Polycystic ovary syndrome (PCOS) is a common endocrine disorder characterized by obesity-related risk factors for cardiovascular disease. The objective of our study was to determine values of key lipid and lipoprotein fractions in PCOS, and their possible relation to insulin resistance. A total of 75 women with PCOS (aged 23.1 +/- 5.1 years, BMI 24.9 +/- 4.7 kg/m(2)), and 56 age- and BMI-matched controls were investigated. In all subjects, basal glucose, cholesterol (total, HDL, and LDL), oxidized LDL (OxLDL), triglycerides, apolipoprotein (apo)A1, apoB, and apoE, nonesterified fatty acids, insulin, testosterone, sex hormone-binding globulin, homeostasis model assessment (HOMA) index, and free androgen index were determined in the follicular phase of the cycle. PCOS patients compared with controls had increased indices of insulin resistance, basal insulin (p < 0.001), and HOMA index (p < 0.001), and worsened insulin resistance-related dyslipidemia with decreased HDL cholesterol (p < 0.01), elevated triglycerides (p = 0.010), and pronounced LDL oxidation (p < 0.001). In conclusion, characteristic dyslipidemia of insulin resistance and unfavorable proatherogenic lipoprotein ratios were present only in women with PCOS and not in controls. Elevated OxLDL and the relation of apoE and nonesterified fatty acids with insulin resistance suggest that women with PCOS are at increased risk for premature atherosclerosis.

BACKGROUND

This study evaluated the lipid abnormalities associated with different stages of albuminuria in type 2 diabetic patients.

RESULTS

A total of 549 patients (245 men and 304 women) with mean age of 63.4 were studied. Normoalbuminuria (n=251), microalbuminuria (n=242) and macroalbuminuria (n=56) were defined as albumin-to-creatinine ratio of < 30, 30-299 and>> or = 300 microg/mg, respectively. Lipid parameters included total cholesterol, triglyceride (TG), high- and low-density lipoprotein (LDL) cholesterol, apolipoproteins A1 and B (ApoB), and lipoprotein(a) [Lp(a)]. Results showed that ApoB differed significantly (p<0.05) between normoalbuminuria and microalbuminuria/macroalbuminuria and Ln[Lp(a)] differed between normoalbuminuria/microalbuminuria and macroalbuminuria. Ln(TG) increased progressively with increasing albuminuria. In multivariate logistic regression analyses, only ApoB showed significant odds ratio (95% confidence interval) for microalbuminuria: 1.013 (1.004-1.022); and both ln(TG) and ln[Lp(a)] were significant for macroalbuminuria [respective odds ratios: 1.995 (1.010-3.938) and 1.708 (1.200-2.430)].

CONCLUSIONS

A differential dyslipidemia is observed for microalbuminuria and macroalbuminuria. Apo(B) and Lp(a) increase at the stages of microalbuminuria and macroalbuminuria, respectively. However, TG increases significantly throughout the three stages of albuminuria.

To determine the acute effect of neurological lesion on body composition, plasma leptin level, and the lipid profile, 7 male patients with acute and complete spinal cord injury (SCI) and 9 able-bodied (AB) males were investigated. At 16, 24, 36, and 48 weeks after injury, plasma leptin level and the lipid profile were analyzed, while whole body (WB) and regional fat mass (FM) and fat-free soft tissue (FFST) were measured by dual-energy x-ray absorptiometry (DXA). At all stages, despite no difference being found between both groups for body mass index (BMI), SCI patients had higher FM at WB (P < .01), lower (P < .01), and upper limbs (P < .05), while FFST was lower at WB (P < .05) and lower limbs (P < .01). The leptin level increased gradually from week 24 and was higher at weeks 16, 36, and 48 in SCI patients than in AB patients (7.0 +/- 3.9; 9.7 +/- 5.1; 10.6 +/- 5.3, respectively, v 3.5 +/- 2.5 ng. mL(-1)). SCI patients had lower high-density lipoprotein-cholesterol (HDL-C) (P < .05) and apolipoprotein (apo) A1 (P < .01), while no difference was found for total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), or ApoB levels. At all stages, leptin was strongly and positively correlated with WB and regional FM % (r>> 0.75; P < .05) and with TC, LDL-C, and ApoB levels (r>> 0.65; P < .05). Leptin was negatively correlated with FFST and the ApoA1/ApoB ratio (r>> -0.75; P < .05). In conclusion, neurological lesion induced an early and acute alteration in body composition and lipid profile. The strong relationship between serum leptin and FM suggests that this hormone can be used as a surrogate marker of FM in acute SCI patients and thus would serve as a good indicator for cardiovascular disease risk.

