Short cDNA fragments covering the entire coding region for apolipoprotein (apo) B have been cloned in the pING expression vector. A monoclonal antibody specific for the Ag(d) epitope on apo B has been used, together with the expressed apo B peptides, to locate this epitope to a stretch of 26 amino acids. Sequencing of this region from several genomic DNAs of known Ag(a1/d) genotype showed a single T-to-C substitution at nucleotide 1981, creating an Alu I restriction site and resulting in a val to ala residue change in the corresponding peptide (at position 591 in the mature protein). Southern blots, using the Alu I restriction endonuclease and a short probe for this region of the cDNA, showed perfect correspondence between the restriction fragment length polymorphism and the Ag(a1/d) immunochemical polymorphism in all 17 persons examined.

The biosynthetic pathway of the CoQ polyisoprenoid side chain, starting from acetyl-CoA and proceeding through mevalonate and isopentenylpyrophosphate, is the same as that of cholesterol. We performed this study to evaluate whether vastatins (hypocholesterolemic drugs that inhibit HMG-CoA reductase) modify blood levels of ubiquinone. Thirty-four unrelated outpatients with hypercholesterolemia (IIa phenotype) were treated with 20 mg of simvastatin for a 6-month period (group S) or with 20 mg of simvastatin plus 100 mg CoQ10 (group US). The following parameters were evaluated at time 0, 45, 90, 135 and 180 days: total plasma cholesterol (TC), HDL-cholesterol, LDL-cholesterol (LDL-C), triglycerides (TG), apo A1, apo B and CoQ10 in plasma and platelets. In the S group, there was a marked decrease in TC and LDL-C (from 290.3 mg/dl to 228.7 mg/dl for TC and from 228.7 mg/dl to 167.6 mg/dl for LDL-C) and in plasma CoQ10 levels from 1.08 mg/dl to 0.80 mg/dl. In contrast, in the US group we observed a significant increase of CoQ10 in plasma (from 1.20 to 1.48 mg/dl) while the hypocholesterolemic effect was similar to that observed in the S group. Platelet CoQ10 also decreased in the S group (from 104 to 90 ng/mg) and increased in the US group (from 95 to 145 ng/mg). This study demonstrates that simvastatin lowers both LDL-C and apo B plasma levels together with the plasma and platelet levels of CoQ10, and that CoQ10 therapy prevents both plasma and platelet CoQ10 decrease, without affecting the cholesterol lowering effect of simvastatin.

BACKGROUND

We aimed to determine the relationship between ruptured abdominal aortic aneurysm (AAA) and serum concentrations of lipids and apolipoproteins.

METHODS

A cohort of 21 520 men, aged 35-64 years, was recruited from men attending the British United Provident Association (BUPA) clinic in London for a routine medical examination in 1975-1982. Smoking habits, weight, height and blood pressure were recorded at entry. Lipids and apolipoproteins were measured in stored serum samples from the 30 men who subsequently died of ruptured AAA and 150 matched controls.

RESULTS

Triglyceride was strongly related to risk of ruptured AAA. In univariate analyses the risk in men on the 90th centile of the distribution relative to the risk in men on the 10th (RO10-90) was 12 (95% confidence interval [CI] : 3.8-37) for triglyceride, 5.5 (95% CI: 1.8-17) for apolipoprotein B (apoB) (the protein component of low density lipoprotein [LDL]), 0.15 (95% CI : 0.04-0.56) for apo A1 (the protein component of high density lipoprotein [HDL]), 3.7 (95% CI: 1.4-9.4) for body mass index and 3.0 (95% CI: 1.1-8.5) for systolic blood pressure. Lipoprotein (a) (Lp(a)) was not a significant risk factor (RO10-90 = 1.6, 95% CI: 0.6-3.0). In multivariate analysis triglyceride retained its strong association.

CONCLUSIONS

Triglyceride appears to be a strong risk factor for ruptured AAA, although further studies are required to clarify this. If this and other associations are cause and effect, then changing the distribution of risk factors in the population (by many people stopping smoking and adopting a lower saturated fat diet and by lowering blood pressure) could achieve an important reduction in mortality from ruptured AAA.

OBJECTIVE

The objectives were to investigate into the relationship between lipid profile including Apolipoprotein-A1 (Apo-A1) and Apolipoprotein-B (Apo-B) and smokers and to relate them with smoking pack years.

METHODS

A total of 274 active male smokers without any other illnesses and age matched male healthy control subjects (78) with similar socio-cultural background were assessed for clinical details, dietary habits, physical activities, smoking and alcohol consumption. Standard methods were adopted to check the lipid levels. The data were analyzed statistically.

