BACKGROUND

The lipid profile status among breast cancer patients at initial diagnosis and during chemotherapy remain controversial. The aim of this study is to study the status of lipid and lipoprotein in female breast cancer patients at initial diagnosis and during chemotherapy.

METHODS

We conducted a retrospective cohort study of the status of the lipid and lipoprotein in 1054 primarily diagnosed breast cancer patients and 2483 normal controls with age stratification, from July 2015 to October 2016. At the same time, the status of lipid and lipoprotein were also analyzed among 394 breast cancer patients before and after adjuvant chemotherapy.

RESULTS

The incidence of dyslipidemia was significantly lower in breast cancer group(42.98%) compared to normal group(58.28%)(P < 0.001). The levels of total cholesterol (TC), triglycerides (TG), HDL cholesterol (HDL-C), LDL cholesterol (LDL-C) among breast cancer group were significantly lower compared to normal control group (P < 0.05). With age stratification, the levels of TC and LDL-C in breast cancer group were still significantly lower than those in control group (P < 0.001). And the levels of TC, TG, LDL-C, apolipoprotein B were significantly higher among post chemotherapeutic patients compared to prechemotherapeutic patients, however HDL-C and Apo-A1 levels were contrary.

CONCLUSIONS

Breast cancer patients have lower incidence of dyslipidemia compared to normal populations. However, the situation of dyslipidemia may become worsened after chemotherapy. Therefore, lipid monitoring and dyslipidemia prevention and treatment should be conducted for breast cancer patients at initial diagnosis and during chemotherapy.

BACKGROUND

High consumption of fish carries a lower risk of cardiovascular disease as a consequence of dietary omega-3 long chain polyunsaturated fatty acid (n-3 PUFA; especially EPA and DHA) content. A controversy exists about the component/s responsible of these beneficial effects and, in consequence, which is the best proportion between both fatty acids. We sought to determine, in healthy Wistar rats, the proportions of EPA and DHA that would induce beneficial effects on biomarkers of oxidative stress, and cardiovascular disease risk.

METHODS

Female Wistar rats were fed for 13 weeks with 5 different dietary supplements of oils; 3 derived from fish (EPA/DHA ratios of 1:1, 2:1, 1:2) plus soybean and linseed as controls. The activities of major antioxidant enzymes (SOD, CAT, GPX, and GR) were determined in erythrocytes and liver, and the ORAC test was used to determine the antioxidant capacity in plasma. Also measured were: C reactive protein (CRP), endothelial dysfunction (sVCAM and sICAM), prothrombotic activity (PAI-1), lipid profile (triglycerides, cholesterol, HDLc, LDLc, Apo-A1, and Apo-B100), glycated haemoglobin and lipid peroxidation (LDL-ox and MDA values).

RESULTS

After three months of nutritional intervention, we observed statistically significant differences in the ApoB100/ApoA1 ratio, glycated haemoglobin, VCAM-1, SOD and GPx in erythrocytes, ORAC values and LDL-ox. Supplementation with fish oil derived omega-3 PUFA increased VCAM-1, LDL-ox and plasma antioxidant capacity (ORAC). Conversely, the ApoB100/ApoA1 ratio and percentage glycated haemoglobin decreased.

CONCLUSIONS

Our results showed that a diet of a 1:1 ratio of EPA/DHA improved many of the oxidative stress parameters (SOD and GPx in erythrocytes), plasma antioxidant capacity (ORAC) and cardiovascular risk factors (glycated haemoglobin) relative to the other diets.

OBJECTIVE

The screening and therapeutic guidelines for the management of lipid abnormalities are reasonably well established. However, other risk factors like hyperhomocysteinemia (HCA) and single nucleotide polymorphisms involving the angiotensin converting enzyme (ACE) and angiotensinogen genes, various clotting factors etc., have yet to be established firmly as other causative factors of atherothrombotic disease. Our study was aimed at finding the relationship between HCA, folate, vitamins B12 levels, and mutations in the 5,10-methylenetetrahydrofolate reductase (MTHFR) and cystathionine beta-synthase (CBS) genes.