Apolipoprotein (apo) A1 plays a central role in the metabolism of HDL. We describe a novel genetic variant of the apoA1 gene identified in a patient with low concentrations of plasma HDL cholesterol. The proband, a 12-year-old Japanese boy, exhibited markedly low levels of both plasma apoA1 and HDL cholesterol. Genomic DNA sequencing of apoA1 genes of the patient showed a compound heterozygosity for an A to C substitution at 27 bp upstream of the transcription start site of 1 apoA1 allele, and a C to T substitution in another allele at residue 84 resulting in aberrant termination. The point mutation at nucleotide position -27 changed ATAAATA of the putative TATA box signal sequence to ATACATA. In addition to this mutation, the patient was heterozygous for a G to A substitution at position -75. Immunoblotting of an isoelectric focusing electrophoresis gel of the proband's plasma showed a trace amount of normal apoA1. No measurable plasma apoA1 and HDL cholesterol in a patient with homozygosity for nonsense mutation at residue 84 has been reported previously. To determine the effects of substitution either at position -27 or -75, plasmids containing the 5'-flanking region of the human apoA1 promoter fused to the CAT reporter gene were constructed and transfected in HepG2 cells. A construct with the A to C substitution at position -27 showed 41. 8+/-4.2%, and G to A substitution at position -75 showed 72.8+/-15. 2% (means+/-SD, n=3) of CAT activities, compared with the wild-type promoter sequence. A construct with the double substitutions at positions -27 and -75 showed only 22.8+/-1.3% (mean+/-SD, n=3) activity relative to the wild type. Our patient is the first case with a TATA box mutation etiologically related to lipoprotein disorders.

OBJECTIVE

To investigate involvement of specific apolipoproteins in the process of human oocyte maturation and age-related infertility as molecular constituents of follicular fluid.

METHODS

Laboratory-based observational study.

METHODS

Basic science laboratory at a large academic institution.

METHODS

Follicular fluid obtained from healthy women aged 18 to 45 years undergoing in vitro fertilization for unexplained infertility, ovulatory dysfunction, tubal disease, male factor infertility, or oocyte donation.

METHODS

None.

METHODS

Specific concentration of apolipoproteins and content of lipoprotein particles in follicular fluid and blood plasma as related to reproductive aging.

RESULTS

We registered a decline of follicular apolipoprotein A1 (Apo A1) and apolipoprotein CII (Apo CII) and an increase of the apolipoprotein E (Apo E) with age, which parallels a lower number of retrieved mature oocytes in older women. Follicular apolipoprotein A1, apolipoprotein B (Apo B), apolipoprotein E, and apolipoprotein C II are present in diverse heterogeneous complexes including very-low-density lipoproteins (VLDL), intermediate-low-density lipoproteins (IDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL) that vary with patient age and differ from the blood plasma lipoprotein complexes.

CONCLUSIONS

Age-related variation in follicular apolipoprotein content and distribution in the cholesterol particles may be associated with the decrease in production of mature oocytes and the age-related decline in fertility potential.

BACKGROUND

As many patients with rheumatoid arthritis (RA) have increased fat mass (FM) and increased frequency of cardiovascular diseases we evaluated if total physical activity (MET-hours) had impact on body composition and cardiovascular risk factors in women with RA.

METHODS

Sixty-one out-ward RA women, 60.8 (57.3-64.4) years, answered a self-administered questionnaire, to estimate total daily physical activity during the previous year. Physical activity level was given as metabolic equivalents (MET) × h/day. Diet content was assessed by a food frequency questionnaire and body composition by whole-body dual-energy X-ray absorptiometry. Blood lipids and antibodies against phosphorylcholine (anti-PC) were determined.

RESULTS

Forty-one percent of the women had BMI>> 25, 6% were centrally obese and 80% had FM%>> 30%. The median (IQR) total physical activity was 40.0 (37.4-47.7), i.e. the same activity level as healthy Swedish women in the same age. Total physical activity did not significantly correlate with disease activity, BMI or FM%. Disease activity, BMI and FM% did not differ between those in the lowest quartile of total physical activity and those in the highest quartile. However, the women in the lowest quartile of physical activity had lower HDL (p = 0.05), Apo A1 (p = 0.005) and atheroprotective natural anti-PC (p = 0.016) and higher levels of insulin (p = 0.05) and higher frequency of insulin resistance than those in the highest quartile. Women in the lowest quartile consumed larger quantities of saturated fatty acids than those in the highest quartile (p = 0.042), which was associated with high oxidized low-density lipoprotein (oxLDL).

CONCLUSIONS

This cross sectional study demonstrated that RA women with fairly low disease activity, good functional capacity, high FM and high frequency of central obesity had the same total physical activity level as healthy Swedish women in the same age. The amount of total physical activity was not associated with functional capacity or body composition. However, low total physical activity was associated with dyslipidemia, insulin resistance, low levels of atheroprotective anti-PC and consumption of saturated fatty acids, which is of interest in the context of increased frequency of cardiovascular disease in RA.