RESULTS

Their ages ranged from 40 to 59 years, systolic BP from 110 to 130 mmHg, and diastolic BP from 76 to 88 mmHg. All of them had similar pattern of diet (vegetarianism with occasional meat). None was on any medication influences lipid level. Their physical activity was moderate. Number of pack years varied from 10 to 14 (mild), 15 to 19 (moderate) and 20 and above (heavy) among 69, 90 and 115 cases, whose mean ages were 43, 44 and 49 respectively. The mean (+SD) values in mg/dl of total cholesterol (TC), Triglyceride (TGL), Apo-B, low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol and Apo-A1 in mg/dl among mild/ moderate/ heavy smokers and control subjects were 198 (30.6)/ 224 (27.2)/ 240 (24.3) and 160 (20.4); 164(42.6)/ 199 (39.5)/ 223(41.7) and 124 (31.6); 119 (24.9)/ 121 (27)/ 127 (28.3) and 116 (21.4); 94 (19.7)/ 104 (21.8)/ 120 (20.5) and 82 (17.6); 42 (5.9)/ 39 (3.1)/ 35(4.4) and 48 (5.3); and 120 (17)/ 119 (21)/ 115 (25) and 126 (19), respectively. In smokers, there was a rise in TC, TGL, LDL, Apo-B and fall in HDL and Apo-A; these changes were significant (P < 0.05).

CONCLUSIONS

Number of pack years was directly proportional to abnormal lipid profile. It is also concluded that changes in Apo-A1 and Apo-B were more significant when compared to HDL and LDL cholesterol among smokers. In the view of double risk for smokers (smoking and altered lipid profile) efforts may be made to introduce smoking cessation program.

Angelica keiskei is a traditional herb peculiar to Japan and abundantly contains vitamins, dietary fiber and such polyphenols as chalcone. We investigated in the present study the effect of A. keiskei on insulin resistance and hypertriglyceridemia in fructose-drinking rats as a model for the metabolic syndrome. Male Wistar rats were given a 15% fructose solution as drinking water for 11 weeks. Fructose significantly increased the levels of serum insulin and triglyceride (TG) compared with the control level. Treatment with an ethanol extract of A. keiskei (AE) significantly reduced the levels of blood glucose (-16.5%), serum insulin (-47.3%), HOMA-R (-56.4%) and TG (-24.2%). A hepatic gene analysis showed that fructose reduced the expression of the genes related to fatty acid β-oxidation and high-density lipoprotein (HDL) production. Treatment with AE enhanced the expression of the acyl-CoA oxidase 1 (ACO1), medium-chain acyl-CoA dehydrogenase (MCAD), ATP-binding membrane cassette transporter A1 (ABCA1) and apolipoprotein A1 (Apo-A1) genes. These results suggest that AE improved the insulin resistance and hypertriglyceridemia of the fructose-drinking rats.

This study was designed to evaluate coagulation and fibrinolysis activity and their relationship with left ventricular function in young obese subjects with central fat distribution. We assessed coagulation and fibrinolysis activity by evaluation of factor VII activity, fibrinogen and plasminogen, plasminogen activator inhibitor (PAI), and tissue plasminogen activator antigen basally (tPA1) and after venous occlusion (tPA2). These measures were evaluated in young (< 40 years) obese subjects with central fat distribution (n = 19) and in comparable lean subjects (n = 20). Blood glucose, triglycerides, total and high-density lipoprotein (HDL) cholesterol, apolipoprotein (apo) A1 and apo B, fasting immunoreactive insulin, and lipoprotein(a) levels were also measured by current methods. Left ventricular ejection fraction (LVEF) and peak filling rate (PFR) determined by radionuclide angiocardiography and left ventricular mass (LVM) and LVM indexed for body height (LVM/H) determined by echocardiographic study were calculated. Central obesity was evaluated by the waist to hip ratio (WHR) according to the criteria of the Italian Consensus Conference of Obesity. Factor VII (P < .001), fibrinogen (P < .001), plasminogen (P < .001), PAI activity (P < .001), tPA1 (P < .02), fasting blood glucose (P < .01), apo B (P < .02), and immunoreactive insulin (P < .01) were significantly higher in obese than in lean subjects. In contrast, HDL cholesterol (P < .01), tPA2 (P < .01), LVEF (P < .001), and PFR (P < .02) were significantly lower in obese than in lean subjects. In all subjects, WHR correlated directly with fibrinogen and inversely with tPA2; LVEF correlated inversely with tPA1, PAI, and fibrinogen; and PFR correlated inversely with factor VII activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Palm oil is an excellent choice for food manufacturers because of its nutritional benefits and versatility. The oil is highly structured to contain predominantly oleic acid at the sn2-position in the major triacylglycerols to account for the beneficial effects described in numerous nutritional studies. Oil quality and nutritional benefits have been assured for the variety of foods that can be manufactured from the oil directly or from blends with other oils while remaining trans-free. The oxidative stability coupled with the cost-effectiveness is unparalleled among cholesterol-free oils, and these values can be extended to blends of polyunsaturated oils to provide long shelf-life. Presently the supply of genetic-modification-free palm oil is assured at economic prices, since the oil palm is a perennial crop with unparalleled productivity. Numerous studies have confirmed the nutritional value of palm oil as a result of the high monounsaturation at the crucial 2-position of the oil's triacylglycerols, making the oil as healthful as olive oil. It is now recognized that the contribution of dietary fats to blood lipids and cholesterol modulation is a consequence of the digestion, absorption, and metabolism of the fats. Lipolytic hydrolysis of palm oil glycerides containing predominantly oleic acid at the 2 position and palmitic and stearic acids at the 1 and 3 positions allows for the ready absorption of the 2-monoacrylglycerols while the saturated free fatty acids remain poorly absorbed. Dietary palm oil in balanced diets generally reduced blood cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides while raising the high-density lipoprotein (HDL) cholesterol. Improved lipoprotein(a) and apo-A1 levels were also demonstrated from palm oil diets; an important benefits also comes from the lowering of blood triglycerides (or reduced fat storage) as compared with those from polyunsaturated fat diets. Virgin palm oil also provides carotenes apart from tocotrienols and tocopherols that have been shown to be powerful antioxidants and potential mediators of cellular functions. These compounds can be antithrombotic, cause an increase of the prostacyclin/thromboxane ratio, reduce restenosis, and inhibit HMG-CoA-reductase (thus reducing) cholesterol biosynthesis). Red palm oil is a rich source of beta-carotene as well as of alpha-tocopherol and tocotrienols.

