Recent pharmacological studies confirmed the role of hypercholesterolemia in the pathogenesis of coronary atherosclerosis. A 10% reduction in cholesterol levels can reduce the risk of coronary heart disease by 15%. However many hypercholesterolemic patients often suffer from arterial hypertension and drugs such as thiazide diuretics cause an imbalance in lipid metabolism. The efficacy and the tolerability of simvastatin (a inhibitor of HGM-CoA reductase) with that of gemfibrozil (a fibric acid derivative, which can reduce the VLDL level) were compared in a placebo-controlled study in 2 groups of patients with primary hypercholesterolemia and mild-to-moderate essential hypertension treated with hydrochlorothiazide. After 10 weeks standard hypolipidemic diet and hydrochlorothiazide (25 mg od) therapy, 30 patients whose cholesterol levels were still greater than or equal to 250 mg/100 ml and whose diastolic blood pressure was less than 95 mmHg were randomized to one of the following treatments: simvastatin, 20 mg od, gemfibrozil, 600 mg bid or placebo, while continuing dietetic and diuretic treatment. After 24 weeks treatment, simvastatin induced a 37% reduction in cholesterol plasma levels, a 9% increase of HDL and a 16% reduction of LDL. APO-A1 showed a 4% increase, while APO-B showed a 3% reduction. Gemfibrozil induced a 20% reduction in plasma triglycerides and a 13% decrease in plasma cholesterol, with a significant 19% increase in HDL and a 11% reduction in LDL. No significant variations in any of the lipid parameters monitored were observed in the placebo group. Treatment with simvastatin or gemfibrozil in hypertensive patients in hydrochlorothiazide monotherapy can reduce total cholesterol and LDL-cholesterol plasma levels, while significantly increasing HDL plasma levels compared to placebo. Simvastatin, however, resulted more efficient than gemfibrozil on total cholesterol or cholesterol fractions.

Selected parameters of lipid metabolism were studied in a group of 76 children aged 12-13 years. The children were divided into 4 subgroups according to the duration of neonatal nutrition (no breast feeding, breast feeding for 3, 6 or more than 6 months). We studied the concentration of total serum cholesterol, its distribution into lipoprotein fractions, the concentration of serum triacylglycerols and apolipoproteins A1 (Apo A1) and B (Apo B). Atherogenic indexes were calculated from the data obtained. The highest cholesterol levels (5.20+/-0.15 mmol x l(-1)) were found in children who had been breast-fed for more than 6 months, while the highest concentrations of Apo B (0.80+/-0.07 g x l(-1)) and Apo A1 (1.76+/-0.06 g x l(-1)) and the highest Apo B/Apo A1 ratio (0.45+/-0.04) were found in children with the shortest period of breast-feeding. No significant sex-related differences in total, VLDL, LDL, HDL cholesterol, triacylglycerols and apolipoproteins were observed.

Human apolipoprotein A-IV (APO A-IV) exhibits a common protein polymorphism detectable by isoelectric focusing (IEF) due to a single base substitution at codon 360 which replaces the frequently occurring glutamine residue (allele 1) with histidine (allele 2). Recently, sequence analysis of the APO A-IV coding region has revealed another common nucleotide substitution at codon 347 which converts the commonly present threonine residue (allele A) into serine (allele T). In order to investigate the extent of genetic variation at codon 347, we screened DNA samples from 192 unrelated individuals using a polymerase chain reaction based assay. The frequencies of the two alleles, A-IV*A and A-IV*T, were 0.81 and 0.19, respectively, with average heterozygosity 0.31. Genetic screening of the corresponding 192 plasma samples by IEF gave frequencies of 0.922 and 0.078 for the A-IV*1 and A-IV*2 alleles, respectively, at codon 360 with average heterozygosity 0.14. Genotype data at the two polymorphic sites were used to assign unequivocal haplotypes to all the 384 chromosomes. Of the expected four haplotypes (A1, T1, A2, and T2) only three were observed and their frequencies were 0.732 for A1, 0.190 for T1 and 0.078 for A2, with average heterozygosity 0.42. Although our data indicate significant linkage disequilibrium between the two sites (chi 21 = 7.65, P < 0.006, standardized disequilibrium constant phi = -0.14) the degree of nonrandom association varied between alleles at the two sites. Based upon allele frequency data and variable linkage disequilibrium between alleles, we propose that the A2 and T1 haplotypes may have evolved from the parental A1 haplotype by two independent mutations.