METHODS

We studied 230 subjects, which included patients with angiographically documented coronary heart disease (CHD) (n=115) and controls (n=115) with no history of CHD.

RESULTS

Elevated levels of plasma homocysteine, above 18 nmoles/ml, were detected in 19.13% and 18.26% of our patients and controls, respectively. Homocysteine was significantly correlated to Apo A1 (r=0.51, p < 0.05) and Apo B (r=0.49, p < 0.05). The heterozygous MTHFR mutation was found to be 54.5% (12/22) in our patients with HCA. Of these, 31.8% (7/22) were deficient for plasma folate. Heterozygosity for T833C mutation in the CBS gene was observed in 9.99% (2/22) of our patients with HCA. Both these patients were also deficient for plasma folate and vitamin B12.

CONCLUSIONS

In our study, heterozygosity for the thermolabile MTHFR mutation was found to be associated with hyperhomocysteinemia (HCA). This genetic predisposition to HCA could be risk factor for CHD and can be correlated with vitamin supplementation. To the best of our knowledge this is the first report from India on plasma homocysteine levels and its genetic aspect in patients with CHD.

Mycobacterium tuberculosis is an obligate human respiratory pathogen that encodes approximately 10 arsenic repressor (ArsR) family regulatory proteins that allow the organism to respond to a wide range of changes in its immediate microenvironment. How individual ArsR repressors have evolved to respond to selective stimuli is of intrinsic interest. The Ni(II)/Co(II)-specific repressor NmtR and related actinomycete nickel sensors harbor a conserved N-terminal α-NH(2)-Gly2-His3-Gly4 sequence. Here, we present the solution structure of homodimeric apo-NmtR and show that the core of the molecule adopts a typical winged-helix ArsR repressor (α1-α2-α3-αR-β1-β2-α5) "open conformation" that is similar to that of the related zinc sensor Staphylococcus aureus CzrA, but harboring long, flexible N-terminal (residues 2-16) and C-terminal (residues 109-120) extensions. Binding of Ni(II) to the regulatory sites induces strong paramagnetic broadening of the α5 helical region and the extreme N-terminal tail to residue 10. Ratiometric pulse chase amidination mass spectrometry reveals that the rate of amidination of the α-amino group of Gly2 is strongly attenuated in the Ni(II) complex relative to the apo state and noncognate Zn(II) complex. Ni(II) binding also induces dynamic disorder on the microsecond to millisecond time scale of key DNA interacting regions that likely contributes to the negative regulation of DNA binding by Ni(II). Molecular dynamics simulations and quantum chemical calculations reveal that NmtR readily accommodates a distal Ni(II) hexacoordination model involving the α-amine and His3 of the N-terminal region and α5 residues Asp91', His93', His104, and His107, which collectively define a new metal sensing site configuration in ArsR family regulators.

Thyroid function and lipid tests were measured in 29 premenopausal women with subclinical hypothyroidism. This group was compared with 41 euthyroid women matched for age and metabolic parameters. In basal condition there was no difference in thyroid hormone levels between the two groups except for TSH concentration (P less than 0.01). Total cholesterol, triglycerides and apolipoprotein (apo A1, A2, B) of women with subclinical hypothyroidism were not different from controls. HDL cholesterol was significantly decreased in subclinical hypothyroidism compared to the controls (P less than 0.01). With thyroxine therapy, normalization of serum TSH was associated with (1) no significant change in total cholesterol and triglycerides, (2) an increase of HDL cholesterol (P less than 0.01) and apoprotein A1 (P less than 0.05) levels. Total cholesterol/HDL cholesterol ratio was increased in subclinical hypothyroidism (P less than 0.01). During L-thyroxine therapy this ratio returned to normal value. Decreased HDL cholesterol concentration might cause coronary heart disease reported in women with subclinical hypothyroidism.

