Biogenesis of high-density lipoproteins (HDL) is coupled to the transmembrane protein, ATP-binding cassette transporter A1 (ABCA1), which transports phospholipid (PL) from the inner to the outer membrane monolayer. Using a combination of computational and experimental approaches, we show that increased outer lipid monolayer surface density, driven by excess PL or membrane insertion of amphipathic helices, results in pleating of the outer monolayer to form membrane-attached discoidal bilayers. Apolipoprotein (apo)A-I accelerates and stabilizes the pleats. In the absence of apoA-I, pleats collapse to form vesicles. These results mimic cells overexpressing ABCA1 that, in the absence of apoA-I, form and release vesicles. We conclude that the basic driving force for nascent discoidal HDL assembly is a PL pump-induced surface density increase that produces lipid monolayer pleating. We then argue that ABCA1 forms an extracellular reservoir containing an isolated pressurized lipid monolayer decoupled from the transbilayer density buffering of cholesterol.

Lipoprotein cholesterol metabolism dysfunction in the arterial wall is a major contributor to atherosclerosis, and excessive lipid intake and failed cholesterol homeostasis may accelerate the atherogenic process. Curcumin exerts multiple effects by alleviating inflammation, hyperlipidemia, and atherosclerosis; however, its role in cholesterol transport homeostasis and its underlying impact on inflammatory M1 macrophages are poorly understood. This work aimed to investigate the effect of curcumin on cholesterol transport, the inflammatory response and cell apoptosis in M1 macrophages. RAW264.7 macrophages (M0) were induced with LPS plus IFN-γ for 12 h to develop a M1 subtype and were then incubated with curcumin at different concentrations (6.25 and 12.5 μmol/L) in the presence or absence of oxLDL. Then, cholesterol influx/efflux and foam cell formation as well as inflammation and apoptosis were evaluated. It was found that curcumin increased cholesterol uptake measured by the Dil-oxLDL binding assay, and simultaneously increased cholesterol efflux carried out by Apo-A1 and HDL in M1 cells. Curcumin further reinforced ox-LDL-induced cholesterol esterification and foam cell formation as determined by Oil Red O and BODIPY staining. Moreover, curcumin dramatically reduced ox-LDL-induced cytokine production such as IL-1β, IL-6 as well as TNF-α and M1 cell apoptosis. We also found that curcumin upregulated CD36 and ABCA1 in M1 macrophages. Curcumin increased PPARγ expression, which in turn promoted CD36 and ABCA1 expression. In conclusion, curcumin may increase the ability of M1 macrophages to handle harmful lipids, thus promoting lipid processing, disposal and removal, which may support cholesterol homeostasis and exert an anti-atherosclerotic effect.

ATP-binding cassette transporters (ABC) A1 and G1 are key molecules in cholesterol efflux from macrophages, which is an initial step of reverse cholesterol transport (RCT), a major anti-atherogenic property of high-density lipoprotein (HDL). Astaxanthin is one of the naturally occurring carotenoids responsible for the pink-red pigmentation in a variety of living organisms. Although astaxanthin is known to be a strong antioxidant, it remains unclear through what mechanism of action it affects cholesterol homeostasis in macrophages. We therefore investigated the effects of astaxanthin on cholesterol efflux and ABCA1/G1 expressions in macrophages. Astaxanthin enhanced both apolipoprotein (apo) A-I- and HDL-mediated cholesterol efflux from RAW264.7 cells. In supporting these enhanced cholesterol efflux mechanisms, astaxanthin promoted ABCA1/G1 expression in various macrophages. In contrast, peroxisome proliferator-activated receptor γ, liver X receptor (LXR) α and LXRβ levels remained unchanged by astaxanthin. An experiment using actinomycin D demonstrated that astaxanthin transcriptionally induced ABCA1/G1 expression, and oxysterol depletion caused by overexpression of cholesterol sulfotransferase further revealed that these inductions in ABCA1/G1 were independent of LXR-mediated pathways. Finally, we performed luciferase assays using human ABCA1/G1 promoter-reporter constructs to reveal that astaxanthin activated both promoters irrespective of the presence or absence of LXR-responsive elements, indicating LXR-independence of these activations. In conclusion, astaxanthin increased ABCA1/G1 expression, thereby enhancing apoA-I/HDL-mediated cholesterol efflux from the macrophages in an LXR-independent manner. In addition to the anti-oxidative properties, the potential cardioprotective properties of astaxanthin might therefore be associated with an enhanced anti-atherogenic function of HDL.