The amphipathic helical theory of Segrest and colleagues (FEBS Lett.:38:247-253, 1974) proposes that the lipid-binding segments of serum apolipoproteins are in an alpha helical conformation. Furthermore the helices have a hydrophobic face and a hydrophilic face with a specific distribution of positively and negatively charged residues. The importance of the pattern of the charged residues in the lipid binding and lecithin:cholesterol acyltransferase (LCAT) activation by the segments is still debated. We designed a 30-residue peptide, GALA, which in the alpha helical conformation has a hydrophilic face composed of glutamic acid residues (Sabbarao et al.: Biochemistry 26:2964-2972, 1987). GALA behaves like the serum apolipoproteins in its interaction with dimyristoylphosphatidylcholine (DMPC) at neutral pH; the amino terminal tryptophan of GALA undergoes a blue shift in its fluorescence emission spectrum, and the circular dichroism (CD) spectrum indicates that GALA acquires alpha helical structure in the presence of DMPC. A DMPC-GALA:19/1 (molar ratio) complex can be isolated by gel-permeation chromatography. This complex has a discoidal structure with the approximate dimensions of 44-A edge thickness and a 170- to 350-A diameter. GALA activates LCAT with DMPC but not with unsaturated phospholipids as the substrate. The apparent partition coefficient of GALA into DMPC vesicles is 100-fold larger than into egg phosphatidylcholine vesicles. The interaction of GALA with unsaturated lipids at neutral pH is so weak that no detectable change in the spectroscopic properties of GALA or the structure of the liposomes can be detected under the conditions used here. The sequence of GALA differs from previously studied model Apo A1 peptides by the absence of positively charged residues on the hydrophilic face. This indicates that positive charges in Apo A1-like peptides are not required in order to form discoidal structures with saturated phospholipids or to activate LCAT with such lipid substrates.

OBJECTIVE

To determine the relationship of apolipoprotein B (Apo-B) and arterial stiffness determined by brachial-ankle pulse wave velocity (baPWV) in systemic lupus erythematosus (SLE) subjects.

METHODS

Eighty-seven Thai SLE subjects with inactive disease activity were studied. Fasting blood was collected for creatinine, glucose, lipid profiles, Apo-B and Apo-A1. Pearson correlation and stepwise-linear regression were used for the analysis.

RESULTS

The mean age of the subjects was 36.69 ± 10.85 years; 6.90% of them had stage 3 or more severe chronic kidney disease, 49.40% took anti-hypertensive drugs and 4.60% had abnormal glucose metabolism. The mean value for baPWV was 1332 ± 274.12 cm/s. Thirty-six percent of the subjects had increased arterial stiffness with mean Apo-B levels of 1.05 ± 0.31 g/L compared to 0.94 ± 0.24 in normal arterial stiffness. There were correlations of baPWV with age, systolic blood pressure (BP), diastolic BP and creatinine clearance. Apo-B tended to be associated with baPWV (P = 0.06) whereas low-density lipoprotein cholesterol did not (P = 0.2). By multiple regression analysis, systolic BP, age and Apo-B were the significant predictors of baPWV.

CONCLUSIONS

Apo-B was independently associated with arterial stiffness in SLE subjects.

OBJECTIVE

Overproduction of hepatic very low-density lipoprotein (VLDL) particles is a major abnormality of lipoprotein dysregulation in type 2 diabetes (T2D). We sought to examine the relationship between systemic/hepatic inflammation associated with insulin resistance and apolipoprotein (apo)B100-containing VLDL production.

RESULTS

At the age of 19 wks, Otsuka Long-Evans Tokushima Fatty (OLETF) rats showed systemic inflammation (plasma TNF-α and interleukin (IL)-6 levels increased), insulin resistance (plasma retinol binding protein 4 and soluble CD36 levels were higher), dyslipidemia and fatty liver (plasma and liver triglyceride and cholesterol levels were higher as well as total VLDL-, VLDL(1)-, VLDL(2)-apoB100 and VLDL-triglycerides were overproduced), compared with the control rats. In livers of OLETF rats, mRNA levels of tnf, il1b and il6 were increased, but an anti-inflammatory protein, zinc finger protein 36, and its mRNA expression were decreased. We also found that the liver mRNA, protein levels, and tyrosine phosphorylation (pY) of insulin receptor (InsR) substrate (IRS) 2, but not IRS1, were decreased in OLETF rats; pY of InsR and Akt protein and phospho-Akt (ser437) were also reduced; but protein tyrosine phosphatase-1B protein was overexpressed. The gene expressions of glucose transporters 1 and 2, and glycogen synthase were decreased, but phosphatase and tensin homolog deleted on chromosome ten and glycogen synthase kinase 3β mRNAs were overexpressed, compared with the controls. Sterol regulatory element binding protein-1c mRNA, ATP-binding cassette transporter A1 mRNA, microsomal triglyceride transfer protein mRNA/protein, and CD36 mRNA/protein levels were increased and lipoprotein lipase and Niemann-Pick c1-like1 mRNA levels were decreased, which are all involved in lipogenesis. Decreased sirtuins1-3 mRNA levels were also observed in OLETF rats.

CONCLUSIONS

These abnormal genes, proteins expression and phosphorylation of multiple pathways related to inflammatory, insulin signaling and lipogenesis may be important underlying factors in VLDL-apoB100 particles overproduction observed in T2D. Our data contribute to the further understanding of an association of dyslipoproteinemia with systemic metabolic disorders, fatty liver and dysregulated hepatic metabolic pathways.