The mechanism of formation of functional high-density lipoprotein (HDL) from secreted lipid-free apolipoprotein A1 (apo A1) was determined using human liver-derived (HepG2) cells, human intestine-derived (CaCO2) cells, and CHO cells stably expressing full-length human apo A1 (CHO-A1 cells). In each cell line, a significant proportion of secreted apo A1 had a Stokes radius of 2.6 nm and was inactive in binding phospholipids (PL) or free cholesterol (FC). Extracellularly, in a reaction dependent on membrane transporter ABCA1, prealpha-migrating 2.6 nm apo A1 was converted to a prebeta-migrating product that was able to bind PL. Both forms were reactive with mAb55201, a monoclonal antibody specific for native plasma lipid-poor (prebeta1) HDL [Nakamura, Y., et al. (2004) Biochemistry 43, 14311-14318]. The physical properties of precursor and product apo A1 suggested that both are monomers, with Stokes radii of 2.6 and 3.6 nm, respectively, consistent with the absence of intermolecular cross-linking of apo A1 in lipid-poor HDL, reported previously. Product but not precursor apo A1 promoted reverse cholesterol transport (RCT) from human aortic smooth muscle cells. These studies suggest an important contribution of secreted lipid-free apo A1 to HDL formation.

The prediction of coronary heart disease (CHD) and stroke by total and low density lipoprotein (LDL) cholesterol in older persons remains problematical. This study tests the hypothesis that cholesterol and other risk factors may be differentially predictive of CHD and ischaemic stroke in older persons when they are segregated into different age groups. CHD and ischaemic stroke outcomes were recorded during 129 months follow-up in a cohort of 2805 men and women of 60 years and older. There were 899 CHD events (32/100) and 326 stroke events (12/100). Using Cox proportional hazards, outcomes were modelled for the total cohort and for age groups 60-69, 70-79, and 80+ years. Total cholesterol, LDL cholesterol, serum apo-B, total cholesterol/high density lipoprotein (HDL) cholesterol and apo-B/apo-A1 were significant predictors of CHD in the total cohort, but significant only in the sub-group of 60-69 years. The respective hazard ratios (CI 95%) were 1.21 (1.09-1.35), 1.21 (1.09-1.35), 1.25 (1.13-1.39), 1.25 (1.14-1.37) and 1.21 (1.10-1.38). Similar findings were applicable with respect to ischaemic stroke in the age group of 60-69 years. Total cholesterol predicted CHD in men above a threshold value of 7.06 mmol/l and in women above 7.8 mmol/l, but with stroke the prediction was incremental. Other risk factors such as HDL cholesterol, triglycerides, lipoprotein(a), diabetes, hypertension and smoking predicted CHD, although only HDL and hypertension similarly predicted ischaemic stroke. The findings support a case for cholesterol testing in older subjects up to 70 years, in whom there is ancillary evidence of CHD and stroke prevention through treatment designed to reduce LDL cholesterol.

BACKGROUND

Efficacy and safety of an alpha-tocopherol-enriched emulsion incorporating soybean, coconut, olive, and fish oils (SMOF) are compared in terms of biologic parameters to those of soybean oil-based emulsion (LIPOVEN).

METHODS

Twenty stressed patients were randomly assigned in a double-blind study to receive at least a 5-day course of total parenteral nutrition. Plasma activities of liver enzymes, C-reactive protein, antioxidant capacity, alpha-tocopherol, retinol, and low density lipoprotein (LDL)-alpha-tocopherol levels were determined. LDL-lipid oxidation is measured after incubation of the LDL in the presence of a prooxidant.