The first generation peroxisome proliferator-activated receptor (PPAR) alpha agonist gemfibrozil reduces the risk of major cardiovascular events; therefore, more potent PPARalpha agonists for the treatment of cardiovascular diseases have been actively sought. We describe two novel, potent oxybenzylglycine PPARalpha-selective agonists, BMS-687453 [N-[[3-[[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]methoxy]phenyl]methyl]-N-(methoxycarbonyl)-glycine] and BMS-711939 N-[[5-[[2-(4-chlorophenyl)-5-methyl-4-oxazolyl]methoxy]-2-fluorophenyl]methyl]-N-(methoxycarbonyl)-glycine], that robustly increase apolipoprotein (Apo) A1 and high-density lipoprotein cholesterol in human ApoA1 transgenic mice and lower low-density lipoprotein-cholesterol and triglycerides in fat-fed hamsters. These compounds have much lower potency against mouse PPARalpha than human PPARalpha; therefore, they were tested in PPARalpha-humanized mice that do not express murine PPARalpha but express human PPARalpha selectively in the liver. We developed hepatic gene induction as a novel biomarker for efficacy and demonstrate hepatic gene induction at very low doses of these compounds. BMS-711939 induces fecal cholesterol excretion, which is further increased upon cotreatment with a liver X receptor (LXR) agonist. It is surprising that this synergistic increase upon coadministration is also observed in mice that express PPARalpha in the liver only. BMS-711939 also prevented the LXR agonist-induced elevation of serum triglycerides. Such PPARalpha agonists could be attractive candidates to explore for the treatment of cardiovascular diseases, especially in combination with a suitable LXR agonist.

The chaperone heat shock protein 90 (hsp90) associates with signaling proteins in cells including soluble guanylate cyclase (sGC). hsp90 associates with the heme-free (apo) sGC-β1 subunit and helps to drive heme insertion during maturation of sGC to its NO-responsive active form. Here, we found that NO caused apo-sGC-β1 to rapidly and transiently dissociate from hsp90 and associate with sGC-α1 in cells. This NO response (i) required that hsp90 be active and that cellular heme be available and be capable of inserting into apo-sGC-β1; (ii) was associated with an increase in sGC-β1 heme content; (iii) could be mimicked by the heme-independent sGC activator BAY 60-2770; and (iv) was followed by desensitization of sGC toward NO, sGC-α1 disassociation, and reassociation with hsp90. Thus, NO promoted a rapid, transient, and hsp90-dependent heme insertion into the apo-sGC-β1 subpopulation in cells, which enabled it to combine with the sGC-α1 subunit to form the mature enzyme. The driving mechanism likely involves conformational changes near the heme site in sGC-β1 that can be mimicked by the pharmacologic sGC activator. Such dynamic interplay between hsp90, apo-sGC-β1, and sGC-α1 in response to NO is unprecedented and represent new steps by which cells can modulate the heme content and activity of sGC for signaling cascades.

The aim of the present study was to establish mitochondrial cholesterol trafficking 18 kDa translocator protein (TSPO) as a potential therapeutic target, capable of increasing macrophage cholesterol efflux to (apo)lipoprotein acceptors. Expression and activity of TSPO in human (THP-1) macrophages were manipulated genetically and by the use of selective TSPO ligands. Cellular responses were analysed by quantitative PCR (Q-PCR), immunoblotting and radiolabelling, including [3H]cholesterol efflux to (apo)lipoprotein A-I (apoA-I), high-density lipoprotein (HDL) and human serum. Induction of macrophage cholesterol deposition by acetylated low-density lipoprotein (AcLDL) increased expression of TSPO mRNA and protein, reflecting findings in human carotid atherosclerosis. Transient overexpression of TSPO enhanced efflux (E%) of [3H]cholesterol to apoA-I, HDL and human serum compared with empty vector (EV) controls, whereas gene knockdown of TSPO achieved the converse. Ligation of TSPO (using PK11195, FGIN-1-27 and flunitrazepam) triggered increases in [3H]cholesterol efflux, an effect that was amplified in TSPO-overexpressing macrophages. Overexpression of TSPO induced the expression of genes [PPARA (peroxisome-proliferator-activated receptor α), NR1H3 (nuclear receptor 1H3/liver X receptor α), ABCA1 (ATP-binding cassette A1), ABCG4 (ATP-binding cassette G4) and APOE (apolipoprotein E)] and proteins (ABCA1 and PPARα) involved in cholesterol efflux, reduced macrophage neutral lipid mass and lipogenesis and limited cholesterol esterification following exposure to AcLDL. Thus, targeting TSPO reduces macrophage lipid content and prevents macrophage foam cell formation, via enhanced cholesterol efflux to (apo)lipoprotein acceptors.