BACKGROUND

The relationship between serum minerals and homocysteine, lipoprotein and glucose homeostasis markers at birth has been scarcely reported. This study aims to determine a) the relationship between calcium, magnesium, cardiovascular disease (CVD) markers (e.g. lipids, lipoproteins, homocysteine) and insulin sensitivity/ resistance markers (e.g. glucose, insulin, HOMA) in cord serum; and b) to find out the possible influence of reduced or increased levels of serum calcium and magnesium on those markers.

METHODS

Forty-eight eutocic, normoweight and appropriated-for-gestational age, full-term, singleton without foetal distress newborns from the Mérida Study were studied. Parameter percentiles for serum calcium and magnesium as well as for the Ca/Mg ratio were stated. CVD and insulin sensitivity/resistance markers in neonates within the first quartile for calcium, magnesium and their ratio were compared with those of neonates within the forth quartile for these minerals.

RESULTS

Serum calcium negative correlated with HDL-c (p<0.05), arylesterase (AE) (p<0.01), the Apo A1/Apo B (p<0.05) and AE/HDL-c (p<0.05) ratios. Also, negative and significant correlations were found between the Ca/Mg ratio and AE (p<0.01), and AE/HDL-c (p<0.05). Neonates within the highest quartile for Mg displayed significantly higher levels of LDL-c and homocysteine (p<0.05). Newborns within the Ca/Mg ratio first quartile presented higher activities of AE while those of with high Ca/Mg ratio showed low levels of insulin.

CONCLUSIONS

Calcium and magnesium levels appear related to CVD and insulin sensitivity/resistance markers at birth. Future follow-up studies, mostly in neonates, with high magnesemia and/or high Ca/Mg ratio at birth are recommended.

OBJECTIVE

African-American women (AAW) suffer disproportionately from higher rates of cardiovascular disease (CVD) mortality compared with white American women (WAW), despite favorable lipid and lipoprotein profile. Therefore, we used nuclear magnetic resonance (NMR) to examine lipoprotein particle concentrations and sizes in overweight/obese AAW and WAW with pre-diabetes.

METHODS

We studied 69 AAW and 41 WAW, with mean age 46.5±11.3 years and body mass index (BMI) 37.8±6.4 kg/m(2). All participants completed standard oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIVGTT). Insulin sensitivity (Si) was calculated using MINIMOD method. Body composition was assessed using dual-energy X-ray absorptiometry (DEXA). Fasting blood was obtained for traditional lipids/lipoproteins and NMR-derived lipoprotein particle sizes and concentrations.

RESULTS

We found that AAW with pre-diabetes were more obese (BMI 38.8±6.7 vs 36.0±5.4 kg/m(2), p=0.02) than WAW. Mean Si was not significantly different. However, the mean serum triglycerides were lower, whereas the high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A1 (Apo A1) were significantly higher in AAW versus WAW. The large HDL particle concentration (6.1±3.1 vs 4.6±3.1 µmol/L, p=0.02) was significantly higher in AAW versus WAW. Mean total very low-density lipoprotein (VLDL) particle concentration was lower in AAW versus WAW (39.9±24.4 vs 59.2±25.6 nmol/L, p≤0.001). While mean total LDL particle concentrations were not different, mean small LDL particle concentrations were lower in AAW versus WAW (538.8±294.1 vs 638.4±266 nmol/L, p=0.07).

CONCLUSIONS

We found a more favorable NMR-derived lipoprotein profile in AAW that extends the traditional antiatherogenic lipid/lipoprotein profiles. Clinically, these favorable lipid/lipoprotein profiles cannot explain the paradoxically higher CVD mortality in AAW than WAW and warrant further prospective outcome studies.

BACKGROUND

The long-term effect of recombinant human erythropoietin (rhEPO) on the blood-lipid profile has not been well documented. The aim of this study was to evaluate whether rhEPO therapy affects the lipid pattern.

METHODS

A group of 102 maintenance haemodialysis patients were treated for 2 years with rhEPO given intravenously at the end of the dialysis session. Attempts were made to keep the haemoglobin (Hb) at 10-11 g/dl and/or the haematocrit (Hct) at 30-35%. Twenty maintenance haemodialysis patients not treated with rhEPO were examined as controls. Total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, apolipoproteins A1 and B, and lipoprotein (a)[Lp (a)] were assessed at baseline (without rhEPO), and 1 and 2 years after the beginning of treatment. Hb, Hct and ferritin were measured monthly, and Kt/v was evaluated monthly and kept above 1.1.

RESULTS

During follow-up, in both groups, there was a significant increase in Apo A1 and no significant changes in the other lipid parameters. In the treated group, Hb and Hct increased significantly after the fourth month of treatment.

CONCLUSIONS

Erythropoietin therapy does not affect significantly the levels of total cholesterol, LDL- and HDL-cholesterol, triglycerides, Apo B and Lp (a) in maintenance hemodialysis patients.

BACKGROUND

Few studies have examined the changes in lipoproteins over time and how inflammation is associated with lipoprotein concentrations among patients with end-stage renal disease on dialysis. One possible explanation for the association of low LDL cholesterol concentration and adverse outcomes is that inflammation reduces selected apolipoprotein concentrations.