Recombinant expression systems have become powerful tools for understanding the structure and function of proteins, including the apolipoproteins that comprise human HDL. However, human apolipoprotein (apo)A-II has proven difficult to produce by recombinant techniques, likely contributing to our lack of knowledge about its structure, specific biological function, and role in cardiovascular disease. Here we present a novel Escherichia coli-based recombinant expression system that produces highly pure mature human apoA-II at substantial yields. A Mxe GyrA intein containing a chitin binding domain was fused at the C terminus of apoA-II. A 6× histidine-tag was also added at the fusion protein's C terminus. After rapid purification on a chitin column, intein auto-cleavage was induced under reducing conditions, releasing a peptide with only one extra N-terminal Met compared with the sequence of human mature apoA-II. A pass through a nickel chelating column removed any histidine-tagged residual fusion protein, leaving highly pure apoA-II. A variety of electrophoretic, mass spectrometric, and spectrophotometric analyses demonstrated that the recombinant form is comparable in structure to human plasma apoA-II. Similarly, recombinant apoA-II is comparable to the plasma form in its ability to bind and reorganize lipid and promote cholesterol efflux from macrophages via the ATP binding cassette transporter A1. This system is ideal for producing large quantities of recombinant wild-type or mutant apoA-II for structural or functional studies.

The influence of liver failure, ascites, and energy expenditure on the response to oral nutrition was assessed in a group of 55 alcoholic cirrhotic patients. Caloric intake, nutritional status, resting energy expenditure (REE), and Child-Pugh score were evaluated before and after 1 mo of oral nutrition. Patients were severely malnourished, 73% had muscular midarm circumference (MMAC) below the 5th percentile of a reference population, 51% had triceps skinfold thickness below the 25th percentile. Eleven patients were in class A of Child, 19 in class B, and 25 in class C. Twenty-six patients were nonascitic, whereas ascites was resolved in 10 ascitic patients by the end of the study and 19 patients had refractory ascites. Liver damage was more pronounced and did not improve during the study in patients with refractory ascites. Caloric intake was approximately 40 kcal/kg of body weight and was in the same range in the three groups according to Child classification. Fat mass (FM) increased, respectively, from 17.4% +/- 1.7% to 19.5% +/- 1.4%, P < 0.01, in Child A patients; from 17.1% +/- 1.4% to 19.3% +/- 1.4%, P < 0.001, in Child B patients; and from 17.6% +/- 1.5% to 18.8% +/- 1.5%, P < 0.05, in Child C patients. The increase in FM was comparable in the three groups, whereas MMAC and the creatinine/height ratio did not change significantly. FM was lower and did not increase in patients with refractory ascites. Child C patients were characterized by an increase in the rate of glucose oxidation (P < 0.02) and a decrease in the rate of lipid oxidation (P < 0.05). High-density lipoprotein cholesterol and apolipoprotein (Apo) A1 were reliable indices of improvement of liver function in patients with severe liver failure, ApoA1 was also a marker of improvement of metabolic impairment. With respect to the measured REE/predicted REE ratio calculated according to Harris-Benedict equation (r), 19 patients were considered hypermetabolic (r < 1.1), 30 normometabolic (0.9 < r < 1.1), and 6 hypometabolic (r < 0.9). An increase in FM correlated with r (P < 0.01) and was more marked in hypermetabolic patients. In contrast to the other two groups, Child-Pugh score and nutritional status remained unchanged in the hypometabolic patients. These results show that severe liver failure did not preclude improvement of nutritional status provided caloric intake was high. In Child C patients, improvement of nutritional status paralleled improvement of liver function and normalization of oxidative metabolism. Refractory ascites had negative effects on changes in nutritional status and liver function. Despite adequate caloric intake to energy requirements, hypometabolism has a poor prognosis regarding both nutritional status and liver function.