To examine how prevalence of the small dense LDL phenotype (LDL particle diameter < or =25.5 nm) is associated with coronary artery disease (CAD) in type 2 diabetic and non-diabetic Japanese men, an ethnic group with a low incidence of CAD, 85 non-diabetic men and 45 type 2 diabetic men with angiographically documented CAD, and 142 control men and 76 type 2 diabetic men without CAD were studied. Mean LDL particle diameter was determined using 2-16% polyacrylamide gel electrophoresis. LDL particle diameters in CAD patients were much smaller than those in controls (25.2+/-0.7 vs. 26.0+/-0.4 nm, mean+/-S.D., P<0.0001). LDL size was smaller in diabetic subjects (25.6+/-0.6 nm) and became even smaller in diabetics with CAD (25.0+/-1.0 nm). Prevalence of small dense LDL was markedly higher in both non-diabetic and diabetic CAD patients than that in non-diabetic and diabetic patients without CAD (71, 76, 23 and 42%, respectively). CAD patients had lower HDL-cholesterol and apo A1 levels, and higher triglyceride levels than those in diabetic and non-diabetic CAD-free patients, while total- and LDL-cholesterol levels were even lower in CAD group, and remnant-like particle-cholesterol, lipoprotein (a) and insulin levels were comparable among four groups. LDL size was significantly associated with triglyceride, HDL-cholesterol and glycemic control. Logistic regression analysis revealed that the small dense LDL phenotype was significantly associated with the incidence of CAD independent of low levels of HDL-cholesterol or high levels of triglyceride in both non-diabetic and diabetic cases. These results suggest that high prevalence of small dense LDL is a leading cause of CAD in both diabetic and non-diabetic Japanese men. Type 2 diabetes shows a greater capacity to reduce LDL size, which may contribute to the high incidence of CAD in the diabetic population.

Moderate alcohol consumption has various effects on immune and inflammatory processes, which could accumulatively modulate chronic disease risk. So far, no comprehensive, integrative profiling has been performed to investigate the effects of longer-term alcohol consumption. Therefore, we studied the effects of alcohol consumption on gene expression patterns using large-scale profiling of whole-genome transcriptomics in blood cells and on a number of proteins in blood. In a randomised, open-label, cross-over trial, twenty-four young, normal-weight men consumed 100 ml vodka (30 g alcohol) with 200 ml orange juice or only orange juice daily during dinner for 4 weeks. After each period, blood was sampled for measuring gene expression and selected proteins. Pathway analysis of 345 down-regulated and 455 up-regulated genes revealed effects of alcohol consumption on various signalling responses, immune processes and lipid metabolism. Among the signalling processes, the most prominently changed was glucocorticoid receptor signalling. A network on immune response showed a down-regulated NF-κB gene expression together with increased plasma adiponectin and decreased pro-inflammatory IL-1 receptor antagonist and IL-18, and acute-phase proteins ferritin and α1-antitrypsin concentrations (all P < 0.05) after alcohol consumption. Furthermore, a network of gene expression changes related to lipid metabolism was observed, with a central role for PPARα which was supported by increased HDL-cholesterol and several apo concentrations (all P < 0.05) after alcohol consumption. In conclusion, an integrated approach of profiling both genes and proteins in blood showed that 4 weeks of moderate alcohol consumption altered immune responses and lipid metabolism.

BACKGROUND

The association of ATP-binding cassette (ABC) transporter single nucleotide polymorphisms (SNPs) and serum lipid profiles is inconsistent. The present study was undertaken to detect the association of ABCG5/G8 SNPs and several environmental factors with serum lipid levels.

RESULTS

Genotyping of the ABCG5 (rs4131229 and rs6720173) and ABCG8 (rs3806471 and rs4148211) SNPs was performed in 719 unrelated subjects of Mulao nationality and 782 participants of Han nationality. There were no differences in the genotypic and allelic frequencies of four SNPs between the two ethnic groups besides the genotypic frequencies of rs4131229 SNP in Han. The levels of triglyceride (TG), apolipoprotein (Apo) A1, and ApoA1/ApoB ratio (rs4131229); low-density lipoprotein cholesterol (LDL-C) and ApoB (rs6720173); high-density lipoprotein cholesterol (HDL-C), ApoA1, ApoB, and ApoA1/ApoB ratio (rs3806471); and HDL-C, ApoA1, and ApoA1/ApoB ratio (rs4148211) in Han were different among their genotypes (P<0.05-0.001). The levels of LDL-C (rs6720173) and ApoA1 (rs3806471) in Mulao were also different among their genotypes (P<0.05 for each). The levels of TC, TG, HDL-C, ApoA1, and ApoA1/ApoB ratio (rs4131229); LDL-C and ApoB (rs6720173); HDL-C, ApoA1, and ApoA1/ApoB ratio (rs3806471); and TG, HDL-C, ApoA1, and ApoA1/ApoB ratio (rs4148211) in Han males; and ApoA1/ApoB ratio (rs4131229); LDL-C, ApoB, and ApoA1/ApoB ratio (rs3806471); HDL-C, ApoA1, and ApoA1/ApoB ratio (rs4148211) in Han females were different between the genotypes (P<0.05-0.001). The levels of LDL-C in Mulao females were also different between GG and GC/CC genotypes of rs6720173 (P<0.05). The correlation between serum lipid parameters and genotypes of four SNPs was observed in Han, especially in Han males. Serum lipid parameters were also correlated with several environmental factors.