METHODS

Serum samples were collected from a subsample of patients enrolled into the Comprehensive Dialysis Study every 3 months for up to 1 year. We examined the relation between temporal patterns in levels of inflammatory markers and changes in apolipoproteins (apo) A1 and B and the apo B/A1 ratio using linear mixed effects modeling and adjusting for potential confounders.

RESULTS

We enrolled 266 participants from 56 dialysis facilities. The mean age was 62 years, 45% were women and 26% were black. Apo A1 was lower among patients with higher Quetelet's (body mass) index (BMI), diabetes mellitus and atherosclerosis. Apo B was lower among older patients, patients with higher serum creatinine and patients with lower BMI. Over the course of a year, apo A1 changed inversely with serum concentrations of the acute phase proteins C-reactive protein (CRP) and α1 acid glycoprotein (α1AG), while apo B did not. Changes in α1AG were more strongly associated with changes in apolipoprotein concentrations than were changes in CRP; increases in α1AG were associated with decreases in apo A1 and increases in the apo B/A1 ratio.

CONCLUSIONS

Changes in inflammatory markers were associated with changes in apo A1, but not apo B over 1 year, suggesting that reductions in high-density lipoprotein cholesterol are associated with inflammation, either of which could mediate cardiovascular risk, but not supporting a hypothesis linking increased risk of low levels of apo B containing lipoproteins to the risk associated with inflammation.

Indian studies on lipid profile abnormalities in chronic renal failure (CRF) have varied from no abnormalities at all to significant abnormality (hypertriglyceridemia and reduced HDL) as described in the Western literature. Moreover, there is no Indian study on the effect of renal transplantation on the abnormal lipid profile of CRF. The aim of our study was to determine the lipid profile of CRF patients on conservative treatment, end stage renal disease (ESRD) patients on maintenance hemodialysis (HD) treatment and renal transplant patients. We also looked at the effect of fish oil rich in polyunsaturated fatty acids (Max-EPA) on hypertriglyceridemia of CRF. The study included 4 groups; Gp I: control subjects (n = 9, age = 30 +/- 5 yrs), Gp II: CRF patients on conservative treatment (n = 9, age = 49 +/- 17 yrs), Gp III: ESRD patients on HD for at least 3 months (n = 19, age = 53 +/- 9 yrs), Gp IV: 3 months post-renal transplant patients (n = 9, age 31 +/- 11 yrs). The lipids and lipoproteins analysed include total cholesterol, HDL, LDL, triglycerides, Apo A1 and Apo B. It was observed that in Gp II patients triglycerides were significantly elevated (p < .05) and Apo A1/Apo B significantly abnormally lower (p < .001) compared to Gp I. In Gp IV patients, there was no significant difference in lipid profile compared to Gp I. With the use of Max-EPA in 5 patients with hypertriglyceridemia, there was a significant improvement in hypertriglyceridemia (p < .05). Our study suggests: 1) significant hypertriglyceridemia does develop in a majority of CRF patients. The abnormality probably improves with dialysis treatment and renal transplantation. 2) A lower Apo A1/Apo B ratio in CRF patients may account for higher risk of atherosclerosis. 3) Fish oil rich in polyunsaturated fatty acids improves hypertriglyceridemia of CRF.

Advanced Chronic Renal Disease (CKD) is closely associated with a pro-inflammatory condition, with an increase in triglyceride-rich lipoproteins and decrease in HDL level. HDL contains antioxidant enzymes such as paraoxonase (PON), whose activity is diminished in CKD. The aim of our study was to evaluate the relationship between PON activity with HDL cholesterol, apo A1 and hs-CRP levels, which are known to be inflammatory markers in hemodialyzed patients. Forty-two patients were studied; age, median (range) = 50 (25-67) years old, gender M/F = 22/20, duration of hemodialysis = 4.4 ± 0.5 years, BMI: 23 ± 0.5 kg/m2. After a 12 h fast, a blood sample was obtained and classic components of lipid profile were determined, as well as apoproteins A1 and B, PON by means of its arylsterase activity and hs-CRP levels. On the basis of the latter, patients were divided into two groups: hs-CRP ≤ 1 (low risk, range: 0.1 to 1.0 mg/l) and>> 1 mg/l (moderate and high risk, 1.1 to 10.7 mg/l). No difference was found in triglycerides, LDL cholesterol and apo B in the groups. Patients with hs-CRP>> 1 showed lower HDL cholesterol (40 ± 2 mg/dl) and apo A1 (118 ± 4 mg/dl) than patients with hs-CRP ≤ 1 (50 ± 4 and 133 ± 5, respectively); p < 0.05. PON was lower in hs-CRP>> 1 = 90.5 ± 24.0 µmol/ml.min than in hs-CRP ≤ 1 = 105.2 ± 18.0. Consequently, inverse correlations were obtained between apo A1 and hs-CRP, r = -0.381, p = 0.013 and between PON and hs-CRP, r = -0.32, p = 0.042. Furthermore, increase in hs-CRP correlated positively with BMI r = 0.318, p = 0.042. Since apo A1 has an anti-inflammatory role and PON an antioxidant activity, the decrease in HDL and its components, cholesterol, apo A1 and PON, in subjects with higher chronic inflammatory condition might explain, in part, the increased cardiovascular risk in these patients.

