 min in subjects studied before supplementation with fish oils was almost completely absent in the same subjects after 6 weeks of n-3 fatty acid supplementation. Analysis of fasting concentrations of metabolites and hormones was carried out on the combined data from the two studies. There were no significant differences in total, low-density-lipoprotein- or high-density-lipoprotein-cholesterol concentrations during fish-oil supplementation, although there was considerable individual variation in cholesterol responses to the supplement. Concentrations of Apo-B and Apo-A1 were unchanged during supplementation with fish oils. Fasting and early morning postprandial GIP concentrations were lower in subjects taking fish oils, possibly due to acute effects of fish-oil capsules taken on the evening before the studies. In both studies fasting insulin and glucose and postprandial insulin concentrations remained unchanged following fish-oil supplementation. The results do not support the view that triacylglycerol-lowering effects of n-3 fatty acids are due to modulation of insulin secretion mediated via the enteroinsular axis. Further studies are required to determine the precise mechanism by which fish oils reduce both fasting and postprandial triacylglycerol concentrations.

Dyslipidemia is universal but hypercholesterolemia per se is present in around 50% of dialysis patients. Although dietary therapy is of benefit in some, the majority require drug therapy. We compared the efficacy and safety of simvastatin plus an optimized lipid-lowering dialysis diet with placebo plus diet in a randomized, double-blind trial stratified for dialysis modality. Patients treated with hemodialysis (HD) or continuous ambulatory peritoneal dialysis (CAPD) for at least 9 months and with serum non-high-density lipoprotein (HDL) cholesterol greater than 135 mg/dL, low-density lipoprotein (LDL) greater than 116 mg/dL, and triglyceride less than 600 mg/dL after a 6-week dietary treatment phase and an 8-week diet plus placebo run-in phase, were enrolled in the 24-week double-blind treatment phase. Fifty-seven patients (16 men, 41 women, median age 63 years, range 22-75 yr) were randomized 2:1 to diet plus 5 mg/day simvastatin (n = 38: 22 HD, 16 CAPD) or diet plus placebo (n = 19: 12 HD, 7 CAPD) for 24 weeks. Dose was doubled bimonthly (maximum 20 mg/day) if non-HDL cholesterol was greater than 135 mg/dL. Forty-two patients (73.7%) completed the trial. Comparing baseline and 24 weeks, simvastatin (median 10 mg/day) was significantly more effective than placebo in reducing serum non-HDL cholesterol concentrations. For HD, the median percentage changes for total cholesterol (TC) (simvastatin versus placebo) were -21.4% and -12.1% (P = 0.011), respectively; for LDL cholesterol, -33.0% and -8.8% (P = 0.023); for non-HDL cholesterol, -25.2% and -14.0% (P = 0.008); and for TC:HDL, -17.65% and -1.67% (P = 0.008). For CAPD, changes for TC were -22.1% and -1.5% (P = 0.003), respectively; for LDL, -36.4% and 0.0% (P = 0.001); for non-HDL cholesterol, -24.9% and -3.6% (P = 0.002); and for TC:HDL ratio, -21.49% and +9.74% (P = 0.045). Changes with CAPD in apolipoprotein (Apo) A1 were -4.7% and +4.0% (P = 0.031); and for ApoB, -19.9% and +2.6%, respectively (P = 0.031). There were no significant changes in ApoA1 or ApoB with HD. Compared with placebo, triglyceride levels fell 10.2% with HD and 6.2% with CAPD. HDL cholesterol was unchanged with HD but rose 8.5% with CAPD. These trends, however, did not reach statistical significance (P>> 0.05). There was no effect on Lp (a). The incidence of clinical and laboratory adverse experiences were not increased in the simvastatin-treated patients compared with placebo. Simvastatin appears to be a safe and effective treatment for the reduction of serum non-HDL cholesterol levels in both HD and, particularly, CAPD patients.

OBJECTIVE

To determine oxidative stress status and its association with clinical and metabolic parameters in Chinese women with different clinical phenotypes of polycystic ovary syndrome (PCOS).

METHODS

A cross-sectional study.

METHODS

A total of 544 patients with PCOS and 468 control women were included.

METHODS

The total oxidant status (TOS) was determined using a microplate colorimetric method. Total antioxidant capacity (T-AOC), oxidative stress index (OSI, the ratios of TOS to T-AOC) and clinical, hormonal and metabolic parameters were also analysed.