CONCLUSIONS

The associations of four ABCG5/G8 SNPs and serum lipid levels are different between the Mulao and Han populations, or between males and females, suggesting that there may be a racial/ethnic- and/or sex-specific association between ABCG5/G8 SNPs and some serum lipid parameters.

The sera from 62 of 68 patients with coronary heart disease (CHD) caused a two to five fold elevation in the intracellular cholesterol in primary cultures of subendothelial cells derived from grossly normal intima of human aorta. The sera from 33 of 42 healthy subjects did not show atherogenic properties in culture. Atherogenic potential correlated directly with the serum apolipoprotein-B-apolipoprotein A1 ratio, but not with the level of total cholesterol, high-density-lipoprotein cholesterol, apo-B, or apo-A1. The sera from patients with CHD also facilitated deposition of lipids in the medial smooth muscle cells of human aorta and mononuclear blood cells, though to a lesser degree. They had no such effect on endothelial cells of human aorta and umbilical vein, or human embryo fibroblasts.

Blood serum of most patients with coronary heart disease (CHD) caused a 2- to 5-fold increase in the lipid content of smooth muscle cells cultured from unaffected human aortic intima, i.e., possessed an atherogenic potential manifested in culture. Treatment of the CHD patients' serum with 2.5% polyethylene glycol 6000 removed the circulating immune complexes. The serum subjected to this treatment lost its atherogenic properties, i.e., failed to increase the content of lipids in cultured cells. Incubation of smooth muscle cells derived from human aortic intima with circulating immune complexes isolated from an atherogenic patient's serum caused a 1.5- to 3-fold rise in the intracellular cholesterol. Circulating immune complexes contained apolipoprotein B (apo B), but not apolipoproteins A1 and E. The apo B content strongly correlated with the total cholesterol content. The cholesterol/apo B ratio of the complexes was characteristic of low density lipoproteins (LDL), but not of very low density lipoproteins or intermediate density lipoproteins. The composition of the main lipid classes in these complexes was similar to that in LDL. Blood sera of most (90%) CHD patients was characterized by a high cholesterol and apolipoprotein B content in circulating immune complexes. The ability of these sera to induce lipid accumulation in cultured cells directly correlated with the cholesterol and apolipoprotein B level of circulating immune complexes (r = 0.91). These findings suggest that the atherogenic potential of CHD patients' blood serum is due to LDL-containing immune complexes.

Fish skin mucus is the first line of defense against infections and it discriminates between pathogenic and commensal bacterial strains. Mucus composition varies amongst fish species and is influenced by endogenous and exogenous factors. This study describes the first proteome map of the epidermal mucus of farmed gilthead seabream (Sparus aurata). We used an integrative proteomic approach by combining a label-free procedure (LC-MS/MS) with the classical 2-DE-PMF-MS/MS methodology. The identified mucosal proteins were clustered in four groups according to their biological functions. Structural proteins (actins, keratins, tubulins, tropomyosin, cofilin-2 and filamin-A) and metabolic proteins (ribosomal proteins, proteasomal subunits, NACA, VCP, histones, NDPK, transferrin, glycolytic enzymes, ATP synthase components, beta-globin, Apo-A1 and FABP7) were the best represented functional categories. We also found proteins involved in stress response (WAP65, HSPC70, Cu,Zn-SOD, and PRDX1 and PRDX2) and signal transduction (PP2A 65kDa regulatory subunit, 14-3-3 protein beta/alpha, tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, RhoGDI and PEBP1). Most of the identified proteins address different aspects of the innate immune response. Additionally, we analyzed bacterial peptides identified in the skin mucus of healthy S. aurata. These results revealed that genera belonging to the Lactobacillales order constitute the most abundant microorganism populations in this habitat.