Peritoneal dialysis can worsen dislipemia, which is frequent in chronically uremic patients. In order to verify the therapeutic possibilities, we retrospectively studied 20 chronically uremic patients who had been previously treated with continuous ambulatory peritoneal dialysis (CAPD) and who had developed an IV-type dislipemia. Twelve have continued CAPD treatment and have been simultaneously treated with simvastatin; 8 have withdrawn from CAPD and have begun HD, without any antidislipemic pharmacological support. The results, after 3, 6, 12, and 18 months of treatment, showed the following: in patients treated with CAPD and simvastatin, highly significant decreases were noted in total cholesterol (T-cho) and triglycerides (TG) (p < 0.001), and highly significant increases were noted in HDL-cholesterol (HDL-cho) (p < 0.005) and apolipoprotein-A1 (Apo-A1) (p < 0.01). In patients treated with HD, only slightly significant decreases were noted in T-cho (p < 0.01) and TG (p < 0.02), a slightly significant increase in Apo-A1 (p < 0.05), and no significant change in HDL-cho. Apolipoprotein-B showed no change in the two groups. Therefore, patients undergoing CAPD, with dislipemia only, can continue the treatment, because simvastatin is capable of correcting dislipemia, while those patients who have displemia as well as other complications strictly due to CAPD must abandon treatment and must be transferred to extracorporeal methods.

BACKGROUND

We investigate the effects of omega-3 plus vitamin E and vitamin C plus zinc supplementations on cardiovascular risk markers in postmenopausal women with type 2 diabetes.

METHODS

In this double-blind placebo-controlled clinical trial, 75 postmenopausal women with type 2 diabetes were randomly assigned to one of three groups to take, daily, for 12 weeks: (1) 1.8 g omega-3 fatty acids plus 400 mg vitamin E; (2) 5 mg zinc plus 300 mg vitamin C; or (3) a placebo.

RESULTS

Although the cardiovascular risk markers variations decreased at the end of intervention, we did not find any significant differences in cardiovascular risk markers between therapeutic groups and the control group. Results of repeated measures analysis of variance (ANOVA) of markers showed that total cholesterol, low-density lipoprotein (LDL) cholesterol, Apo A1 and Apo B100 in two time periods were significant (p = 0.001). The level of total and LDL cholesterol decreased significantly (p = 0.05) in patients diagnosed with diabetes equal or less than 7 years in the group receiving omega-3 plus vitamin E. However, decreased LDL cholesterol (p = 0.003) and increased high-density lipoprotein (HDL) cholesterol (p = 0.03) were predominant in patients who had been diagnosed with diabetes equal or less than 7 years in the group receiving zinc plus vitamin C.

CONCLUSIONS

The effectiveness of nutraceutical supplementation was varied on biochemical biomarkers based on the kind of supplement or supplement pharmacogenomics, duration of diabetes affected and other pathophysiologic status in studied groups.

BACKGROUND

Studies have shown that patients with chronic renal failure have a high frequency of cardiovascular atheromatous disease.

METHODS

We examined serum lipoprotein (a) [Lp(a)], very-low density lipoprotein cholesterol (VLDL-C), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C), apolipoprotein A1 (apo A1) and B (apo B), triglyceride (TG) and total cholesterol (TC) levels as possible risk factors for atherosclerosis in 45 patients with chronic renal failure (CRF) treated by hemodialysis (HD) and in 15 CRF patients who were not on HD. A control group of 20 healthy subjects was also studied.

RESULTS

The proportion of smokers and body mass indexes were similar between the groups. In both patient groups, higher TG, TC and Lp(a) and lower apo A1 and HDL-C levels in serum were found than in those of controls. Serum apo B and LDL-C were similar in the patients treated by HD and the controls. Serum VLDL-C and LDL-C were similar in the CRF patients who were not on HD and the controls. The highest ratios of apo B/apo A1 and LDL-C/HDL-C were found in HD patients. The highest ratio of TC/HDL-C was found in the other patient group. We found significant correlations between Lp(a) and other parameters of lipoprotein metabolism in CRF patients, both those who were and those who were not on HD.

CONCLUSIONS

Our results indicate that CRF patients who both were and were not on HD show atherogenic changes in the lipoprotein pattern, and that the increase in Lp(a) during the CRF phase is basically related to the loss of renal function and may also depend on the resultant alterations which are produced in other lipoprotein variables.

BACKGROUND

Familial hypercholesterolemia (FH) is characterized by exposure to severely elevated LDL-cholesterol from birth, which produces lipid deposits, which can be measured by means of intima-media thickness (IMT).

METHODS

The IMT and concentrations of cholesterol and its fractions, triglycerides, alipoproteins Apo-A1, Apo-B and endothelial risk factors (homocysteine and high sensitivity protein C ) were determined in 89 patients (44 males) from 2 to 19 years (9.54+/-3.91 years). IMT was measured by ultrasound using a 12MHz linear array transducer in both carotids to 1cm of the bulb. The IMT mean was compared with age, sex and analytical parameters using multiple regression analysis.