RESULTS

TOS and OSI were significantly higher in each of the four PCOS phenotypes based on the Rotterdam criteria than in the control women and higher in patients with hyperandrogenism (HA) than in those without HA (P < 0·05). TOS, T-AOC and OSI were higher in lean patients than in lean controls (P < 0·05). These values, except OSI, were also higher in overweight/obese patients than in lean patients, and lean or overweight/obese controls (P < 0·05). Multivariate regression analysis demonstrated that apolipoprotein (apo)A1, the Ferriman-Gallwey score, triglyceride (TG), oestradiol (E2 ), high-density lipoprotein cholesterol (HDL-C) and 2-h glucose levels were the main predictors of TOS; the Ferriman-Gallwey score, E2 , apoA1, TG and HDL-C levels were the main predictors of OSI.

CONCLUSIONS

Patients with PCOS with HA have higher oxidative stress levels compared with those without HA. The increased oxidative stress in PCOS is related to HA status, increased plasma glucose, TG, HDL-C and E2 levels, decreased apoA1 concentrations and a relative shortage of antioxidant capacity.

BACKGROUND

The high prevalence of metabolic syndrome (MetS) has highlighted the need for effective dietary interventions to combat this growing problem.

OBJECTIVE

To assess the impact of a Mediterranean-style low-glycemic-load diet (control arm, n = 44) or the same diet plus a medical food containing phytosterols, soy protein, and extracts from hops and acacia (intervention arm, n = 45) on cardiometabolic risk variables in women with MetS.

METHODS

In this 12-week, 2-arm randomized trial, baseline, week 8 and 12, fasting blood samples were drawn to measure plasma lipids, apolipoproteins, and homocysteine. Dietary records were also collected and analyzed.

RESULTS

There were decreases in fat and sugar intake (P < .001 for both) and increases in docosahexaenoic acid and eicosapentaenoic acid intake (P < .001 for both) over time, consistent with the prescribed diet. Regarding MetS variables, there were decreases in waist circumference, systolic and diastolic blood pressure, and plasma triglycerides in all subjects (P < .001 for all) with no differences between arms. Plasma low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, apolipoprotein (apo) B, and apo B/apo A1 were reduced over time but to a greater extent in the intervention arm (P < .05 for all), indicating the medical food had a greater effect in altering lipoprotein metabolism. Further, medical food intake was associated with reduced plasma homocysteine (P < .01) compared to the control arm.

CONCLUSIONS

A Mediterranean-style low-glycemic-load diet effectively reduces the variables of MetS. Addition of the medical food results in a less atherogenic lipoprotein profile and lower plasma homocysteine.

OBJECTIVE

The aim of the present study was to compare the effects of simvastatin and L-carnitine coadministration versus simvastatin monotherapy on lipid profile, lipoprotein(a) (Lp(a)) and apoprotein(a) (Apo(a)) levels in type II diabetic patients.

METHODS

In this double-blind, randomized clinical trial, 75 patients were assigned to one of two treatment groups for 4 months. Group A received simvastatin monotherapy; group B received L-carnitine and simvastatin. The following variables were assessed at baseline, after washout and at 1, 2, 3 and 4 months of treatment: body mass index, fasting plasma glucose, glycated hemoglobin, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, Apolipoprotein A1, Apo B, lipoprotein(a) and apoprotein(a).

RESULTS

At the end of treatment in the carnitine and simvastatin combined group compared with the simvastatin alone group, we observed a significant decrease in glycemia (p < 0.001), triglycerides (p < 0.001), Apo B (p < 0.05), Lp(a) (p < 0.05), apo(a) (p < 0.05), while HDL significantly increased (p < 0.05).

CONCLUSIONS

The coadministration of carnitine and simvastatin resulted in a significant reduction in Lp(a) and apo(a) and may represent a new therapeutic option in reducing plasma Lp(a) levels, LDL cholesterol and Apo B100.

Apolipoprotein A1 (apo A1), the major protein of high-density lipoprotein, is secreted as a proprotein and then cleaved by an uncharacterized metalloproteinase. Here this enzyme is identified as C-terminal procollagen endoproteinase/bone morphogenetic protein-1 (BMP-1). Studies with recombinant BMP-1, BMP-1 antibody, and BMP-1 siRNA establish this proteinase as the major or only apo A1-converting activity secreted by human liver-derived (HepG2) cells and CHO cells stably expressing human apo A1. BMP-1 stimulates the conversion of newly secreted proapo A1 to its phospholipid- (PL-) binding form. In this way it promotes formation of functional HDL and reverse cholesterol transport, while inhibiting filtration and clearance of uncleaved proprotein. Alpha2-macroglobulin, a protease inhibitor secreted as part of the innate immune response, inhibits BMP-1 activity and blocks the maturation of proapo A1. The decrease in circulating apo A1 levels that is characteristic of the response to inflammation and infection may be mediated, at least in part, via BMP-1 by this novel mechanism.