UNASSIGNED

This work shows that proteomic methods can be used to characterize fish skin mucus. Using a coupled approach of LC-MS/MS and a 2-DE-PMF-MS/MS, we have obtained the first comprehensive view of the skin mucosal proteome of S. aurata, a fish species that is economically relevant for Mediterranean aquaculture. We identified a panel of proteins involved in a variety of biological functions, particularly in the innate immune response. Furthermore, to our knowledge, this is the first time a proteomic approach has been used to examine the microbiota in the skin mucus of a fish species. Overall, these results support further immunological researches in S. aurata and are relevant for the culture of this important fish species.

High fat diet, as an important risk factor, plays a pivotal role in atherosclerotic process. Celastrol is one of the active triterpenoid compounds with antioxidative and anti-inflammatory characters. The aims of this study were to evaluate the effect of celastrol on weight, blood lipid and oxidative injury induced by high fat emulsion, and investigate its potential pharmacological mechanisms. Male Sprague-Dawley rats were fed with high fat emulsion for 6 wk to mimic high fat mediated oxidative injury. The effects of celastrol on weight and blood lipid were evaluated, and its mechanisms were disclosed by applying western blot, ELISA and assay kits. Long-term consumption of high fat emulsion could significantly increase weight by enhancing total cholesterol (TC), triacylglycerol (TG), apolipoprotein B (Apo B), low-density lipoprotein cholesterol (LDL-c) levels, attenuating ATP-binding cassette transporter A1 (ABCA1) expression, and decreasing the levels of high-density lipoprotein cholesterol (HDL-c) and apolipoprotein A-I (Apo A-I), and inhibit antioxidant enzymes activities, improve nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. Comparing with model group, celastrol was able to effectively suppress weight and attenuate high fat mediated oxidative injury by improving ABCA1 expression, reducing the levels of TC, TG, LDL-c and Apo B in plasma, and increasing antioxidant enzymes activities and inhibiting NADPH oxidase activity, and decreasing the serum levels of Malondialdehyde (MDA) and reactive oxygen species in dose-dependent way. These data demonstrated that celastrol was able to effectively suppress weight and alleviate high-fat mediated cardiovascular injury via mitigating oxidative stress and improving lipid metabolism.

Apolipoprotein (apo) A-I-containing nascent HDL particles produced by the ATP binding cassette transporter A1 have different sizes and compositions. To understand the molecular basis for this heterogeneity, the HDL particles produced by apoA-I-mediated solubilization of phospholipid (PL)/free (unesterified) cholesterol (FC) bilayer membranes in cell and cell-free systems are compared. Incubation of apoA-I with ATP binding cassette transporter A1-expressing baby hamster kidney cells leads to formation of two populations of FC-containing discoidal nascent HDL particles. The larger 11-nm diameter particles are highly FC-enriched (FC/PL = 1.2/1 mol/mol) relative to the smaller 8 nm particles and the cell plasma membrane (FC/PL = 0.4/1). ApoA-I-mediated spontaneous solubilization of either multilamellar or unilamellar vesicles made of a membrane-PL mixture and FC yields discoidal HDL particles with diameters in the range 9-17 nm and, as found with the cell system, the larger particles are relatively enriched in FC despite the fact that all particles are created by solubilization of a common FC/PL membrane domain. The size-dependent distribution of FC among HDL particles is due to varying amounts of PL being sequestered in a boundary layer by interaction with apoA-I at the disc edge. The presence of a relatively large boundary layer in smaller discoidal HDL promotes preferential distribution of phosphatidylserine to such particles. However, phosphatidylcholine and sphingomyelin which are the primary PL constituents of nascent HDL do not exhibit selective incorporation into HDL discs of different sizes. This understanding of the mechanisms responsible for the heterogeneity in lipid composition of nascent HDL particles may provide a basis for selecting subspecies with preferred cardio-protective properties.

OBJECTIVE

The ATP-binding cassette transporter A1 (ABCA1) lipidates apolipoprotein (apo) A-I. The hypothesis that hepatocyte-specific ABCA1 overexpression results in high-density lipoprotein (HDL) dysfunction was evaluated by comparing the effects of murine ABCA1 (AdABCA1) and human apo A-I (AdA-I) transfer on lipoprotein profile, HDL function, and progression of atherosclerosis.

RESULTS

Gene transfer in male and female C57BL/6 apo E(-/-) mice was performed at the age of 3 months with E1E3E4-deleted adenoviral vectors containing hepatocyte-specific expression cassettes. Atherosclerosis was quantified at baseline and 56 days later in AdABCA1, AdA-I, and control mice. HDL cholesterol after AdA-I transfer was 1.7-fold (P < 0.001) and 1.8-fold (P < 0.001) higher in male and female mice, respectively, and potently inhibited atherosclerosis progression compared with respective controls. Notwithstanding a 1.4-fold (P < 0.01) and a 1.7-fold (P < 0.01) increase of HDL cholesterol in male and female mice, respectively, after AdABCA1 transfer, the intima was 2.2-fold (P < 0.001) larger in male and 1.3-fold (P = NS) larger in female mice compared with respective controls. HDL isolated from control and AdA-I mice but not from AdABCA1 mice enhanced endothelial progenitor cell (EPC) migration in vitro and reduced endothelial cell death in vitro after serum and growth factor withdrawal. Scavenger receptor class B type I (SR-BI) protein level in the liver was significantly lower in AdABCA1 mice than in control and AdA-I mice.