RESULTS

The plasma activities of liver enzymes and the phospholipids/apo A1 ratio were increased in both groups. However, in the SMOF group the increases were lower than in the LIPOVEN group and non-significant for the CRP plasma level and the alanineamino-transferase activity. Before parenteral nutrition, the plasma antioxidant status was markedly reduced in both groups. After parenteral nutrition discontinuation, the antioxidant capacity and the amount of LDL-derived oxidation by-products formed were comparable in both groups. There was a significant improvement in plasma lipophilic antioxidant vitamins and LDL-alpha-tocopherol levels only in the SMOF group.

CONCLUSIONS

The lower increase of plasma liver enzymes and phospholipids/apo A1 ratio in the SMOF group suggest a better liver function than in the LIPOVEN group. This beneficial effect results in a higher liver mobilization and plasma levels of lipophilic antioxidants. They could, together with higher delivery of omega-3 fatty acids to peripheral tissues, contribute positively to survival rate of stressed patients.

BACKGROUND

Four single nucleotide polymorphisms (SNPs) (rs2237892, rs2237895, rs2237897, and rs2283228) in KCNQ1 are reported to be associated with type 2 diabetes mellitus (T2DM), possibly caused by a reduction in insulin secretion and higher fasting glucose, but the results are inconsistent. We investigated whether these 4 genetic markers are associated with serum lipid metabolism in a middle-aged Chinese Han population.

METHODS

We enrolled 398 consecutive patients, including 180 with premature coronary artery disease (CAD) (male < 55 years, female < 65 years) and 218 controls without documented CAD. All subjects were genotyped for 4 SNPs by using the ligase detection reaction method. Fasting blood sugar (FBS) and plasma concentrations of total cholesterol, triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1(apo A1), and apolipoprotein B (apo B) were determined by standard biochemical methods. Main anthropometric and metabolic characteristics are analyzed among 3 genotypes at rs2283228, rs2237895, rs2237897, or rs2237892 in KCNQ1.

RESULTS

The 3 genotypes AA, AC, and CC were present in rs2283228 and rs2237895, and the 3 genotypes CC, CT, and TT were present in rs2237897 and rs2237892. The minor genotypes CC at rs2283228 and TT at rs2237892 were associated with higher levels of TG (P = 0.007 and 0.026, respectively). Furthermore, subjects with the CC genotype at rs2283228 had lower levels of HDL-C and apo A1 than in the other 2 genotype groups (P = 0.052 and 0.055, respectively). No other associations were detected between these 4 SNPs and FBS or other lipid parameters.

CONCLUSIONS

Our data suggest that rs2283228 and rs2237892 in KCNQ1 are associated with lipid metabolism in a middle-aged Chinese Han population.

OBJECTIVE

The aim of the study is to evaluate the effect of moderate Sicilian red wine consumption on cardiovascular risk factors and, in particular, on some inflammatory biomarkers.

METHODS

A total of 48 subjects of both sexes who were nondrinkers or rare drinkers of moderate red wine were selected and randomly subdivided into two groups assigned to receive with a crossover design a Sicilian red wine (Nero d'Avola or Etna Torrepalino) during meals: Group A (n = 24), in whom the diet was supplemented for 4 weeks with 250 ml/day of red wine, followed by 4 weeks when they returned to their usual wine intake; and Group B (n = 24), in whom the usual wine intake was maintained for 4 weeks, followed by 4 weeks when the diet was supplemented with 250 ml/day of red wine. The following were values measured in all tests: blood glucose, total and HDL-cholesterol and triglycerides, LDL-cholesterol, LDL/HDL ratio, apolipoproteins A1 and B, Lp(a), plasma C-reactive protein, TGFbeta1, D-Dimer, Factor VII , PAl Ag, t-PA Ag, fibrinogen, oxidized LDL Ab, total plasma antioxidant capacity.

RESULTS

At the end of the red wine intake period, LDL/HDL, fibrinogen, factor VII, plasma C-reactive protein and oxidized LDL Ab were significantly decreased, while HDL-C, Apo A1,TGFbeta1, t-PA, PAI and total plasma antioxidant capacity were significantly increased.