The liver X receptor (LXR) agonist TO901317 inhibited the synthesis of apolipoprotein A1 (apo A1) by human liver-derived cells, including the formation of lipid-poor, prebeta-migrating high-density lipoprotein (HDL). Despite activation of the lipid transporter ABCA1 under these conditions, cellular efflux of PL and cholesterol from liver cells was also reduced. By assaying transcription from full-length and truncated promoters and by site-directed mutagenesis, the effect of LXR and its ligand was localized to a binding site for hepatic nuclear factor-4 (HNF4) in the proximal apo A1 promoter (-132/-119 bp). Chromatin immunoprecipitation analysis of apo A1 transcription complexes from control and ligand-activated cells showed an increase in the binding of reported apo A1 transcriptional inhibitor COUP-TF, which competes with HNF4 for DNA binding. It also identified LXR in the apo A1 transcription complex of TO901317-treated cells. Displacement of HNF4 from the -132/-119 bp promoter DNA sequence in the presence of TO901317 was confirmed by gel shift analysis. These data indicate that LXR can be a significant negative regulator of apo A1 transcription and HDL synthesis.

In a screening investigation in 1982, which included medical history, clinical examination, general laboratory investigation, and quantification of lipids, lipoproteins, and apoproteins A1 and B, 5020 male subjects aged 40 to 59 years took part. All subjects were free of any heart or vascular disease at the basic examination. Of them 40 suffered fatal or nonfatal myocardial infarction (MI) during the first 3-year observation period between January 1982 and December 1984 (incidence cases), the others remained free of heart or vascular diseases (reference group). Comparison with the reference group revealed a strong relationship between MI-incidence rate and LDL cholesterol (correlation coefficient according to univariate regression analysis r = +0.248; P value according to Chi-square test P less than 0.001). The relationship was less strong but significant for age (r = +0.189; P less than 0.001), total serum cholesterol (r = +0.197; P less than 0.001), and apoprotein B (r = +0.195; P less than 0.001). Although statistically significant, the relationships to the MI-incidence rate were comparatively weak for HDL cholesterol (r = -0.09; P less than 0.01), apo-A1 (r = -0.09; P less than 0.01), systolic blood pressure (r = +0.067; P less than 0.05), and blood glucose level (r = +0.066; P less than 0.05). Body mass index, diastolic blood pressure, and plasma levels of uric acid, triglycerides, and VLDL did not exert relevant influences on the MI-incidence rate in our study population.(ABSTRACT TRUNCATED AT 250 WORDS)

We investigated the changes of low-density lipoprotein (LDL) size and serum lipids during pregnancy and postpartum not only in normal pregnant women but also in preeclampsia. Serum triglyceride (TG) and total cholesterol levels as well as serum high-density lipoprotein (HDL)-cholesterol, apolipoprotein (Apo) A1, B, E and remnant-like particle (RLP)-cholesterol levels were increased in normal pregnant women. The LDL peak particle diameter (PPD) in normal pregnant women was decreased during pregnancy and that at 37 weeks of gestation showed significant decrease compared with the women at 4 weeks after delivery (25.8 +/- 1.0 vs.26.8 +/- 0.7 nm, p < 0.05). The LDL-PPD in the preeclamptic women at admission (mean gestational age: 36 +/- 2.4 weeks) was significantly lower than that in normal pregnancy at 37 weeks of gestation (24.7 +/- 1.2 vs. 25.8 +/- 1.0 nm, p < 0.05). Moreover, the LDL-PPD in the preeclamptic women was significantly higher after delivery compared with the level at admission (27. +/- 0.7 vs. 24.7 +/- 1.2 nm, p < 0.05) accompanied by an improvement in plasma lipids profile. These findings suggest that the predominance of small, dense LDL, a potential contributor to endothelial dysfunction, may be a possible predictor of preeclampsia.

Apolipoprotein B (Apo B) is a component of chylomicrons, low-density lipoproteins (LDL), very low density lipoproteins (VLDL), and intermediate-density lipoproteins (IDL) and is the ligand for the LDL receptor. Thereby, Apo B plays a central role in lipoprotein metabolism and in maintaining the normal homeostasis of serum cholesterol levels. Several Apo B restriction fragment length polymorphisms (XbaI, EcoRI, MspI) have been reported to be associated with variation in lipid levels, obesity and/or coronary artery disease. To date, no data are available on relationship between XbaI Apo B polymorphism and lipid levels in Tunisian population. Here, we report frequencies of the XbaI polymorphism of the Apo B gene and we assess the effect of this polymorphism on lipid and lipoprotein concentrations in Tunisian population. Blood samples from 296 Tunisian individuals (112 women and 184 men, aged 51.4+/-9.6 years), were analysed for total cholesterol, triglycerides, HDL-cholesterol and apolipoproteins A1 and B. In parallel, genotyping by means of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) was performed. The XbaI polymorphism was associated with differences in plasma cholesterol (p=0.04), triglyceride (p=0.02) and apolipoprotein A1 (p=0.004), individuals with the genotype X1X1 have the lowest mean levels and those with the genotype X2X2 have the highest, with the individuals heterozygous for the polymorphism having intermediate levels. According to sex, the XbaI polymorphism effect was only observed for triglyceride in men. Thus, the results demonstrate an influence of XbaI polymorphism of Apo B gene on serum total-cholesterol, triglycerides and apolipoprotein A1 concentrations among Tunisian population.