This study aimed to detect the association of the suppressor of cytokine signaling 3 gene (SOCS3) A+930->>G (rs4969168) single nucleotide polymorphism (SNP) and environmental factors with serum lipid levels in the Han and Mulao populations. Genotyping of the SOCS3 A+930->>G (rs4969168) SNP was performed in 752 of Han and 690 of Mulao participants using polymerase chain reaction and restriction fragment length polymorphism. The genotype and allele frequencies were significantly different between the Han and Mulao populations (GG, 57.71% vs. 51.16%, GA, 36.97% vs. 41.16%, AA, 5.32% vs. 7.68%, P = 0.023; G, 76.20% vs. 71.74%, A, 23.80% vs. 28.26%; P = 0.006; respectively). Serum apolipoprotein (Apo) A1 levels in Han were different among the genotypes (P < 0.05). Subgroup analyses showed that the levels of ApoA1 in Han females, and ApoA1 and low-density lipoprotein cholesterol (LDL-C) in Mulao males were different among the genotypes (P < 0.05). Serum lipid parameters were also associated with several environmental factors in both ethnic groups (P < 0.05-0.001). These findings suggest that there may be a racial/ethnic- and/or sex-specific association between the SOCS3 A+930->>G (rs4969168) SNP and serum lipid parameters in some populations.

The associations between four restriction fragment length polymorphisms (RFLPs) of the gene for human apolipoprotein B (apo B) and five antigen group (Ag) protein-polymorphisms of apo B have been investigated in 24 unrelated Finnish individuals. In this sample a complete correlation exists between the EcoRI RFLP and the Ag(t/z) polymorphism. There is strong association between the alleles of the XbaI RFLP and Ag(c/g) and a weaker one of the same XbaI site with Ag(x/y). Linkage disequilibrium is observed between the PvuII RFLP and the Ag(a1/d) polymorphism. These associations confirm that the Ag variants are true protein sequence polymorphisms of apo B.

OBJECTIVE

To investigate the effects of Apo A1 and B gene polymorphism on avascular necrosis of the femoral head (ANFH) in north Chinese Han population.

METHODS

Polymerase chain reaction-restriction fragment length polymorphisms (PCR-RFLP) technique was used in samples of 143 cases with documented ANFH and 92 healthy control matched by age and sex individuals selected from north Chinese Han nationality. The studied loci include promoter region (-75bp) and the intron 1 (+83 bp) of Apo A1 gene, Eco RI,Xba I of Apo B gene; polymerase chain reaction was used to study 3'-VNTR of Apo B gene.

RESULTS

At -75 bp in promoter, the frequency of A/A genotype in ANFH group was significantly higher than that in control group (P < 0.01), while the frequency of G/A genotype in ANFH group was significantly lower than that in control group (P < 0.01). No difference was found in the frequency of genotype at +83bp in intron 1 of Apo A1 gene, Eco RI, Xba I and 3'-VNTR loci of Apo B gene.

CONCLUSIONS

Apolipoprotein A1 gene A/A substitution at position -75 in promotor is associated with ANFH, the mutation may be one of the sensitive genes of ANFH, first reported inside and abroad. But no evident relationship was found between gene polymorphism of +75 bp loci of Apo A1 gene, Eco RI loci of Apo B gene, Xba I loci of Apo B gene or 3'-VNTR of Apo B gene and ANFH.

The association of polymorphisms affecting lipid metabolism with the risk of myocardial infarction (MI) in type 2 diabetes mellitus was investigated. The Genetics, Outcomes and Lipids in type 2 Diabetes (GOLD) Study is a prospective, multicenter study, conducted on 990 patients presenting diabetes and MI (n=386), or diabetes without previous manifestation of stroke, peripheral or coronary arterial disease (n=604), recruited from 27 institutions in Brazil. APO A1 (A/G -75 and C/T +83) and APO C3 (C/G 3'UTR) non-coding sequences, CETP (Taq 1B), LPL (D9N), APO E (epsilon2, epsilon3, epsilon4,), PON-1 (Q192R), and two LCAT variants Arg(147)->>Trp and Tyr(171)->>Stop were tested by PCR-RFLP. There was a higher prevalence of LPL DN genotype (19% vs.12%, p=0.03) and a higher frequency of the N allele (11% vs. 7%) among subjects with MI when compared to controls, with an odds ratio of MI for carriers of 9N allele of 2.46 (95% CI=1.79-3.39, p<0.0001). This association was present in men and women, in non-smokers and in hypertensive patients. A logistic regression model including gender, duration of diabetes, systolic blood pressure, HDL-C, left ventricle hypertrophy and D9N polymorphism showed that the latter still remained significantly associated with MI (OR=1.50, 95% CI=1.02-2.25, p=0.049). These findings suggest that D9N polymorphism can be a useful risk marker for myocardial infarction and that further potential candidate genes should be screened for exploratory analysis and for future therapeutic intervention in diabetes.