RESULTS

The mean values were: IMT 0.334+/-0.088mm, total cholesterol 273.62+/-91.93mg/dl, LDL-cholesterol 204.21+/-86.16mg/dl, LDL/HDL 3.83+/-1.45, apoprotein A1 134.61+/-26.49mg/dl, apoprotein B 130.59+/-40.59mg/dl, homocysteine (median) 7.16mmol/dl, Protein C (median) 0.3mg/l. Using multiple regression analysis, only age was associated with IMT (P=0.049), a mean 0.005mm (95% CI: 0.000-0.010) being the annual increase: up to 12 years the increase in IMT was 0.002mm/year on (95% CI: -0.007-0,010) and then from that age it was 0.013mm/year (95% CI: -0.023-0.049).

CONCLUSIONS

The measurement of the carotid IMT could become an objective parameter in the evaluation of the FH in childhood. In our study, it is only associated with age, the increase being most marked from 12 years onwards.

Background: The saturated fatty acid stearic acid (C18:0) lowers HDL cholesterol compared with palmitic acid (C16:0). However, the ability of HDL particles to promote cholesterol efflux from macrophages (cholesterol efflux capacity; CEC) may better predict coronary heart disease (CHD) risk than HDL cholesterol concentrations.

Objective: We examined effects of exchanging dietary palmitic acid for stearic acid on ATP-binding cassette transporter A1 (ABCA1)-mediated CEC, and other conventional and emerging cardiometabolic risk makers.

Design: In a double-blind, randomized, crossover study with two 4-week isocaloric intervention periods, 34 healthy men and postmenopausal women (61.5 ± 5.7 years, BMI: 25.4 ± 2.5 kg/m²) followed diets rich in palmitic acids or stearic acids. Difference in intakes was 6% of daily energy. ABCA1-mediated CEC was measured from J774 macrophages to apolipoprotein (apo)B-depleted serum.

Results: Compared with the palmitic-acid diet, the stearic-acid diet lowered serum LDL cholesterol (-0.14 mmol/L; p = 0.010), HDL cholesterol (-0.09 mmol/L; p=<0.001), and apoA1 (-0.05 g/L; p < 0.001). ABCA1-mediated CEC did not differ between diets (p = 0.280). Cholesteryl ester transfer protein (CETP) mass was higher on stearic acid (0.11 mg/L; p = 0.003), but CETP activity was comparable. ApoB100 did not differ, but triacylglycerol concentrations tended to be higher on stearic acid (p = 0.100). Glucose concentrations were comparable. Effects on insulin and C-peptide were sex-dependent. In women, the stearic-acid diet increased insulin concentrations (1.57 μU/mL; p = 0.002), while in men, C-peptide concentrations were lower (-0.15 ng/mL; p = 0.037). Interleukin 6 (0.15 pg/mL; p = 0.039) and tumor necrosis factor alpha (0.18 pg/mL; p = 0.005), but not high-sensitivity C-reactive protein, were higher on stearic acid. Soluble intracellular adhesion molecule (9 ng/mL; p = 0.033), but not soluble vascular cell adhesion molecule and endothelial-selectin concentrations decreased after stearic-acid consumption.

Conclusions: As expected, stearic-acid intake lowered LDL cholesterol, HDL cholesterol, and apoA1. Insulin sensitivity in women and low-grade inflammation might be unfavorably affected by stearic-acid intake. However, palmitic-acid and stearic-acid intakes did not differently affect ABCA1-mediated CEC.

Clinical trial registry: This trial was registered at clinicaltrials.gov as NCT02835651.

Keywords: Cardiometabolic risk markers; Cholesterol efflux capacity; Human intervention study; Palmitic acid; Stearic acid.

BACKGROUND

Hypothyroidism is one of the most common metabolic disorders associated with dyslipidemia which poses a higher risk of Coronary Artery Disease (CAD) in such patients. Biochemical markers which can pick up the risk promptly are becoming imperative now-a-days and thus the assessment beyond the conventional lipid profile is the need of the hour.

OBJECTIVE

To assess the association of non-conventional lipid parameters like small dense Low Density Lipoprotein (sd LDL), oxidized Low Density Lipoprotein (ox LDL), Apolipoprotein A (Apo A1), Apolipoprotein B (Apo B) and Lipoprotein (a) {Lp(a)} in hypothyroid patients and compare their values with the conventional lipid parameters such as Total Cholesterol (TC), Triglyceride (TG), Low-Density Lipoprotein Cholesterol (LDL-C) and High-Density Lipoprotein Cholesterol (HDL-C).

METHODS

One hundred and thirty clinically proven patients of hypothyroidism aged 20-60 years and equal number of age and gender matched healthy individuals were included in this case control study. Serum sd LDL, ox LDL, Apo A1, Apo B, Lp (a), lipid profile, Thyroid Stimulating Hormone (TSH), Free Triiodothyronine (FT3) and Free Tetraiodothyronine (FT4) levels were measured in both the groups. The data was recorded and analysed on SPSS system. The results of cases and controls were compared by student t-test and one-way ANOVA. All the parameters were correlated with TSH by Pearson's correlation.