The safety and efficacy of combined bezafibrate-simvastatin therapy was evaluated in 49 patients with diet-resistant mixed hyperlipidaemia (type IIb). After a two-month placebo phase, patients were randomized to receive either Bezafibrate Slow Release (SR) 400 mg mane or simvastatin 20 mg nocte followed by three months combination therapy. Total cholesterol, triglycerides and high-density lipoprotein (HDL) cholesterol were measured at monthly intervals. Apolipoproteins (apo) A1 and B, lipoprotein (a) [Lp(a)] and fibrinogen were measured before and after each treatment. Simvastatin was more effective than Bezafibrate SR in reducing total cholesterol (2.0 vs. 1.1 mmol/l, p = 0.003) and lowering LDL cholesterol (1.7 vs. 0.4 mmol/l, p = 0.0001) whereas Bezafibrate SR was more effective in reducing triglycerides (by 41% vs. 17%, p = 0.001) and fibrinogen (by 23% vs. 3%, p = 0.004). Compared with simvastatin monotherapy, combined drug therapy induced further reductions in triglycerides (by 26%, p = 0.0003) and apoB (by 11 mg/dl, p = 0.03) and an increase in apoA1 (by 21 mg/dl, p = 0.0008). Symptomatic and biochemical adverse events did not occur more frequently on combined drug therapy than on monotherapy. The combination of bezafibrate and simvastatin was more effective in controlling mixed hyperlipidaemia than either drug alone and did not provoke more adverse events.

Progressive capillary occlusion often leads to severe retinopathy within 15-20 years of the onset of Type 1 (insulin-dependent) diabetes mellitus. Lipoprotein(a), a complex formed by apolipoprotein(a), apo B-100 and lipids, is considered an independent, genetically determined, predictor of cardiovascular disease. It may have antifibrinolytic properties in view of its similarity to plasminogen. To test the hypothesis that circulating lipoprotein(a) is associated with the process that leads to clinically active diabetic retinopathy, we measured the circulating levels of apolipoprotein(a) (which are strictly correlated with those of lipoprotein(a)) in two groups of patients with Type 1 diabetes of at least 15 years duration: 25 with active retinopathy and 27 without clinically detectable retinal lesions. Thirty-eight healthy subjects of the same age and sex served as controls. Serum apolipoprotein(a) was higher in the patients with active retinopathy (36(2-193) U/dl, geometric mean and range) than in those without clinically detectable retinal lesion (17(1-160)) and the control subjects (14(0-115)), p < 0.01 in both cases. The distribution of apolipoprotein(a) levels was skewed to the left, as expected, in the patients without clinically evident retinal lesions and the control groups, but there was a bimodal trend of distribution among those with active retinopathy. The levels of glycated haemoglobin were similar in the two groups of diabetic patients, and no significant differences were found for total and HDL cholesterol, triglycerides or apolipoproteins A1 and B between them and the control subjects. These preliminary results suggest that serum apolipoprotein(a) is elevated in patients with active retinopathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Recent findings suggest that hypertension, dyslipidemia, diabetes mellitus, coronary heart disease are more common in adults who born with intrauterine growth restriction (IUGR). Several studies have shown that polymorphisms in angiotensin-converting enzyme (ACE) and apolipoprotein-E (Apo-E) are effective in developing the insulin resistance and also in increasing the risk of coronary heart disease. In present study, the frequencies of ACE, Apo-E gene polymorphisms, apolipoprotein-B (Apo-B) mutation and lipid compositions were determined in full-term newborn infants with IUGR. Forty-four newborn infants who had completed 36 weeks of gestational age, 24 healthy infants and 20 with IUGR, were taken into the scope of the study. While total cholesterol (TC) and Apo-B concentrations in infants with IUGR was found to be significantly higher than that of the control group (p<0.05), triglyceride (TG), low-density lipoproteins (LDL), high-density lipoproteins (HDL) and Apo-A1 levels were similar (p>0.05). An insertion/deletion (I/D) polymorphism with a significantly increased frequency was observed in the IUGR group (65%) as compared with the control group (33%) (p<0.05). When the distribution of the Apo-E gene polymorphism (E2, E3 and E4) was studied, no difference was found between the IUGR and control groups with respect to frequency. No Apo-B gene mutation was identified in the study groups. In conclusion, we may suggest that I/D polymorphism is responsible, though in part, for the etiology of intrauterine growth restriction. Levels of total cholesterol and Apo-B are elevated in IUGR infants, suggesting a linkage between low birth weight and atherosclerosis.