BACKGROUND

The reduction in plasma LDL-C concentrations with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy has been reported to reduce cardiovascular risk and mortality in individuals with or without preexisting coronary artery disease and elevated LDL-C concentrations. Atorvastatin is a statin used for lowering LDL-C concentrations. A generic formulation of atorvastatin is being developed in Korea. This study was undertaken for the purposes of marketing the generic formulation.

OBJECTIVE

This study was designed to compare the efficacy and tolerability of a generic formulation of atorvastatin 20 mg/d versus a branded formulation at the same dosage in hypercholesterolemic Korean adults at high risk for cardiovascular events.

METHODS

This 8-week, multicenter, randomized, double-blind, double-dummy study was conducted at 10 clinical centers in Korea between September 2008 and May 2009. Male and female patients aged 20 to 85 years at high risk for cardiovascular events (defined as an elevated LDL-C concentration [≥100 mg/dL]) were enrolled. Eligible patients were randomly assigned to receive generic or branded atorvastatin 20 mg once daily for 8 weeks. The primary end point was the percentage change from baseline to 8 weeks in LDL-C concentration. Secondary end points were the percentage changes from baseline in total cholesterol (TC), triglycerides (TG), HDL-C, apolipoprotein (apo) A1 and B, and high-sensitivity C-reactive protein concentrations; small, dense LDL (sdLDL) fraction; and tolerability. Tolerability was assessed using physical examination, laboratory testing, and by recording adverse events (AEs) at each visit. An additional secondary end point was the proportion of patients who achieved an LDL-C goal of <100 mg/dL.

RESULTS

A total of 244 patients were randomized to treatment, and 33 patients were withdrawn from the study (9 patients did not receive the study medication, 11 patients due to AEs, and 13 patients due to withdrawal of consent). A total of 211 patients completed the study (50.7% male; 100% Asian; mean [SD] age, 61.7 [9.2] years) (106 patients in the group that received Accepted for publication October 5, 2010. the generic formulation and 105 patients in the group that received the branded formulation). LDL-C concentrations were reduced from the baseline by 44% and 46% after 8 weeks of treatment with the generic and branded formulations, respectively (P = NS). The percentage changes from baseline to study end in HDL-C, TC, TG, apo A1, apo B, and hsCRP concentrations and sdLDL fraction the proportions of patients who achieved the LDL-C goal between the 2 groups did not reach statistical significance. The most commonly reported events were hepatobiliary laboratory abnormality (1.7%), general somatic discomfort (1.7%), and epigastric pain (0.8%) in the group that received the generic formulation, and myalgia (1.7%), epigastric pain (0.9%), and elevation of creatinine phosphokinase (0.9%) in the group that received the branded formulation. No serious AEs were reported in either group.

CONCLUSIONS

After 8 weeks of treatment, the differences in the LDL-C-lowering effects between the generic and branded formulations of atorvastatin 20 mg/d did not reach statistical significance in these Korean patients at high risk for cardiovascular events. Both formulations were generally well tolerated.

We examined the relationship between abdominal visceral fat (AVF) and plasma concentrations of lipids and lipoproteins in 19 females (F) (not on estrogen) and 31 males (M) over the age of 60 (age = 66.8 years). In addition, the effects of growth hormone (GH) release, fitness (Vo(2) peak), insulin, and glucose concentrations (both fasting and in response to an oral glucose tolerance test) on lipids were examined. Subjects were categorized by low (L) and high (H) AVF (L < 130 cm(2), H>> 130 cm(2)), fat mass (FM) (above or below median value), and AVF corrected for fat mass. Factorial analysis of variance (ANOVA) showed that when subjects were divided by AVF and FM, similar results were observed with H>> L (P <.05) for very-low-density lipoprotein-cholesterol (VLDL-C), triglycerides (TG), VLDL-TG, apolipoprotein (apo)-B, apo-B VLDL, cholesterol (Chol)/high-density lipoprotein (HDL), LDL/HDL, apoB/A1 and L>> H for HDL, HDL(2), HDL(3), apo A1, and LDL/apo-B LDL. Gender differences were also observed with F>> M for Chol, LDL, HDL, and HDL(2). When AVF was corrected for FM, these gender differences were still present. After correcting for FM, differences remained between H and L AVF groups for VLDL, TG, VLDL-TG, apo-B, apo-B LDL, apo-B VLDL, apoB/A1 (P <.05). Twenty-four hour integrated GH concentration (IGHC) was inversely related to VLDL, TG, VLDL TG, LDL TG, apoB, apoB VLDL, apoB LDL, Chol/HDL, LDL/HDL, and apoB/A1 in F, but not M (P <.05). Vo(2) peak was directly related to Chol, LDL, HDL(3), and apoB LDL with stronger relationships observed in F. Fasting insulin was related to lipids and lipoproteins in both men and women. These data suggest that, in older adults, elevated levels of AVF, FM, and AVF corrected for FM are associated with unfavorable lipid-lipoprotein profiles and extend similar findings reported in younger males and females with elevated AVF. These data also support previous findings indicating that AVF is a primary determinant of GH release.