CONCLUSIONS

Hepatocyte-specific ABCA1 transfer decreases SR-BI protein level in the liver and abrogates beneficial effects of HDL on EPCs and endothelial cells. Decreased HDL function may underlie accelerated atherosclerosis in AdABCA1 apo E(-/-)mice.

BACKGROUND

Although coronary artery disease (CAD) becomes symptomatic much later in life, the early identification and modification of risk factors may reduce its later incidence.

METHODS

100 subjects 2-18 years old, evenly divided by sex, were randomly selected from among children of patients suffering from premature myocardial infarction (<55 years); the controls were 100 age- and sex-matched subjects without a similar family history. In the Pediatric Preventive Cardiology Clinic at the Isfahan Cardiovascular Research Center, the subjects completed a special questionnaire consisting of anthropometric data, blood pressure, skinfold thickness, rate of physical activity, and active or passive cigarette smoking. Fasting venous blood was analyzed for serum lipids, lipoproteins fibrinogen, and apolipoproteins A1 and B100. The data were analyzed with SPSS V6/win using the independent t-test, Kruskal-Wallis, chi-squared, and standard linear multiple regression tests.

RESULTS

The data showed higher prevalence of some major and new risk factors in the experimental group than in the controls. The mean total cholesterol, LDL-C, TG, fibrinogen and Apo B100 were significantly higher in the experimental group, while the mean values of HDL-C and Apo A1 were significantly lower. The differences in terms of Body Mass Index, percentage body fat, rate of regular physical activity, and active and passive smoking were not significant between groups.

CONCLUSIONS

Major and new CAD risk factors should be identified and modified as early as possible in children with high family risk by screening and health education at an early age.

Despite the well known importance of apolipoprotein (Apo) E in cholesterol efflux, the effect of ApoE on the expression of ATP-binding cassette transporter A1 (ABCA1) has never been investigated. The objective of this study was to determine the effect of ApoE on ApoB-carrying lipoprotein-induced expression of ABCA1, a protein that mediates cholesterol efflux. Our data demonstrate that ApoB-carrying lipoproteins obtained from both wild-type and ApoE knockout mice induced ApoAI-mediated cholesterol efflux in mouse macrophages, which was associated with an enhanced ABCA1 promoter activity, and an increased ABCA1 mRNA and protein expression. In addition, these lipoproteins increased the level of phosphorylated specificity protein 1 (Sp1) and the amount of Sp1 bound to the ABCA1 promoter. However, all these inductions were significantly diminished in cells treated with ApoE-free lipoproteins, when compared to those treated with wild-type lipoproteins. Enrichment with human ApoE3 reversed the reduced inducibility of ApoE-free lipoproteins. Moreover, we observed that inhibition of Sp1 DNA-binding by mithramycin A diminished ABCA1 expression and ApoAI-mediated cholesterol efflux induced by ApoB-carrying lipoproteins, and that mutation of the Sp1-binding motif in the ABCA1 promoter region diminished ApoB-carrying lipoprotein-induced ABCA1 promoter activity. Collectively, these data suggest that ApoE associated with ApoB-carrying lipoproteins has an upregulatory role on ABCA1 expression, and that induction of Sp1 phosphorylation is a mechanism by which ApoE upregulates ABCA1 expression.

BACKGROUND

Elevated levels of plasma homocysteine (Hcy) have been implicated as a significant risk factor for cardiovascular disease. Although long-term treatment with metformin can increase Hcy levels in patients with type II diabetes mellitus or coronary heart disease, it is becoming an increasingly accepted and widespread medication in polycystic ovary syndrome (PCOS). In the literature, only one study has demonstrated that metformin increases Hcy levels in PCOS patients, but the effect of other insulin sensitizers on Hcy levels have not been reported previously in women with PCOS. We aimed to assess the effects of metformin and rosiglitazone on plasma Hcy levels in patients with PCOS.

METHODS

Thirty women were randomized to two groups: 15 women in group 1 received 850 mg of metformin twice daily for 3 months. In group 2, 15 women received 4 mg of rosiglitazone for 3 months. In both groups, body mass index, menstrual pattern, and plasma total Hcy, insulin, glucose and lipid metabolism parameters were recorded at baseline and at 3 months.