CONCLUSIONS

Our results show a positive effect of two Sicilian red wines on many risk factors and on some inflammatory biomarkers, suggesting that a moderate consumption of red wine in the adult population is a positive component of the Mediterranean diet.

Human serum paraoxonase is physically associated with an apolipoprotein (Apo-A1) and clusterin-containing high-density lipoprotein (HDL) and prevents low-density lipoprotein from lipid peroxidation. The aim of our study was to determine whether paraoxonase activity or phenotype is altered in patients with chronic renal failure and in hyperlipidemic subjects without renal insufficiency and to compare the values with those of healthy controls. We investigated the serum paraoxonase activity and polymorphism in 119 hemodialyzed uremic patients, 107 patients with primary hyperlipoproteinemia, and in 110 healthy control subjects. The serum paraoxonase activity was significantly decreased both in hyperlipidemic (p < 0.01) and uremic patients (p < 0.001) as compared with controls. On comparison, the serum paraoxonase activity was significantly lower (p < 0.001) in uremic than in hyperlipoproteinemic patients. The HDL and Apo-A1 levels were as follows: uremic < hyperlipidemic < control. To assess whether the observed reduction in paraoxonase activity was due to HDL and Apo-A1 level decreases, we standardized the enzyme activity for HDL and Apo-A1 concentrations. We found that the standardized paraoxonase activity (paraoxonase/HDL ratio) was also lower in the uremic patients (103.3 +/- 69.5) as compared with hyperlipidemic patients (137.64 +/- 81.0) and controls (194.45 +/- 94.45). The standardized values for Apo-A1 showed a similar tendency: paraoxonase/Apo-A1 ratio in uremic patients 89.64 +/- 47.8, in hyperlipidemic patients 128.12 +/- 69.83, and in controls 161.40 +/- 47.35. The phenotypic distribution of paraoxonase (AA, AB, BB) did not change significantly in the patient groups. These results suggest that HDL concentration and phenotypic distribution of paraoxonase may not be the only determining factors, but that other as yet undetermined factors could be involved in the enzyme activity changes.

Along with apolipoprotein (apo) E, which promotes cholesterol efflux from foam cells, apoA1-containing high density lipoprotein (HDL) is thought to facilitate the transport of cholesterol from lesions. This role for apoA1 was tested in vivo by lethally irradiating apoE-deficient and apoE- plus apoA1-deficient mice and reconstituting them with bone marrow cells isolated from wild-type (WT) mice. ApoE, but not apoA1, was synthesized by the transplanted bone marrow-derived cells. Therefore, this transplantation procedure generated apoE-deficient animals with atherosclerotic lesions that contained both apoE and apoA1 (E/A1 mice) and apoE-deficient animals with lesions that contained apoE but no apoA1 (E/A1o mice). As shown previously, the transplanted WT macrophage-derived apoE dramatically lowered the plasma hypercholesterolemia in both groups. On feeding with an atherogenic diet after transplantation, plasma cholesterol levels were raised in both groups of mice, but the levels in the E/A1 mice at 20 weeks were 2- to 3-fold higher than in E/A1o mice. Immunohistochemical staining verified that apoE was abundant in lesions of both groups, whereas apoA1 was detected in the lesions of E/A1 mice only. Despite a 2- to 3-fold lower total plasma cholesterol in the E/A1o mice, the free cholesterol recovered from isolated aortas was approximately 60% higher and the mean lesion area in serial sections of the aortic valves 45% larger. Therefore, apoA1 reduces free cholesterol accumulation in vivo in atherosclerotic lesions.