BACKGROUND

The diagnosis and classification of inflammatory bowel disease (IBD) require both clinical and histopathologic data. Serum biomarkers would be of considerable benefit to noninvasively monitor the progression of disease, assess effectiveness of therapies, and assist in understanding disease pathogenesis. Currently, there are limited noninvasive biomarkers for monitoring disease progression in animal IBD models, which are used extensively to develop new therapies and to understand IBD pathogenesis.

METHODS

Serum biomarkers of early and late IBD were identified using multianalyte profiling in mdr1a(-/-) mice with IBD triggered by infection with Helicobacter bilis. The correlation of changes in these biomarkers with histopathology scores and clinical signs in the presence and in the absence of antibiotic treatment was determined.

RESULTS

Serum levels of interleukin (IL)-11, IL-17, 10-kDa interferon-gamma-inducible protein (IP-10), lymphotactin, monocyte chemoattractant protein (MCP)-1, and vascular cell adhesion molecule (VCAM)-1 were elevated early in IBD. In late, more severe IBD, serum levels of IL-11, IP-10, haptoglobin, matrix metalloproteinase-9, macrophage inflammatory protein (MIP)-1gamma, fibrinogen, immunoglobulin A, MIP-3 beta (beta), VCAM-1, apolipoprotein (Apo) A1, and IL-18 were elevated. All late serum biomarkers except Apo A1 correlated with histopathology scores. Antibiotic treatment improved clinical signs of IBD and decreased mean serum values of many of the biomarkers. For all biomarkers, the individual pathology scores correlated significantly with individual serum analyte levels after treatment.

CONCLUSIONS

Serum analyte measurement is a useful, noninvasive method for monitoring disease in a mouse model of bacterial-induced IBD.

This study was to determine the association between several single nucleotide polymorphisms (SNPs) in the dedicator of cytokinesis 7 (DOCK7), proprotein convertase subtilisin/kexin type 9 (PCSK9) and polypeptide N-acetylgalactosaminyltransferase 2 (GALNT2) and serum lipid levels. Genotyping of 9 SNPs was performed in 881 Jing subjects and 988 Han participants. Allele and genotype frequencies of the detected SNPs were different between the two populations. Several SNPs were associated with triglyceride (TG, rs10889332, rs615563, rs7552841, rs1997947, rs2760537, rs4846913 and rs11122316), high-density lipoprotein (HDL) cholesterol (rs1997947), low-density lipoprotein (LDL) cholesterol (rs1168013 and rs7552841), apolipoprotein (Apo) A1 (rs1997947), ApoB (rs10889332 and rs7552841), and ApoA1/ApoB ratio (rs7552841) in Jing minority; and with TG (rs10889332, rs615563, rs7552841, rs11206517, rs1997947, rs4846913 and rs11122316), HDL cholesterol (rs11206517 and rs4846913), LDL cholesterol (rs1168013), ApoA1 (rs11206517 and rs4846913), ApoB (rs7552841), and ApoA1/ApoB ratio (rs4846913) in Han nationality. Strong linkage disequilibria were noted among the SNPs. The commonest haplotype was G-C-G-C-T-G-C-C-G (>10%). The frequencies of C-C-G-C-T-G-T-C-G, G-C-A-C-T-G-C-C-G, G-C-G-C-T-A-C-C-A, G-C-G-C-T-G-C-C-A, G-C-G-C-T-G-T-C-A haplotypes were different between the two populations. Haplotypes could explain much more serum lipid variation than any single SNP alone especially for TG. Differences in lipid profiles between the two populations might partially attribute to these SNPs and their haplotypes.