The induction of rat hepatic mRNA S11 by L-T3 (T3) is a useful model for studying the mechanisms of thyroid hormone action. Although numerous reports have examined the response of mRNA S11 to various physiological and hormonal manipulations, the role of S11 protein in cellular metabolism remains unknown. In this study we show that mRNA S11 is abundantly expressed and regulated by T3 only in liver and small intestine. High levels of the mRNA are present at birth, but drop sharply between 30-60 days of age. These and other features of the S11 gene product were similar to those of rat apolipoprotein-A1 (Apo-A1). The sequence of S11 cDNA was identical to a portion of the Apo-A1 mRNA, thus confirming identity of the S11 mRNA. To examine whether DNA sequences immediately adjacent to the transcription start site mediate the effects of thyroid hormone, we measured the activity of an Apo-A1 gene fragment, U-1 (-474 to -7) using a transient transfection assay. The activity of the full-length U-1 DNA in HuH-7 hepatoma cells was 2- to 2.5-fold higher in the presence of thyroid hormone. This finding closely matched previous results using the in vitro nuclear run-on assay. Internal deletion of a motif that resembles a thyroid hormone response element from U-1 DNA not only abolished the induction by T3, but suppressed promoter activity by 3- to 4-fold in response to the hormone.(ABSTRACT TRUNCATED AT 250 WORDS)

Several studies have demonstrated that high density lipoprotein cholesterol (HDL-C) is increased after either dietary weight loss or aerobic exercise training, but it is unclear whether the effects of these two interventions are separate and independent, or just related to the amount of weight or fat lost. The effect of dietary weight loss or aerobic training on apolipoprotein A1 (Apo-A-I) has not been extensively studied. In the present study we evaluated the effects of either dietary weight loss or aerobic exercise training on lipoproteins and Apo A-I, and assessed whether they are related to changes in body composition. Twenty-six obese, otherwise healthy, untrained, nonsmoking, male subjects were weight stabilized for ten days, during which maximal aerobic capacity, body composition, and fat cell size were measured. At the end of this ten-day period lipoproteins and Apo A-I were measured. Subjects were then randomized into either a dietary weight loss (n = 12) or aerobic exercise group (n = 14). At the end of three months the groups were restabilized and restudied. Although both groups lost weight, the weight loss was greater in the diet group (-13.1 v -2.8 kg, P less than 0.001). Important differences in body composition were also detected after the two interventions with 25% of the total weight loss in the diet group coming from fat free mass. Significant decrements in triglyceride (-54 +/- 67 mg/dL, P less than 0.05), total cholesterol (-29 +/- 27 mg/dL, P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

In analogy with many other proteins, Na(+)/Ca(2+) exchangers (NCX) adapt an inverted twofold symmetry of repeated structural elements, while exhibiting a functional asymmetry by stabilizing an outward-facing conformation. Here, structure-based mutant analyses of the Methanococcus jannaschii Na(+)/Ca(2+) exchanger (NCX_Mj) were performed in conjunction with HDX-MS (hydrogen/deuterium exchange mass spectrometry) to identify the structure-dynamic determinants of functional asymmetry. HDX-MS identified hallmark differences in backbone dynamics at ion-coordinating residues of apo-NCX_Mj, whereas Na(+)or Ca(2+) binding to the respective sites induced relatively small, but specific, changes in backbone dynamics. Mutant analysis identified ion-coordinating residues affecting the catalytic capacity (kcat/Km), but not the stability of the outward-facing conformation. In contrast, distinct "noncatalytic" residues (adjacent to the ion-coordinating residues) control the stability of the outward-facing conformation, but not the catalytic capacity. The helix-breaking signature sequences (GTSLPE) on the α1 and α2 repeats (at the ion-binding core) differ in their folding/unfolding dynamics, while providing asymmetric contributions to transport activities. The present data strongly support the idea that asymmetric preorganization of the ligand-free ion-pocket predefines catalytic reorganization of ion-bound residues, where secondary interactions with adjacent residues couple the alternating access. These findings provide a structure-dynamic basis for ion-coupled alternating access in NCX and similar proteins.