The mechanisms behind secondary hyperlipidemia in patients with various chronic inflammatory diseases are not known in detail. We have recently demonstrated that ACTH exerts strong hypolipidemic effects in healthy volunteers. To test the clinical relevance of this finding, we administrated ACTH during three weeks to nine hyperlipidemic steroid-treated patients with kidney disease. Before administration of ACTH 1-24, plasma ACTH concentrations were low. Treatment with ACTH led to 20 to 50% reductions in serum concentrations of triglycerides, cholesterol, LDL cholesterol and Apo B as well as of Lp(a). HDL cholesterol and Apo A1 concentrations increased by 10 to 25%. HL activity in postheparin plasma decreased by about 40% and LPL activity, which was initially low, increased by about 140%. The effects of ACTH were similar in kidney transplant recipients and in patients with inflammatory kidney disease. Our results indicate that hyperlipidemia in steroid treated patients with kidney disease may at least partly be due to iatrogenic ACTH deficiency.

High circulating levels of triglyceride-rich lipoproteins (TGRL) represent an independent risk factor for coronary artery disease. Here, we show that TGRL inhibit the efflux of cholesterol from 'foam cell' macrophages to lipid-poor apolipoprotein (apo) A1, and may thereby inhibit arterial reverse cholesterol transport and promote the formation of atherosclerotic lesions. Human (THP-1) monocyte-derived macrophages were pre-incubated (48 h) with acetylated low-density lipoprotein (AcLDL) to provide a foam cell model of cholesterol efflux to apoA1. Pre-incubation of macrophage 'foam cells' with TGRL (0-200 microg/ml, 0-24 h) inhibited the efflux of exogenously radiolabelled ([3H]), endogenously synthesised ([14C]) and cellular cholesterol mass to lipid-poor apoA1, but not control medium, during a (subsequent) efflux period. This inhibition is dependent upon the length of prior exposure to, and concentration of, TGRL employed, but is independent of changes in intracellular triglyceride accumulation or turnover of the cholesteryl ester pool. Despite the negative impact of TGRL on cholesterol efflux, major proteins involved in this process--namely apoE, ABCA1, SR-B1 and caveolin-1--were unaffected by TGRL pre-incubation, suggesting that exposure to these lipoproteins inhibits an alternate, and possibly novel, anti-atherogenic pathway.

OBJECTIVE

Cardiovascular disease (CVD) is increased in patients with type 1 diabetes, but lipid and lipoprotein patterns remain favorable. In contrast, nephropathy is associated with an adverse distribution. We compared the associations and predictive power of lipid and lipoprotein disturbances with these complications.

METHODS

A nested case-control study from the EURODIAB cohort of 140 case subjects with evidence of at least one complication and 84 control subjects with no complications were analyzed. Conventional and unconventional lipid and lipoprotein fractions, including apolipoprotein (apo)-A1, lipoprotein (Lp)-A1, LpA1/A2, apoB, and LDL particle size were measured centrally.

RESULTS

CVD was only associated with increased LDL cholesterol (3.6 vs. 3.0 mmol/l, P = 0.02). In contrast, albuminuria was associated with elevated cholesterol, triglyceride, LDL, and apoB and with diminished LDL particle size. No disturbances in HDL and related lipoproteins were noted. In normoalbuminuric patients, CVD was not associated with any significant changes in lipids. CVD in macroalbuminuric patients was associated with increased triglyceride level (2.37 vs. 1.07 mmol/l, P = 0.001; P = 0.02 for CVD/albuminuria interaction) and LDL cholesterol (5.4 vs. 3.3 mmol/l, P = 0.005; P = 0.004 for interaction). Independent associations were observed for total cholesterol and for LDL particle size and albuminuria.

CONCLUSIONS

Abnormalities in lipid and lipoprotein disturbances are more closely related to albuminuria than to CVD in patients with type 1 diabetes. Measurement of conventional parameters provide sufficient risk information. ApoB and LDL particle size offer limited extra information. HDL metabolism remains undisturbed in the presence of complications. These changes reflect associations with glycemic control, which is the key to understanding lipid and lipoprotein disturbances.

OBJECTIVE

Levels of lipids and (apo)lipoproteins are known to increase after menopause, but it is unknown whether the genetic and environmental variability alters or whether lipids and (apo)lipoproteins are influenced by different genes before and after menopause.