BACKGROUND

Ongoing low-grade inflammation and endothelial dysfunction persist in children with coronary lesions diagnosed with Kawasaki disease (KD). Statins, frequently used in the management of high cholesterol, have also shown to improve surrogate markers of inflammation and endothelial dysfunction. This study was undertaken to investigate the efficacy and safety of pravastatin in children with coronary artery aneurysms due to KD.

METHODS

The study enrolled 14 healthy children and 13 male children, aged 2-10 years, with medium-to-giant coronary aneurysms for at least 12 months after the onset of KD. Pravastatin was given orally to the KD group at a dose of 5 mg/day for children under 5 and 10 mg/day for children older than 5 years. To determine the effects of pravastatin on endothelial function, high-frequency ultrasound was performed before the start of the study and 6 months after pravastatin therapy. The parameters measured were brachial artery flow-mediated dilation (FMD), non-flow mediated dilation (NMD), and carotid artery stiffness index (SI). High sensitive C-reactive protein (hs-CRP) levels, the circulating endothelial progenitor cells (EPCs) number, and serum lipid profiles were also determined at baseline and after 6 months of pravastatin treatment.

RESULTS

Before treatment, the KD group had significantly decreased FMD (P<0.05) and increased SI and hs-CRP levels (P<0.05) compared with controls. After 6 months of pravastatin therapy, FMD improved significantly compared to the baseline KD group (3.16±6.49 to 10.05±7.74, P<0.05), but remained significantly less than that in the control group with no significant changes in NMD and SI. There were significant decreases in markers of inflammation after treatment. The hs-CRP levels decreased significantly from 2.93±0.81 mmol/L to 2.14±0.82 mmol/L (P<0.05) and the serum apo-B and apo-B/apo-A1 ratio were also reduced (P<0.05) in the KD group. However, the circulating EPC number was not significantly different between baseline and that following pravastatin treatment in the KD group and the control group (P>0.05). No significant complications were noted with paravastatin therapy.

CONCLUSIONS

Pravastatin improves endothelial function and reduces low-grade chronic inflammation in patients with coronary aneurysms due to KD. Children with coronary aneurysms due to KD may benefit from statin therapy.

BACKGROUND

Little is known about the association of the single nucleotide polymorphism (SNP) of rs364585 near serine palmitoyl-transferase long-chain base subunit 3 gene (SPTLC3) and serum lipid profiles. The present study was detected the association of the SPTLC3 rs364585 SNP and several environmental factors with serum lipid profiles in the Han and Jing populations.

METHODS

Genotyping of the SPTLC3 rs364585 SNP was performed in 824 unrelated individuals of Han and 783 participants of Jing by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing.

RESULTS

There was no significant difference in either genotypic or allelic frequencies between Han and Jing, or between males and females of the both ethnic groups. The levels of serum low-density lipoprotein cholesterol (LDL-C) and the ratio of apolipoprotein (Apo) A1 to ApoB in Han; and total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and LDL-C in Jing were different between the A allele carriers and the A allele non-carriers (P < 0.05-0.001). Subgroup analysis according to sex showed that the levels of LDL-C in Han males; TC and LDL-C in Jing males; and HDL-C and LDL-C in Jing females were different between the A allele carriers and the A allele non-carriers (P < 0.05-0.001), the A allele carriers had higher LDL-C and TC levels, and lower HDL-C levels than the A allele non-carriers. Serum lipid traits were also associated with several environmental factors in the Han and Jing populations, or in males and females of the both ethnic groups.

CONCLUSIONS

The present study demonstrates the association between the SPTLC3 rs364585 SNP and serum TC, HDL-C and LDL-C levels in our study populations. These associations might have ethnic- and/or sex-specificity.

BACKGROUND

Retrospectively registered.

BACKGROUND

Studies in adults have reported associations of low circulating total 25-hydroxyvitamin D with increased cardiovascular disease and risk factors. Evidence of associations in children, however, is limited, and it is unknown whether associations with risk factors differ for each 25-hydroxyvitamin D analog [25-hydroxyvitamin D(2) (25[OH]D(2)) and 25-hydroxyvitamin D(2) (25[OH]D(3))].

OBJECTIVE

The objective of the study was to compare associations of 25(OH)D(2) and 25(OH)D(3) with cardiovascular risk factors in children.

METHODS

The design of the study was a cross-sectional study of 4274 children (mean age 9.9 yr) from the Avon Longitudinal Study of Parents and Children.

RESULTS

The main outcomes included blood pressure, lipids [triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C)], apolipoproteins (Apo-A1 and Apo-B), adiponectin, leptin, C-reactive protein, and IL-6.