RESULTS

We found significantly high levels of sd LDL, ox LDL, Apo B, Lp (a), TC, TG, LDL-C in cases as compared to the controls. Ox LDL has shown maximum correlation with serum TSH (p<0.0001, r=0.801) followed by sd LDL (p<0.0001, r=0.792), Apo B (p<0.001, r=0.783) and LDL-C (p<0.001, r=0.741). Moreover, ox LDL and sd LDL were found to be increased in normolipidemic hypothyroid patients thereby giving a strong supportive evidence that estimation of these parameters can become fundamental in prompt identification of the high risk patients of CAD in hypothyroid population.

CONCLUSIONS

Non-conventional lipid parameters appear to be better markers for the assessment of cardiovascular risk in hypothyroidism and might help in the designing of the effective treatment protocols and areas of intervention by the clinicians as well as researchers.

The ability of peculiar iron oxide nanoparticles (IONPs) to evade the immune system was investigated in vivo. The nanomaterial was provided directly into the farming water of zebrafish ( Danio rerio) and the distribution of IONPs and the delivery of oxytetracycline (OTC) was studied evidencing the successful overcoming of the intestinal barrier and the specific and prolonged (28 days) organotropic delivery of OTC to the fish ovary. Noteworthy, no sign of adverse effects was observed. In fish blood, IONPs were able to specifically bind apolipoprotein A1 (Apo A1) and molecular modeling showed the structural analogy between the IONP@Apo A1 nanoconjugate and high-density lipoprotein (HDL). Thus, the preservation of the biological identity of the protein suggests a plausible explanation of the observed overcoming of the intestinal barrier, of the great biocompatibity of the nanomaterial, and of the prolonged drug delivery (benefiting of the lipoprotein transport route). The present study promises novel and unexpected stealth materials in nanomedicine.

Autopsy studies reveal that atherosclerosis lesions can be found as early as two years of age. To slow the development of this early pathology, obesity and dyslipidemia prevention should start from childhood making it urgent to explore new ways to evaluate dyslipidemia risk in children that can be applied widely, such as the non-invasive anthropometric evaluation.

Assess the metabolic profile of a pediatric population at a specific age to describe the association between anthropometric and biochemical cardiovascular disease risk factors; and evaluate selected anthropometric variables as potential predictors for dyslipidemic cardiovascular risk.

Anthropometric features, bioimpedance parameters and fasting clinical profile were assessed in Lisbon and the Tagus Valley region pre-pubertal nine-year-old children (n = 1.496) from 2009-2013 in a descriptive, cross-sectional study. Anthropometric variables predictive power was evaluated through regression analysis.

At least one abnormal lipid parameter was found in 65% of "normal weight", 73% of "overweight" and 81% of "obese" children according to the International Obesity Task Force (IOTF) standards. Dyslipidemia was present in 67.8% of children. Waist-hip ratio (WHR) explained 0.4% of total cholesterol (TC) variance. Waist circumference (WC) explained 2.8% of apolipoprotein (APO) A1 variance. Waist-circumference-to-height-ratio (WHtR) explained 2.7%, 2.8% and 1.9% of low-density lipoprotein cholesterol (LDL-c), APO B, and N_HDL-c variance, respectively. Children with abnormally high WHR levels had an increase in risk of 4.49, 3.40 and 5.30 times, respectively, for developing cardiovascular disease risk factors measured as high-risk levels of TC, LDL-c and non-HDL-c (N_HDL-c) (p<0.05). Only 29.9% of "normal weight" children had no anthropometric, bioimpedance or biochemical parameters associated with CV risk.

A large proportion of school age children have at least one lipid profile abnormality. BMI, zBMI, calf circumference (CC), hip circumference (HC), WC, and WHR are directly associated with dyslipidemia, whereas HC and calf circumference (CC) adjusted to WC, and mid-upper arm circumference (MUAC), are all inversely associated with dyslipidemia. Selected anthropometric variables are likely to help predict increased odds of having CV risk factors.

In the biogenesis of HDL by exogenous apolipoprotein (apo) A-I in rat astrocytes, apoA-I induced translocation of phospholipase Cgamma (PLCgamma) and PKCalpha to cytosolic lipid protein particle (CLPP) [Ito et al., 2004. J. Lipid Res. 45, 2269] and caused tyrosine-phosphorylation of PLCgamma in CLPP in the initial 5 min. It also induced translocation of caveolin-1 and newly synthesized cholesterol and phospholipid to CLPP, and increased cholesterol biosynthesis prior to the HDL biogenesis [Ito et al., 2002a. J. Biol. Chem. 277, 7929]. Cyclosporin A (CsA), an indirect inhibitor of protein phosphatase 2B (PP2B) and a potential inhibitor of ABC transporter A1 (ABCA1), suppressed all of these apoA-I-induced cellular events. CsA, however, did not affect the basal lipid release by the production of HDL with endogenous apoE, except for moderate decrease of its cholesterol content. Direct inhibitors of PP2B, inhibited only the release of lipids by apoA-I and had no effect on other apoA-I-induced events. CsA thus interferes with cellular cholesterol homeostasis independently of PP2B inhibition, perhaps by direct inhibition of ABCA1 reactivity to exogenous apoA-I, although PP2B may be involved in the lipid release step. CsA could therefore cause some neurological side effects by interfering with cellular cholesterol homeostasis in the brain.