BACKGROUND

Haptoglobin is a plasma protein that scavenges haemoglobin during haemolysis. Phospholipid Transfer Protein (PLTP) transfers lipids from Low Density Lipoproteins (LDL) to High Density Lipoproteins (HDL). PLTP is involved in the pathogenesis of atherosclerosis which causes coronary artery disease, the leading cause of death in North America. It has been shown that Apolipoprotein-A1 (Apo-A1) binds and regulates PLTP activity. Haptoglobin can also bind to Apo-A1, affecting the ability of Apo-A1 to induce enzymatic activities. Thus we hypothesize that haptoglobin inhibits PLTP activity. This work tested the effect of Haptoglobin and Apo-A1 addition on PLTP activity in human plasma samples. The results will contribute to our understanding of the role of haptoglobin on modulating reverse cholesterol transport.

RESULTS

We analyzed the PLTP activity and Apo-A1 and Haptoglobin content in six hyperlipidemic and six normolipidemic plasmas. We found that Apo-A1 levels are proportional to PLTP activity in hyperlipidemic (R2 = 0.66, p < 0.05) but not in normolipidemic human plasma. Haptoglobin levels and PLTP activity are inversely proportional in hyperlipidemic plasmas (R2 = 0.57, p>> 0.05). When the PLTP activity was graphed versus the Hp/Apo-A1 ratio in hyperlipidemic plasma there was a significant correlation (R2 = 0.69, p < 0.05) suggesting that PLTP activity is affected by the combined effect of Apo-A1 and haptoglobin. When haptoglobin was added to individual hyperlipidemic plasma samples there was a dose dependent decrease in PLTP activity. In these samples we also found a negative correlation (-0.59, p < 0.05) between PLTP activity and Hp/Apo-A1. When we added an amount of haptoglobin equivalent to 100% of the basal levels, we found a 64 +/- 23% decrease (p < 0.05) in PLTP activity compared to basal PLTP activity. We tested the hypothesis that additional Apo-A1 would induce PLTP activity. Interestingly we found a dose dependent decrease in PLTP activity upon Apo-A1 addition. When both Apo-A1 and Hpt were added to the plasma samples there was no further reduction in PLTP activity suggesting that they act through a common pathway.

CONCLUSIONS

These findings suggest an inhibitory effect of Haptoglobin over PLTP activity in hyperlipidemic plasma that may contribute to the regulation of reverse cholesterol transport.

BACKGROUND

Both alcohol consumption and the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene polymorphism modulate serum lipid levels, but their interactions on serum lipid profiles are still unknown. The present study was undertaken to detect the interactions of PCSK9 E670G polymorphism and alcohol consumption on serum lipid levels.

METHODS

Genotypes of the PCSK9 E670G in 1352 unrelated subjects (785 non-drinkers and 567 drinkers) were determined by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. The interactions between PCSK9 E670G genotypes and alcohol consumption on serum lipid parameters were detected by using a factorial design covariance analysis after controlling for potential confounders.

RESULTS

The levels of serum triglyceride, high-density lipoprotein cholesterol, apolipoprotein (Apo) A1, and the ratio of ApoA1 to ApoB were higher in drinkers than in non-drinkers (P < 0.01 for all), whereas the levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and ApoB were lower in drinkers than in non-drinkers (P < 0.001 for all). The genotypic and allelic frequencies of PCSK9 E670G were not different between non-drinkers and drinkers (P>> 0.05 for each). The subjects with AA genotype in non-drinkers had higher serum LDL-C levels than the subjects with AG genotype, whereas the subjects with AG genotype in drinkers had higher serum TC levels than the subjects with AA genotypes (P < 0.05 for each). The effects of alcohol consumption on TC and LDL-C levels depended upon genotypes, the subjects with AA genotype had lower serum TC and LDL-C levels in drinkers than in non-drinkers.

CONCLUSIONS

Alcohol consumption can modify the effects of the PCSK9 E670G polymorphism on serum TC and LDL-C levels. The subjects with AA genotype of the PCSK9 E670G benefit more from alcohol consumption than the subjects with AG genotype in decreasing serum TC and LDL-C levels.

OBJECTIVE

Arabinogalactan (AG) is a non-digestible soluble dietary fiber that resists hydrolytic enzyme action and enters the large bowel intact where it is fermented by resident microflora. To determine whether AG has similar physiological properties to other soluble dietary fibers, we examined the effect of 15 and 30 g per day of a commercially available AG from Western Larch on several gastrointestinal and blood parameters.

METHODS

Gastrointestinal parameters included fecal microflora, fecal enzyme activity, fecal short-chain fatty acids, fecal pH, fecal weight, transit time and bowel frequency. Blood parameters included total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, Apo-A1, Apo-B, glucose and insulin. The study consisted of two three-week diet treatments with no washout period. Participants (n=20, 11 males, 9 females) consumed their usual diet in addition to 15 or 30 g AG in a beverage sweetened with aspartame as compared to their usual diet with the control beverage.