RESULTS

In confounder-adjusted models, 25(OH)D(2) was inversely associated with Apo-A1 (change per doubling of exposure: -0.74 mg/dl; 95% confidence interval -0.14, -0.04) and triglycerides (relative percentage change per doubling of exposure: -1.64%; -3.27, 0.01) and positively associated with C-reactive protein (8.42%; 3.40, 13.58) and IL-6 (5.75%; 1.83, 9.25). 25(OH)D(3) was positively associated with HDL-C (0.04 mmol/liter; 0.02, 0.06), Apo-A1 (1.96 mg/dl; 0.65, 3.24), and adiponectin (0.47 μg/ml; 0.15, 0.79). There was statistical evidence that associations of 25(OH)D(2) and 25(OH)D(3) with HDL-C, Apo-A1, and IL-6 differed from each other (all P values for differences ≤0.02).

CONCLUSIONS

Higher circulating 25(OH)D(3) was associated with cardioprotective levels of HDL-C, Apo-A1, and adiponectin in children. Associations of 25(OH)D(2) with cardiovascular risk factors were in mixed directions. It is necessary to see whether these associations are replicated in large prospective studies.

Retinoid X receptors (RXR) are members of the nuclear receptor superfamily of ligand-activated transcription factors that have been characterized in a wide variety of metazoan phyla. They act as heterodimer partners of other nuclear receptors, and in vertebrates also activate transcription as homodimers in the presence of a ligand, 9-cis retinoic acid. In order to test the hypothesis that retinoic acid signaling pathways involving RXRs are present in the Lophotrochozoa, we have sought to isolate conserved members of this family from the platyhelminth parasite Schistosoma mansoni and its intermediate host, the mollusk Biomphalaria glabrata. Here we report that an RXR ortholog from B. glabrata (BgRXR) is better conserved, compared with mouse RXRalpha, both in the DNA-binding domain (89% identity) and in the ligand-binding domain (LBD) (81% identity), than are arthropod homologs. In EMSA, BgRXR binds to the direct repeat response element DR1 as a homodimer or as a heterodimer with mammalian RARalpha, LXR, FXR or PPARalpha. When transfected alone into mammalian cell lines, BgRXR transactivated transcription of a reporter gene from the Apo-A1 promoter in the presence of 9-cis retinoic acid or DHA. Constructs with the Gal4 DNA binding domain fused to the hinge and LBDs of BgRXR were used to show that ligand-dependent activation of transcription by BgRXR required its intact AF-2 activation domain, and that the LBD can form homodimers. Finally, the binding of 9-cis retinoic acid preferentially protected the LBD of BgRXR from degradation by trypsin in a proteolysis protection assay. Our results show that BgRXR binds and is activated by retinoids and suggest that retinoid signaling pathways are conserved in the Lophotrochozoa. The nucleotide sequence reported in this paper has been submitted to the GenBank/EBI Data Bank with accession no. AY048663.

Insulin suppresses secretion of very low density lipoprotein (VLDL) apolipoprotein (apo) B in primary rodent hepatocytes (RH) by favoring the degradation of B100, the larger form of apo B, through post-endoplasmic reticulum proteolysis. Sortilin 1 (sort1), a multi-ligand sorting receptor, has been proposed as a mediator of lysosomal B100 degradation by directing B100 in pre-VLDL to lysosomes rather than allowing maturation to VLDL and secretion. The purpose of our studies was to investigate the role of sort1 in insulin-dependent degradation of apo B. Using liver derived McArdle RH7777 (McA) cells, we demonstrate that insulin suppresses VLDL B100 secretion via a phosphatidylinositide 3-kinase (PI3K) dependent process that is inhibitable by wortmannin in a fashion similar to RH. Using McA cells and in situ cross-linking, we demonstrate that insulin acutely (30min) stimulates the interaction of B100 with sort1. The insulin-induced interaction of sort1-B100 is markedly enhanced when lysosomal degradation is inhibited by Bafilomycin A1 (BafA1), an inhibitor of lysosomal acidification. As BafA1 also prevents insulin suppressive effects on apo B secretion, our results suggest that sort1-B100 interaction stimulated by insulin transiently accumulates with BafA1 and favors B100 secretion by default.

OBJECTIVE

High-density lipoprotein cholesterol (HDL-C) has been well established as an inverse predictor of coronary heart disease (CHD), and in recent years, investigations have focused on the genetic regulation of high-density lipoprotein. Although numerous candidate genes contribute to the low HDL-C phenotype, their impact on CHD is heterogeneous, reflecting diverse gene-gene interactions and gene-environmental relationships. This review summarizes recent data involving HDL regulatory genes and their role in atherothrombosis.