The specificity of human glutathione transferase (GST) A1-1 is drastically altered to favor alkenal substrates in the GIMFhelix mutant designed to mimic first-sphere interactions utilized by GSTA4-4. This redesign serves as a model for improving our understanding of the structural determinants that contribute to the distinct specificities of alpha class GSTs. Herein we report the first crystal structures of GIMFhelix, both in complex with GSH and in apo form at 1.98 and 2.38 A resolution. In contrast to the preorganized hydrophobic binding pocket that accommodates alkenals in GSTA4-4, GSTA1-1 includes a dynamic alpha9 helix that undergoes a ligand-dependent localization to complete the active site. Comparisons of the GIMFhelix structures with previously reported structures show a striking similarity with the GSTA4-4 active site obtained within an essentially GSTA1-1 scaffold and reveal the alpha9 helix assumes a similar localized structure regardless of active site occupancy in a manner resembling that of GSTA4-4. However, we cannot fully account for all the structural elements important in GSTA4-4 within the mutant's active site. The contribution of Phe10 to the Tyr212-Phe10-Phe220 network prevents complete C-terminal closure and demonstrates that the presence of Phe10 within the context of a GSTA4-4-like active site may ultimately hinder Phe220, a key C-terminal residue, from effectively contributing to the active site. In total, these results illustrate the remaining structural differences presumably reflected in the previously reported catalytic efficiencies of GIMFhelix and GSTA4-4 and emphasize the F10P mutation as being necessary to completely accomplish the transformation to a highly specific GST from the more promiscuous GSTA1-1 enzyme.

BACKGROUND

Several common genetic polymorphisms in the low density lipoprotein receptor (LDL-R) gene have associated with modifications of serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels, but the results are not consistent in different populations. Bai Ku Yao is a special subgroup of the Yao minority in China. The present study was undertaken to detect the association of LDL-R gene Ava Ⅱ polymorphism and serum lipid levels in the Guangxi Bai Ku Yao and Han populations.

METHODS

A total of 1024 subjects of Bai Ku Yao and 792 participants of Han Chinese were randomly selected from our previous stratified randomized cluster samples. Genotyping of the LDL-R gene Ava Ⅱ polymorphism was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing.

RESULTS

The levels of serum TC, high density lipoprotein cholesterol (HDL-C), LDL-C, apolipoprotein (Apo) A1 and the ratio of ApoA1 to ApoB were lower in Bai Ku Yao than in Han (P < 0.01 for all). The frequency of A⁻ and A+ alleles was 65.5% and 34.5% in Bai Ku Yao, and 80.7% and 19.3% in Han (P < 0.001); respectively. The frequency of A⁻A⁻, A⁻A+ and A+A+ genotypes was 42.6%, 45.9% and 11.5% in Bai Ku Yao, and 64.9%, 31.6% and 3.5% in Han (P < 0.001); respectively. There was also significant difference in the genotypic frequencies between males and females in Bai Ku Yao (P <0.05), and in the genotypic and allelic frequencies between normal LDL-C (≤ 3.20 mmol/L) and high LDL-C >> 3.20 mmol/L) subgroups in Bai Ku Yao (P < 0.05 for each) and between males and females in Han (P < 0.05 for each). The levels of LDL-C in males and TC and HDL-C in females were different among the three genotypes (P < 0.05 for all) in Bai Ku Yao, whereas the levels of HDL-C in males and HDL-C and ApoA1 in females were different among the three genotypes (P < 0.05-0.001) in Han. The subjects with A+A+ genotype had higher serum LDL-C, TC, HDL-C or ApoA1 levels than the subjects with A-A+ and A⁻A⁻ genotypes. Spearman rank correlation analysis revealed that the levels of LDL-C in Bai Ku Yao and HDL-C in Han were correlated with genotypes (P < 0.05 and P < 0.01; respectively).

CONCLUSIONS

The association of LDL-R gene Ava Ⅱ polymorphism and serum lipid levels is different between the Bai Ku Yao and Han populations. The discrepancy might partly result from different LDL-R gene Ava Ⅱ polymorphism or LDL-R gene-environmental interactions.

OBJECTIVE

Whether serum lipoprotein (a) [Lp(a)] levels are an independent risk factor for coronary heart disease has been controversial. We have investigated its status in a prospective population survey, the Second Northwick Park Heart Study.

METHODS

We recruited 2,616 men 50 to 61 years old from nine primary care practices in the United Kingdom. Baseline serum Lp(a) levels were measured by enzyme-linked immunosorbent assay (ELISA) and were analyzed in 3 groups (<25th percentile, 25th to 75th percentile, and >75th percentile) to overcome the problem of some measurements falling below the threshold of the assay. Coronary end points included sudden cardiac death, acute myocardial infarction, silent myocardial infarction on the electrocardiogram, and coronary artery bypass surgery.