RESULTS

Significant increases in total fecal anaerobes were observed with 15 g (p=0.01) and 30 g AG (p=0.001). A significant increase (p=0.02) in Lactobacillus spp. was observed when subjects consumed AG for a total of six weeks regardless of dose. There were no significant changes in other microflora, fecal enzyme activity, transit time, frequency, fecal weight, fecal pH and short-chain fatty acids. Fecal ammonia levels decreased with 15 g (p=0.001) and 30 g (p=0.002) AG. No significant changes in blood lipids or blood insulin were observed.

CONCLUSIONS

These data suggest that dietary AG is easily incorporated into the diet, well tolerated in subjects and has some positive effects on fecal chemistry.

OBJECTIVE

To study the influence of combined hormone replacement therapy on levels of serum lipids, lipoproteins, and apolipoproteins.

METHODS

One hundred thirty-nine healthy early postmenopausal women selected by means of a questionnaire, a medical examination, and a laboratory screening procedure to be a representative sample of postmenopausal Danish women aged 45 to 55 years old were randomized to four treatment and two placebo groups. The four groups receiving hormone replacement therapy were given 2 mg estradiol valerate equivalents (E), either sequentially combined with 75 micrograms levonorgestrel (E/LNG), 10 mg medroxyprogesterone acetate (E/MPA), or 150 micrograms desogestrel (E/DG), or continuously combined with 1 mg cyproterone acetate (E/CPA). Serum lipids, lipoproteins, and apolipoproteins were measured before institution of hormone replacement therapy and at nine well-defined times during the following 84 days. Total response and cyclical variations were calculated.

RESULTS

All active treatment regimens reduced serum low-density lipoprotein cholesterol (LDL-C) significantly: E/CPA, 6% (95% confidence limits 0.3% to 11.3%); E/LNG, 10.9% (4.9% to 16.6%); E/MPA, 14.4% (7.4% to 20.9%); E/DG, 10.7% (3.3% to 17.6%). The changes in serum total cholesterol and apolipoprotein B were similar but smaller than those in LDL-C. None of these treatment regimens induced significant overall changes in serum high-density lipoprotein cholesterol (HDL-C) or apolipoprotein A1 (Apo A1). The sequentially combined hormone treatments induced significant cyclical variations in HDL-C, with an increase during estrogen therapy and a decrease during combined therapy: E/LNG, 13.3% (7.4% to 19.4%); E/MPA, 6.9% (1.6% to 12.6%); E/DG, 10.3% (5.8% to 14.9%). No cyclical changes in HDL-C were found in the group receiving continuously combined hormone replacement therapy (E/CPA). The changes in Apo A1 parallel those in HDL-C.

CONCLUSIONS

All the treatment regimens produced changes in levels of serum lipids, lipoproteins, and apolipoproteins that may be considered favorable in terms of cardiovascular disease.

A precise knowledge of the genome involved in the expression of a quantitative trait could provide a useful tool in breeding programs; molecular genetic methods are capable of yielding this kind of information. An experimental procedure is presented here for identifying genes whose expression is related to weight variability of abdominal adipose tissue in the growing chicken. Quantitative traits are the result of metabolic pathways exhibiting some major regulation stages that are controlled genetically. These steps involve genes that may act as "major genes". With regard to chicken fat metabolism, most fatty acids are synthesized in the liver and incorporated into very low density lipoprotein (VLDL) particles before their secretion into the plasma. Accordingly, the present study focused on the expression of liver genes. The mRNA of lipogenic enzymes (acetyl-coenzyme-A carboxylase, fatty acid synthase, malic enzyme, and delta 9-desaturase) were analyzed. Also studied were apoprotein (apo)A1, apoVLDL-II, and apoB mRNA from 9-wk-old male chickens from two lines selected for high and low abdominal fat pads. Significant differences for apoA1 mRNA levels occurred between fat and lean birds. Moreover, the total quantity of mRNA provided an accurate estimation of the abdominal fat pad (r = .74 with P < .05).