RESULTS

The primary genetic determinants associated with relative HDL-C deficiency states are the ATP binding cassette protein, ABCA1; apolipoprotein (APO) A1; and lecithin cholesteryl acyl transferase. Other potentially important candidates invoked in low HDL-C syndromes in humans include APOC3, lipoprotein lipase, sphingomyelin phosphodiesterase 1, and glucocerebrosidase. Molecular variation in ABCAI and APOAI and, in selected cases, lecithin cholesteryl acyl transferase deficiency have been associated with increased CHD, whereas two notable variants, APOAIMilano and APOAIParis, are associated with reduced risk.

CONCLUSIONS

Low HDL-C syndromes have generally been correlated with an increased risk of CHD. However, single-gene abnormalities responsible for HDL-C deficiency states may have variable effects on atherothrombotic risk.

High-density lipoprotein (HDL) particles can deliver cholesterol from peripheral tissues to the liver through apolipoprotein A1 (Apo A1), which specifically binds to the scavenger receptor class B type 1 (SR-B1) receptor on the surface of hepatocytes. Therefore, ApoA1 can be potentially used to target drugs to the liver. In this study, we successfully loaded doxorubicin hydrochloride (Dox or Dox-HCl), which is a hydrophilic drug used in a wide variety of clinical applications, into the core of reconstituted HDL (rHDL prepared by apoAI and egg phospholipids) to form a doxorubicin-HDL complex (rHDL-Dox). The MTT assays showed that rHDL-Dox particles also had higher cytotoxicity against several cells lines compared to free drug or Dox encapsulated into liposomes. A cellular uptake assay demonstrated that rHDL-Dox had higher absorption in SR-BI receptor positive liver cells. Importantly, in vivo experiments showed that rHDL-Dox can reduce tumor growth more effectively than liposomes. In addition, an in vitro hemolysis assay showed that rHDL-Dox caused only limited hemolysis in the case of high doses. Taken together, our findings indicate that rHDL is a safe and effective drug delivery system for targeting liver.

Wilms tumor is the most common pediatric tumor of the kidney. Previous studies have identified several serum biomarkers for Wilms tumor; however, they lack sufficient specificity and may not adequately distinguish Wilms tumor from confounding conditions. To date, no specific protein biomarker has been confirmed for this pediatric tumor. To identify novel serum biomarkers for Wilms tumor, we used proteomic technologies to perform protein profiling of serum samples from pre-surgery and post-surgery patients with Wilms tumor and healthy controls. Some common systemic inflammatory factors were included to control for systemic inflammation. By comparing protein peaks among the three groups of sera, we identified two peaks (11,526 and 4,756 Da) showing significant differential expression not only between pre-surgery and control sera but also between pre-surgery and post-surgery sera. These two peaks were identified as serum amyloid A1 (SAA1) and apolipoprotein C-III (APO C-III). Western blot analysis confirmed that both proteins were expressed at higher levels in pre-surgery sera than in post-surgery and control sera. Using the method of leave-1-out for cross detection, we demonstrate that detection of these two candidate biomarkers had high sensitivity and specificity in discriminating pre-surgery sera from post-surgery and normal control sera. Taken together, these findings suggest that SAA1 and APO C-III are two potential biomarkers for Wilms tumor.

The clinical efficacy of the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMGCoA) reductase inhibitor simvastatin in the treatment of hypercholesterolaemia in non-insulin-dependent diabetes (NIDDM), was examined in a double-blind placebo-controlled study of 6 months in 70 patients with NIDDM (age 25-70 years), of whom 57 were randomised to placebo (29 patients) or simvastatin for 6 months, following a 3-month run-in on diet. Patients were hypercholesterolaemic (7.8 (7.6-8.0) (mean (95% confidence intervals)) mmol/l simvastatin vs. 8.0 (7.7-8.5) mmol/l placebo) and mildly hypertriglyceridaemic (2.6 (2.2-3.0) simvastatin vs. 2.9 (2.3-3.5) placebo). Other lipid measures and estimates of glycaemic control and haemostasis were similar in both groups. There were no significant changes in lipids, haemostatic factors, or measures of glycaemic control in the placebo treatment group. Conversely by the end of 24 weeks, simvastatin produced a 28% reduction in cholesterol (to 5.6 (5.0-6.2) mmol/l (P < 0.001)), a 38% reduction in LDL cholesterol (from 5.5 (5.4-5.6) mmol/l to 3.4 (2.8-4.0) mmol/l, P < 0.001), a 15% reduction in triglyceride (to 2.2 (1.8-2.6) mmol/l, P < 0.05, and a 9% rise in HDL (from 1.16 (1.07-1.25) to 1.23 (1.14-1.32) mmol/l, P < 0.05). Improvements in apolipoprotein B (apo B) (-28%, P < 0.001), the LDL cholesterol to apo B ratio (-20%, P < 0.001), and apo A1 (+15%, P < 0.001) were recorded. There were no effects upon fibrinogen, factor VII activity, factor VIII activity, or measures of glycaemic control (fasting glucose, insulin, C-peptide, or HbA1).(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE

Active acromegaly is associated with altered lipid metabolism. The purpose of this study was to investigate the effect of serum IGF-I normalization on serum lipoproteins and insulin, in patients with acromegaly receiving the GH receptor antagonist pegvisomant.

METHODS

Twenty patients (9 male, mean age 58.7 years, range 28-79) with active acromegaly (baseline serum IGF-I>> 130% the age-related upper limit of normal) received pegvisomant and achieved a normal serum IGF-I [585.2 +/- 54.3 (mean +/- SEM) to 169.2 +/- 13.9 ng/ml, P < 0.0001].

METHODS

Total cholesterol (TC), high-density lipoprotein (HDL) cholesterol, triglyceride (TG), apolipoprotein B (apo B), apolipoprotein A1 (apo A1), lipoprotein a [Lp(a)] and insulin were measured in a single batch analysis on samples obtained at baseline and the first occasion of serum IGF-I normalization. Low-density lipoprotein (LDL) was calculated using the Friedewald formula. Paired analysis was performed using Student's paired t-test and the Wilcoxon signed rank test.

RESULTS

Normalization of serum IGF-I resulted in an increase in TC (5.0 +/- 0.3 to 5.7 +/- 0.4 mmol/l, P = 0.0068), an increase in LDL (3.0 +/- 0.25 to 3.7 +/- 0.31 mmol/l, P = 0.0093) and an increase in apo B (110.6 +/- 7.76 to 127.1 +/- 8.86 mg/l, P = 0.014). TC and LDL increased in all but four patients. Despite a significant fall in fasting insulin levels (9.9 to 8.3 mU/l, range 8.85-19.8 to 6.33-11.6, P < 0.001) and insulin resistance (2.7 to 1.9, range 1.2-10.4 to 1-6.2, P < 0.001), mean serum TG and HDL levels were unaffected by IGF-I normalization. The protein component of HDL, apo A1, increased (153 +/- 4 to 166.4 +/- 5.43 mg/l, P = 0.026) and Lp(a) declined (median 342 to 235 mg/l, range 60-1013 to 74-671), P = 0.0035). Baseline serum TC and LDL were below the age- and sex-matched mean population value but after normalization of serum IGF-I the distribution of serum TC and LDL values was similar to that of the general population.

CONCLUSIONS

Active acromegaly is associated with lowered mean serum TC and LDL. Successful management using pegvisomant increases lowered baseline serum TC and LDL levels, restoring the distribution of values to that of the general population, and improves insulin resistance. These findings are consistent with the reported lipoprotein changes following GH administration to normal and GH-deficient individuals.

In order to determine lipid abnormalities in serum in HIV-infected patients and their relation with humoral and cellular immunological changes. Ninety HIV-infected patients without acute inflammatory or malignant disease have been studied. Thirty healthy HIV-negative subjects constituted the control group. As compared with controls, patients with CD4 + lymphocytes>> 400 x 10(6)/l had higher triglycerides and lower high density lipoprotein (HDL)-cholesterol and apolipoprotein (apo)-A1. Lipoprotein comparison by groups of patients according to CD4 + cell counts showed a decrease of HDL-cholesterol in patients with CD4 + cells < or = 200 x 10(6)/l. When CD4 + lymphocyte counts were < 50 x 10(6)/l, total and very low density lipoprotein (VLDL)-triglycerides and VLDL-cholesterol were increased and HDL and low density lipoprotein (LDL)-cholesterol and apo-A1 were decreased. Interferon (IFN)-alpha, beta2-microglobulin and tumor necrosis factor (TNF)-alpha were correlated positively with total and VLDL-triglycerides and negatively with HDL-cholesterol. In conclusion, lipoprotein changes in patients with HIV-infection are related with humoral and cellular immune markers. A decrease of HDL-cholesterol and apo-A1 and an increase of triglyceride levels could be considered as markers of disease progression.