RESULTS

During a mean of 6 years of follow-up, 121 men had coronary events. In a multivariate analysis that also adjusted for fibrinogen, Apo-A1, Apo-B, and triglyceride levels, we identified several independent risk factors for coronary events, including cholesterol level (hazard ratio [HR] = 1.5 per SD 95% confidence interval [CI] 1.3 to 1.8), diabetes (HR = 4.1, 95% CI: 2. 0 to 8.4), current versus never smoking (HR = 2.5, 95% CI: 1.5 to 4.1), diastolic blood pressure (HR = 1.4 per SD, 95% CI: 1.1 to 1.7), Apo-A1 (HR = 0.8 per SD, 95% CI: 0.6 to 0.9), age (HR = 1.3 per SD, 95% CI: 1.1 to 1.6), and Lp(a) (>26.3 mg/dL [75th percentile] versus <2.9 mg/dL [25th percentile], HR = 1.9, 95% CI: 1.1 to 3.3]. There was a statistically significant (P = 0.01) difference in risk between the three levels of Lp(a).

CONCLUSIONS

We found that a high Lp(a) level was an independent predictor of the development of coronary heart disease in middle-aged men.

OBJECTIVE

To examine whether plasma adiponectin level is correlated with osteonecrosis of the femoral head (ONFH).

METHODS

Blood adiponectin level in patients with nontraumatic ONFH (n = 120) was compared with a group of healthy subjects (n = 120). Patients with hip osteoarthritis (OA; n = 30) and traumatic ONFH (n = 45) were included as controls. Potential compounding factors, such as plasma low-density lipoprotein (LDL), high-density lipoprotein (HDL), apolipoprotein A1 (apo A1), apolipoprotein B (apo B), total cholesterol (TC), triglycerides (TG), and C-reactive protein (CRP) were also examined.

RESULTS

Patients with nontraumatic ONFH had significantly lower plasma levels of adiponectin than the healthy controls (7.14 ± 3.53 vs 10.93 ± 3.41 μg/ml, respectively; p < 0.001). Adiponectin level was positively correlated with HDL (r = 0.282, p < 0.001) and age (r = 0.145, p = 0.01), yet negatively correlated with body mass index (r = -0.70, p < 0.001), TG (r = -0.55, p<0.001), LDL/HDL ratio (r = -0.173, p = 0.002), and CRP (r = -0.634, p < 0.001). No correlation was seen with LDL (r = -0.017, p = 0.762). A multiple logistic regression analysis revealed that adiponectin level is an independent predictor of the presence of nontraumatic ONFH (p < 0.001, OR 0.676, 95% CI 0.546 to 0.845).

CONCLUSIONS

Low adiponectin level is significantly associated with the presence of nontraumatic ONFH. This biomarker may be useful in assessing the potential presence of nontraumatic ONFH.

BACKGROUND

Nonalcoholic fatty liver disease (NAFLD) is associated with a higher risk of cardiovascular disease, but the relationship has not been established in nonobese populations. Higher apolipoprotein B (apo B) levels and the apo B/A1 ratio and lower apo A1 levels are associated with an elevated risk of cardiovascular disease. We investigated the associations between apo B, apo A1, and the apo B/A1 ratio and the presence of metabolic syndrome and NAFLD in both normal-weight and overweight Koreans.

METHODS

This cross-sectional study consisted of 8327 consecutive both normal-weight and overweight Koreans with NAFLD diagnosed by ultrasonography at the Samsung Medical Center in Korea from January 2008 to December 2010.

RESULTS

The prevalence of NAFLD was 27.1% among the 8327 participants. Higher serum triglyceride levels and the apo B/A1 ratio and lower high-density lipoprotein cholesterol and apo A1 levels were significantly associated with higher prevalence of metabolic syndrome in both normal-weight group and overweight group. The multivariate-adjusted odds ratios (ORs) for NAFLD in normal-weight group after comparing the fourth vs the first quartiles of the triglyceride, HDL cholesterol, low-density lipoprotein (LDL) cholesterol, apo B, apo A1, and the apo B/A1 ratio data were 2.89 (95% confidence interval [CI], 2.19-3.83; P trend < .001), 0.60 (95% CI, 0.46-0.78; P trend < .001), 1.67 (95% CI, 1.33-2.11; P trend < .001), 1.88 (95% CI, 1.48-2.39; P trend < .001), 0.73 (95% CI, 0.58-0.93; P trend < .001), and 1.86 (95% CI, 1.45-2.38; P trend < .001), respectively. The corresponding adjusted ORs in the overweight group were 3.43 (95% CI, 2.60-4.54; P trend < .001), 0.89 (95% CI, 0.68-1.16; P trend = .221), 1.41 (95% CI, 1.11-1.78; P trend = .001), 1.58 (95% CI, 1.21-2.06; P trend < .001), 0.99 (95% CI, 0.77-1.27; P trend = .958), and 1.53 (1.16-2.01; P trend = .002), respectively.