To evaluate the differential effects of beta-blockers on serum lipids and apolipoproteins in normolipidaemic and dyslipidaemic hypertensives, 330 patients with mild to moderate essential hypertension were studied 1 month after placebo therapy and 6 months after monotherapy with propranolol (n = 53), atenolol (n = 66), metoprolol (n = 58), pindolol (n = 53), or celiprolol (n = 100). Serum total cholesterol, triglycerides, high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), and apolipoproteins (Apo) A1 and B were measured at baseline and study end. A total of 136 (41.2%) patients were considered normolipidaemic (pretreatment LDL-C < 160 mg.dl-1) and 194 (58.8%) were considered dyslipidaemic (LDL-C>> 160 mg.dl-1). Changes in total cholesterol differed between normolipidaemics and dyslipidaemics with propranolol (+13% in normolipidaemics vs -0.5% in dyslipidaemics, P < 0.001), atenolol (+7% vs -2%, P = 0.01), metoprolol (+9% vs -4%, P0.0006), pindolol (+8% vs -9%, P < 0.001), and celiprolol (-1% vs -13%, P = 0.002). HDL-C differed less, with propranolol (-18% vs -13%), atenolol (-6% vs -2%), metoprolol (-2% vs -6%), pindolol (+4% vs +1%), and celiprolol (+9% vs +4%); none of these changes between normolipidaemic and dyslipidaemic patients were statistically significant. LDL-C changes differed the most, with propranolol (+35% vs -1%, P < 0.0001), atenolol (+15% vs -4%, P = 0.001), metoprolol (+12% vs -6%, P = 0.004), pindolol (+12% vs -13%, P < 0.0001), and celiprolol (+3% vs -16%, P = 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

BACKGROUND

Glycation and oxidative modification of lipoproteins enhance the uptake of these lipids by macrophages in the early stages of atherogenesis. Measurement of blood levels of modified LDL particles could thus constitute another useful modality in identifying subjects at high risk of coronary atherosclerosis (CHD).

OBJECTIVE

To measure the glycated LDL level and assess its associations with other metabolic parameters in diabetic and nondiabetic hyperlipidaemic subjects attending a Lipid Clinic in Kuwait.

METHODS

One hundred thirty-three hyperlipidaemic (HL) (72 nondiabetic (ND); 61 diabetic (D)) patients and 42 healthy control (HC) subjects had their fasting serum samples analyzed for glucose, total cholesterol (TC), triglycerides (TG), urate, HDL, LDL (by routine autoanalyzer methods), apolipoproteins A1 and B (by nephelometry), fructosamine (by spectrophotometry) and glycated LDL (gLDL) by ELISA.

RESULTS

The serum gLDL level was significantly higher in HL [D+ND] than in HC (p<0.001). Within the HL group, the DHL patients had higher levels than the NDHL [p<0.001]. These differences were maintained when the gLDL level was also expressed as a percentage of the apo B concentration. The gLDL level correlated positively (p<0.01) with those of glucose, TC, TG and LDL and negatively with HDL (p<0.05) in all the subjects as a whole, healthy and hyperlipidaemia [HC+HL]. In the HL (D+ND) group as a whole, gLDL correlated significantly only with glucose [p<0.01]. In group DHL, however, gLDL correlated significantly with glucose, fructosamine and LDL [all p<0.05]. As expected, fructosamine levels were highest in the DHL group. The significant correlations established between fructosamine and the different analytes measured in the different subject groups were essentially similar to those observed for gLDL, except for the finding of persistent significant negative correlations of fructosamine with LDL in all the subject groups.

CONCLUSIONS

(i) Serum gLDL levels are increased in hyperlipidaemic patients and are further increased with diabetes, suggesting that the significant glycation of LDL occurs in all hyperlipidaemic patients irrespective of their glycaemic status. (ii) The significant correlation of gLDL with glucose and fructosamine in diabetic patients would suggest its potential utility as another index of medium term glycaemic control. (iii) gLDL is easily measurable and its values could provide additional information in ascertaining an individual's aggregate CHD risk.

The objective of the present study was to detect the association of the rs7934205 single nucleotide polymorphism (SNP) near the Suppressor of Ty, domain containing 1 gene (SPTY2D1) and serum lipid levels between males and females in the Mulao and Han populations. Genotyping of SPTY2D1 rs7934205 SNP was performed in 933 of Mulao and 865 of Han participants using polymerase chain reaction and restriction fragment length polymorphism. The T allele frequency was different between Mulao males and females (23.2% vs. 27.9%, P = 0.018). The genotype and allele frequencies were also different between Han males and females (P = 0.020 and P = 0.004; respectively). Serum levels of apolipoprotein (Apo) A1 in Mulao males; and total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), ApoA1 and ApoB in Mulao females were different between the CC and CT/TT genotypes (P < 0.05). Serum TC, ApoB levels in Han males, and ApoB levels in Han females were different between the CC and CT/TT genotypes (P < 0.05). The subjects with CT/TT genotype in both Mulao and Han males and females have more favorable lipid profiles than those with CC genotype. These findings suggest that the association between the SPTY2D1 rs7934205 SNP and serum lipid levels might have ethnic- and/or sex-specificity.