Disturbances in cholesterol homeostasis of the bile duct epithelium, including transport interruption and the hyperaccumulation of intracellular cholesterol can lead to the initiation and progression of cholangiocarcinoma (CCA). Statins, which are lipid-lowering drugs, have been previously documented to exhibit anti-cancer properties. The role of statins in CCA cell cholesterol transport through the expression and function of ATP-binding cassette (ABC) A1 and ABCG1 was investigated in the current study. In four CCA cell lines, ABCA1 and ABCG1 expression was identified. However, neither ABCG5 nor ABCG8 expression was observed. Immunocytochemistry revealed that the expression of ABCA1 was localized in the proximity of the nucleus, while ABCG1 was more dispersed throughout the cytoplasm of KKU-100 cells. A cholesterol efflux assay was performed using bodipy cholesterol, and the translocation of cholesterol via ABCA1 and ABCG1 to Apo-A1 and high density lipoprotein was confirmed, respectively. Simvastatin and atorvastatin demonstrated the inhibitory effects on CCA cell viability. A reduction in intracellular lipid level and a lower expression of ABCA1 and ABCG1 were observed in KKU-100 cells under simvastatin treatment. The pre-exposure of KKU-100 cells to cholesterol diminished the statin effect. Furthermore, when KKU-100 cells were pre-loaded with cholesterol, ABCA1 and ABCG1-mediated exports were unaffected even though they were treated with simvastatin. The results of the current study indicated the limitations of the use of statin in CCA therapy, particularly under hypercholesterolemia conditions.

Hawthorn ingestion is linked to health benefits due to the various polyphenols. The present study investigated the differential effects of polyphenols-enriched extracts from hawthorn fruit peels (HPP) and fleshes (HFP) against liver injury induced by high-fructose diet in mice. It was found that the main species of polyphenols in hawthorn was chlorogenic acid, epicatechin, rutin and hyperoside, and their contents in HPP were all higher than those in HFP. Administration of HPP was better than HFP to alleviate liver injury and hepatocyte apoptosis, reflected by the reduction of ALT, AST and ALP activities, as well as the ratio of Bax/Bcl-2 in mice. Meanwhile, HPP was also more effective than HFP to mitigate liver inflammation and oxidative stress by inhibiting inflammatory cytokine (TNF-α, IL-1 and IL-6) release, and elevating antioxidant enzyme activities and PPARα expression, while reducing Nrf-2 and ARE expression in mice. Interestingly, HPP-treated mice also showed the lower levels of TC, TG, LDL-C, VLDL-C and Apo-B, and the higher levels of HDL-C and Apo-A1 than HFP-treated mice via reducing FAS express. These results together with the histopathology of the liver with H&E and oil red O staining suggest that hawthorn fruit, especially its peel, is an excellent source of natural polyphenolic chemopreventive agents in the treatment of liver disorders.

BACKGROUND

We tested the hypothesis that high-density lipoprotein (HDL) is associated with intracranial aneurysm growth and rupture.

METHODS

We used an observational cohort study design. Age, sex, admission systolic blood pressure (SBP), diabetes, hypertension, coronary artery disease, aneurysmal rupture, apolipoprotein (APO)-A1, APO-B, HDL, low-density lipoprotein, triglycerides, cholesterol, and aneurysm location and size were recorded. Aneurysms <8 mm were categorized as small.

RESULTS

The data from 581 patients with intracranial aneurysms were analyzed. The predictive factors for small size of aneurysms were female sex (odds ratio [OR], 0.630; 95% confidence interval [CI], 0.428-0.927; P = 0.019) and higher HDL (OR, 0.327; 95% CI, 0.159-0.672; P = 0.0002). In the subgroup of male patients, lower HDL was the only risk factor for large size (P = 0.015). The predictors of aneurysmal rupture were small size (OR, 0.875; 95% CI, 0.842-0.910; P = 0.000), higher HDL (OR, 3.716; 95% CI, 1.623-8.509; P = 0.002), no coronary artery disease (OR, 4.736; 95% CI, 1.528-14.681; P = 0.007), lower APO-A1 (OR, 0.202; 95% CI, 0.064-0.641; P = 0.007), and higher admission SBP (OR, 1.024; 95% CI, 1.015-1.032; P = 0.000). An HDL/aneurysm size ratio >0.31 was associated with a 46.2-fold increased likelihood of aneurysmal rupture (OR, 46.214; 95% CI, 13.386-159.548; P = 0.002).

CONCLUSIONS

The HDL level was inversely associated with intracranial aneurysm growth, especially in men. Higher HDL levels and small aneurysm size contributed to a greater risk of aneurysmal rupture. An HDL/size ratio >0.31 was a valuable predictor of intracranial rupture.