RESULTS

Hcy levels increased from 8.93+/-0.49 to 11.26+/-0.86 micromol/l (P = 0.002) and from 10.70+/-0.86 to 12.36+/-0.81 micromol/l (P = 0.01) in the metformin and rosiglitazone groups, respectively. Apolipoprotein (Apo) A1 levels increased from 127.10+/-6.85 to 145.7+/-7.18 mg/dl (P = 0.018) in the metformin group. Total cholesterol (total-C), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), lipoprotein (a) and Apo B levels decreased in the metformin group, but the change was not significant. Total-C levels decreased from 161.15+/-8.94 to 150.23+/-8.73 mg/dl (P = 0.026), HDL-C decreased from 43.13+/-2.65 to 39.15+/-2.52 mg/dl (P = 0.005) and LDL-C levels decreased from 93.83+/-6.06 to 80.7+/-2.30 mg/dl (P = 0.021) in the rosiglitazone group.

CONCLUSIONS

Treatment with insulin sensitizers in women with PCOS may lead to increases in Hcy levels.

Gallstone disease is a complex disorder where both environmental and genetic factors contribute towards susceptibility to the disease. Epidemiological and family studies suggest a strong genetic component in the causation of this disease. Several genetically derived phenotypes in the population are responsible for variations in lipoprotein types, which in turn affect the amount of cholesterol available in the gall bladder. The genetic polymorphisms in various genes for apo E, apo B, apo A1, LDL receptor, cholesteryl ester transfer and LDL receptor-associated protein have been implicated in gallstone formation. However, presently available information on genetic differences is not able to account for a large number of gallstone patients. The molecular studies in the animal models have not only confirmed the present paradigm of gallstone formation but also helped in identification of novel genes in humans, which might play an important role in pathogenesis of the disease. Precise understanding of such genes and their molecular mechanisms may provide the basis of new targets for rational drug designs and dietary interventions.

OBJECTIVE

There is increasing evidence that intake of sour tea (Hibiscus sabdariffa) has hypoglycemic and hypolipidemic effects and may benefit patients suffering from metabolic disorders such as diabetes. The objective of the present study was to investigate the hypolipidemic effects of sour tea in patients with diabetes and compare them with those of black tea.

METHODS

In this sequential randomized controlled clinical trial, 60 patients with diabetes were recruited and randomly assigned into two groups: sour tea (ST) and black tea (BT). They were instructed to consume sour tea or black tea two times a day for 1 month.

METHODS

Fasting blood samples were taken at the beginning and at the end of the study for evaluation of lipids, lipoproteins, and apoproteins.

RESULTS

Fifty-three (53) patients concluded the study. In the ST group, mean of high-density lipoprotein-cholesterol (HDLc) increased significantly (p = 0.002) at the end of the study, whereas changes in apolipoprotein-A1, and lipoprotein (a) were not significant. Also, a significant decrease in the mean of total cholesterol, low density lipoprotein-cholesterol, triglycerides, and Apo-B100 were seen in this group. In the BT group, only HDLc showed significant change (p = 0.002) at the end of the study and changes in the other measures were not statistically significant.

CONCLUSIONS

The results of the present study showed that ST has a significant effect on blood lipid profile in patients with diabetes.

Until recently, coronary artery disease (CAD) was the leading cause of death in the developed countries. Its remarkable decline can be attributed to our knowledge of the major risk factors identified by several studies resulting in better prevention and treatment. Of the major risk factors, the ratio of apolipoprotein (apo) B/apo A1 followed by smoking, diabetes, and hypertension are the most important. A number of risk scores for men and women are now available to estimate the likelihood of development of CAD. However, because of the risk of CAD differs in various populations, some of the algorithms are more appropriate for some countries but not suitable for others. These risk assessment algorithms differ in the parameters they use. All the risk scores have some limitations such as different study populations; the age of the study is also different, and number of points awarded for age categories also differs among the various algorithms. In an effort to further improve the risk prediction, a number of biomarkers have been studied. In addition to plasma lipids, a lot of interest has focused on apo measurements; particularly of apo B. Another valuable biomarker is lipoprotein (a) [Lp(a)]. Lp(a) is not only atherogenic as low-density lipoprotein (LDL) but also prothrombotic, and several studies indicate that Lp(a) is an independent risk factor for CAD. The lipid profile provides a framework for appropriate management. This includes therapeutic lifestyle changes and medications. Lifestyle interventions are the cornerstone of CAD prevention strategies and are the first step in risk factor management. Of particular importance are smoking cessation, achievement and maintenance of ideal body weight, regular exercise, reduction in the intake of saturated fat and sugars, and decreasing level of stress. Of medications, lipid-lowering, anti-hypertensive, and anti-coagulant can be effectively used. The current strategies for risk assessment and prevention have been very successful contributing to the more than 50% decrease in CAD mortality over the last 20 years. Thus, in Canada, cardiovascular disease is no longer the leading cause of death.