OBJECTIVE

To examine the relationship between various hormonal and metabolic variables in a large group of women with unequivocal evidence of polycystic ovarian syndrome (PCOS) to dissect out the metabolic heterogeneity of this condition.

METHODS

Cross-sectional observational study of PCOS (n = 122) and non-PCOS (n = 26) subjects.

METHODS

Reproductive medicine unit in a tertiary teaching hospital.

METHODS

Subjects with presumed PCOS were recruited from the Reproductive Medicine and Gynaecological Clinics and later confirmed as PCOS with recognized criteria. Several other subjects were identified through recruiting reference subjects. The PCOS population consisted of 122 patients. Reference subjects were recruited from partners of male factor infertility patients in the clinics and from the general population (n = 27).

METHODS

A 75 g 2-hour oral glucose tolerance test was performed on all subjects in their midluteal phase. Blood was taken at fasting and at 30, 60, 90, and 120 minutes.

METHODS

Age, body mass index (BMI), waist to hip ratio, levels of integrated glucose and insulin, concentrations of maximum insulin, sex hormone-binding globulin, T, triglyceride, apolipoproteins (Apo A1, B), high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol (LDLC).

RESULTS

Five clusters could be identified. They are characterized as a nonobese group, a moderately obese group, and three very obese groups. The nonobese group (n = 41, BMI = 24.1) exhibited the lowest level of integrated insulin (236.4 mIU/L or microU/mL) and concentration of serum T (5.5 nmol/L). The moderately obese group had the second lowest level of integrated insulin (497.1 mIU/L) whereas the three very obese groups (n = 15, 13, and 5, respectively) had significantly higher but different levels of integrated insulin (group 3: 850.8 mIU/L; group 4: 1,131.5 mIU/L; and group 5: 1,531.9 mIU/L), triglyceride (group 3: 1.39 mmol/L; group 4: 1.76 mmol/L; and group 5: 2.78 mmol/L [1 mmol/L = 88mg/mL]), Apo B (group 3: 1.18 g/L; group 4: 1.08 g/L; and group 5: 1.55 g/L) and LDLC (group 3: 3.81 mmol/L; group 4: 3.05 mmol/L; and group 5: 5.06 mmol/L [1 mmol/L = 38.6 mg/100 mL]).

CONCLUSIONS

The metabolic heterogeneity of the PCOS population is reflected at least partly in patients' levels of insulin, lipids, and lipoproteins, dependent and independent of BMI.

An epithelial intestinal cell line has been established from explants of fetal rat small intestine. After the 9th passage (approx. 25 population doublings) epithelial-like cells acquired the properties of a permanent cell line. The epithelial nature of this cell line, and of clone IRD 98 subsequently isolated, is supported by morphological and ultrastructural criteria, and also by the presence of enzymes characteristic of enterocytes, such as aminopeptidase, alkaline phosphatase, gamma-glutamyl transferase, lactase and maltase. The occurrence of the triglyceride pathway enzyme monoacylglycerol acyltransferase and of apoproteins (Apo A1 and Apo E) can also be demonstrated. Taken together, the results presented here provide evidence that clone IRD 98 is an epithelial cell line, most likely originating from the relatively differentiated cell layer of fetal rat small intestine.

OBJECTIVE

Levocarnitine is an important contributor to cellular energy metabolism. This study aims to evaluate the effects of levocarnitine supplementation on body composition, lipid profile and fatigue in elderly subjects with rapid muscle fatigue.

METHODS

This was a placebo-controlled, randomised, double-blind, two-phase study. Eighty-four elderly subjects with onset of fatigue following slight physical activity were recruited to the study. Prior to randomisation all patients entered a 2-week normalisation phase where they were given an 'ad libitum'diet, according to the National Cholesterol Education Program (Step 2). Subjects were asked to record their daily food intake every 2 days. Before the 30-day treatment phase, subjects were randomly assigned to two groups (matched for male/female ratio, age and body mass index). One group received levocarnitine 2g twice daily (n = 42) and the other placebo (n = 42). Efficacy measures included changes in total fat mass, total muscle mass, serum triglyceride, total cholesterol, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), apolipoprotein (apo)A1, and apoB levels. The Wessely and Powell scale was used to evaluate physical and mental fatigue. Subjects were assessed at the beginning and end of the study period.