CONCLUSIONS

Higher serum triglyceride, LDL cholesterol, apo B1 levels, and the apo B/A1 ratio were significantly associated with NAFLD independent of metabolic syndrome in both normal-weight and overweight Koreans. Lower serum HDL cholesterol and apo A1 levels were related to NAFLD in normal-weight participants. Our results suggest that the presence of NAFLD may be associated with increased risk for coronary artery disease in both normal-weight and overweight Koreans.

The present study was carried out on 20 female patients diagnosed with acute coronary syndrome (ACS). The control group was composed of 20 healthy female volunteers. Plasma malondialdehyde (MDA) levels and serum zinc (Zn), total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and VLDL-cholesterol, Lp(a), Apo-A1, and Apo-B were determined in all patients and controls. Plasma MDA levels were determined to be significantly high in patients with ACS compared to the controls (1.75+/-0.27 vs 0.8+/-0.43 nmol/mL; p<0.05). On the other hand, Zn levels in patients with ACS were determined to be significantly low compared to the control group (67.9+/-14.8 vs 101.8+/-22.4 mg/dL; p<0.05). There was a statistically significant negative correlation between MDA and Zn levels in patients with ACS (r = -0.678, p<0.05). Other lipid parameters were significantly altered in patients with ACS compared to the controls (p<0.05). In conclusion, Zn and lipid peroxidation levels are important in patients with ACS and they must be monitored during diagnosis and treatment of these patients.

OBJECTIVE

Dyslipidemia and non-traditional cardiovascular (CV) risk factors, such as lipoprotein(a) (Lp(a)), homocysteine, oxidative stress and inflammation, are important determinants in the increased CV risk of hemodialysis (HD) patients. The aim of our study was to evaluate the effects of atorvastatin on these parameters in one of the groups with the highest CV risk: diabetic patients with end-stage renal disease under HD therapy.

METHODS

Twenty maintenance HD diabetic patients (mean age 64 +/- 10 years, mean time on HD 25 +/- 11 months) with low-density lipoprotein cholesterol (LDL-C) >2.59 mmol/l received atorvastatin (10 mg/day) for 4 months. Lipid profile, including total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), apolipoproteins A1 and B (Apo-A and Apo-B), and the non-traditional risk factors Lp(a), homocysteine, autoantibodies against oxidized LDL-C (anti-LDLox), total antioxidant status (TAS), and high sensitive C-reactive protein (hs-CRP), were measured at baseline and at the end of the study. Safety was assessed by clinical and laboratory (liver and muscle enzymes) monitoring once a month.

RESULTS

Mean percent reductions for TC, LDL-C and TG were 18.5% (p < 0.001), 22% (p < 0.001) and 19% (p < 0.01), respectively. The ratios of TC/HDL-C and LDL-C/HDL-C decreased after treatment (p < 0.05), whereas the ratios of LDL-C/Apo-B (p < 0.01) and Apo-A/Apo-B (p < 0.001) increased. No significant changes were observed in HDL-C. Concerning the non-traditional risk factors, levels of homocysteine, Lp(a), anti-LDLox and TAS did not change significantly. However, hs-CRP decreased from 5.4 (range 0.9-67.8) to 2.3 mg/l (range 0.4-21) (p < 0.01), whereas a concomitant increase in serum albumin was observed (from 38 +/- 2 to 40 +/- 1.7 g/l, p < 0.01). At baseline, hs-CRP was inversely associated with HDL-C and Apo-A, and directly related to Lp(a). The change in hs-CRP was inversely associated with the change of HDL-C, whereas a direct correlation was found with the change of TG.

CONCLUSIONS

Atorvastatin administration to diabetic patients on HD is associated with improvement of lipid profile and reduction of hs-CRP. These effects may be critical for the reduction of CV risk and mortality in HD population.

The objective of this study was to determine the extent to which common genetic variants can explain the variation of high-density lipoprotein cholesterol (HDL-C) plasma levels in familial hypercholesterolemia (FH). FH is characterized by elevated low-density lipoprotein cholesterol levels and premature cardiovascular disease (CVD). Although low HDL-C levels have been shown to affect the severity of the clinical phenotype, little is known about the factors that determine HDL-C levels in these patients. A cohort of 1002 heterozygous FH patients was genotyped for polymorphisms in the genes encoding for ATP-binding cassette transporter A1, apolipoprotein (apo) AIV, apoCIII, apoE, cholesteryl transfer ester protein, hepatic lipase, lipoprotein lipase, and two paraoxonases. Multiple linear regression showed that, together, these polymorphisms explain only 3.9% of the variation of HDL-C plasma levels. When significant two-way interactions between the polymorphisms were also taken into account, the explained variation rose to 12.5%. In a regression model that also incorporated sex, smoking, alcohol use, body mass index, and concomitant beta-blocker use as covariates, the explained variation of HDL-C plasma levels even increased to 32.5%. This study provides direct evidence that multiple, modestly penetrant, but highly prevalent, polymorphisms can explain a substantial part of the variation of HDL-C plasma levels in a representative large cohort of heterozygous FH patients.