RESULTS

At the end of the study, compared with placebo, the levocarnitine-treated patients showed significant improvements in the following parameters: total fat mass (-3.1 vs -0.5 kg), total muscle mass (+2.1 vs +0.2 kg), total cholesterol (-1.2 vs +0.1 mmol/L), LDL-C (-1.1 vs -0.2 mmol/L), HDL-C (+0.2 vs +0.01 mmol/L), triglycerides (-0.3 vs 0.0 mmol/L), apoA1 (-0.2 vs 0.0 g/L), and apoB (-0.3 vs -0.1 g/L). Wessely and Powell scores decreased significantly by 40% (physical fatigue) and 45% (mental fatigue) in subjects taking levocarnitine, compared with 11% and 8%, respectively, in the placebo group (p < 0.001 vs placebo for both parameters). No adverse events were reported in any treatment group.

CONCLUSIONS

Administration of levocarnitine to healthy elderly subjects resulted in a reduction of total fat mass, an increase of total muscle mass, and appeared to exert a favourable effect on fatigue and serum lipids.

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder, which is considered not only a reproductive disease but also a metabolic disorder associated with long-term health risks. The aim of this study was to assess the effects of metformin on insulin resistance, oxidant-antioxidant status, endothelial dysfunction, lipid metabolism and their contribution to the risks of cardiovascular disease in women with PCOS. Fifteen women with PCOS and 17 healthy women were included in this case-control study. Nitric oxide (NO), endothelin-1 (ET-1), malondialdehyde (MDA), Apo A1, Apo B, small, dense LDL cholesterol (sdLDL-C), lipid levels and paraoxonase 1 (PON1) activity were measured in serum/plasma obtained from study groups. Insulin resistance (HOMA index - Homeostasis Model Assessment) and serum sex hormone profiles were also evaluated. Significantly decreased NO levels and PON1 activities, but increased MDA, ET-1 and sdLDL-C were found in PCOS patients compared to those of controls. Serum MDA, ET-1, HOMA and sdLDL-C levels decreased and PON1 activity and NO levels increased significantly after the metformin treatment. There was a positive correlation between MDA and free testosterone (fT), ET-1 and fT; and a negative correlation between PON1 activity and fT. Insulin resistance, dyslipidemia, endothelial dysfunction and oxidative stress might contribute to the excess risk of cardiovascular disease reported in PCOS. Metformin seemed to decrease oxidative stress and improve insulin resistance, dyslipidemia and endothelial dysfunction in PCOS patients.

Osteoprotegerin (OPG) regulates bone mass by inhibiting osteoclast differentiation and activation, and also plays a role in vascular calcification. The objective of this study was to evaluate the relationship between serum OPG levels, and carotid artery intima-media thickness (IMT) and carotid plaque formation in healthy postmenopausal women. We recruited 68 healthy postmenopausal women for the study. Carotid plaque presence and IMT were evaluated by high resolution B-mode ultrasound. IMT was positively correlated with presence of plaque, age, menopause age and OPG, and inversely correlated with Apolipoprotein A1 (Apo A1). Serum OPG level was positively correlated with IMT (r = 0.366; p < 0.003) and age (r = 0.324; p < 0.008), and negatively correlated with Apo A1 (r = -0.481; p < 0.0001). We did not observe any significant relation between plaque occurrence and levels of serum OPG. In regression analysis OPG (p < 0.02) and menopause age (p < 0.05) were independent risk factors for IMT, and age (p < 0.05) and IMT (p < 0.05) were independent risk factors for plaque formation. Although the role of OPG in the vascular biology is poorly understood, our results suggest that elevated levels of serum OPG is associated with IMT and may play a role in the pathogenesis of atherosclerotic disease.

BACKGROUND

The preventive role of polyunsaturated fatty acids in cardiovascular disease has been recognized. We conducted a cross-sectional study to assess the association between walnut consumption (oil and kernel) as a source of polyunsaturated fatty acids and blood lipid levels.

METHODS

Seven hundred ninety-three persons, males and females, ages 18-65 years, living in a walnut production area (Dauphiné, France) attended health screening visits organized by the Agriculture Social Security. Past diet (1-year recall, including walnut and animal fat consumption) and cardiovascular risk factors were ascertained using food frequency questionnaires. For each participant a blood sample was taken to measure HDL, LDL, and total cholesterol; apo A1; and apo B.

RESULTS

A high level of HDL cholesterol and apo A1 was associated with a high amount of walnut consumption (oil and kernel) in the regular diet, with a positive trend with increasing degree of walnut consumption. This association did not appear to be confounded by dietary animal fat and alcohol as measured in this study. Other blood lipids did not show significant associations with walnut consumption.

CONCLUSIONS

The positive effect of walnut consumption on blood HDL cholesterol and apo A1 is of special interest since these lipid parameters have been shown to be negatively correlated with cardiovascular morbidity.