RESULTS

We studied 453 monozygotic and 1280 dizygotic pairs of female white twins recruited from the St. Thomas' UK Adult Twin Registry and measured total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL), triglycerides, lipoprotein(a) [Lp(a)], apolipoprotein A1 (apoA1), and apolipoprotein B (apoB). Variance components software was used to estimate genetic and environmental influences on serum lipid levels in premenopausal and postmenopausal women. Total variance was higher for triglycerides, HDL, and apoB after menopause. Postmenopausal women showed larger genetic variance for most lipids, apart from apoB and Lp(a). In premenopausal females, total cholesterol, LDL, HDL, apoA1, and apoB all showed an influence of the shared environment (22% to 34%), which, after menopause, decreased in HDL and completely disappeared in total cholesterol, LDL, and apoA1. Only for Lp(a), with a high heritability of 87%, did the same model fit premenopausal and postmenopausal women. Generally, there was no indication that different genes influence lipids before and after menopause.

CONCLUSIONS

These findings imply that genetic studies of lipids can pool results from premenopausal and postmenopausal women and that family-based interventions, such as changes in diet, are more likely to succeed in younger women, in whom the environmental influences are greater.

To investigate structural requirement of helical apolipoprotein to phosphorylate and stabilize ATP-binding cassette transporter A1 (ABCA1), synthetic peptides (Remaley, A. T., Thomas, F., Stonik, J. A., Demosky, S. J., Bark, S. E., Neufeld, E. B., Bocharov, A. V., Vishnyakova, T. G., Patterson, A. P., Eggerman, T. L., Santamarina-Fojo, S., and Brewer, H. B. (2003) J. Lipid Res. 44, 828-836) were examined for these activities. L37pA, an L amino acid peptide that contains two class-A amphiphilic helices, and D37pA, the same peptide with all D amino acids, both removed cholesterol and phospholipid from differentiated THP-1 cells more than apolipoproteins (apos) A-I, A-II, and E. Both peptides also mediated lipid release from human fibroblasts WI-38 similar to apoA-I. L2D37pA, an L-peptide whose valine and tyrosine were replaced with D amino acids also promoted lipid release from WI-38 but less so with THP-1, whereas L3D37pA, in which alanine, lysine, and asparatic acid were replaced with D amino acids was ineffective in lipid release for both cell lines. ABCA1 protein in THP-1 and WT-38 was stabilized against proteolytic degradation by apoA-I, apoA-II, and apoE and by all the peptides tested except for L3D37pA, and ABCA1 phosphorylation closely correlated with its stabilization. The analysis of the relationship among these parameters indicated that removal of phospholipid triggers signals for phosphorylation and stabilization of ABCA1. We thus concluded that an amphiphilic helical motif is the minimum structural requirement for a protein to stabilize ABCA1 against proteolytic degradation.

Hepatocytes, which are the main site of apolipoprotein (apo)A-I and ATP-binding cassette transporter A1 (ABCA1) expression, are also the main source of circulating high density lipoprotein. Here we have characterized the intracellular lipidation of newly synthesized apoA-I, in primary hepatocytes cultured with [3H]choline to label choline-phospholipids, low density lipoprotein-[3H]cholesterol to label the cell surface, or [3H]mevalonate to label de novo synthesized cholesterol. Phospholipidation of apoA-I is significant and most evident in endoplasmic reticulum (ER) and medial Golgi, both in the lumen and on the membrane fractions of the ER and medial Golgi. In the presence of cycloheximide, endogenous apoA-I is substantially phospholipidated intracellularly but acquires some additional lipid after export out of the cell. In cells labeled with low density lipoprotein-[3H]cholesterol, intracellular cholesterol lipidation of apoA-I is entirely absent, but the secreted apoA-I rapidly accumulates cholesterol after secretion from the cell in the media. On the other hand, de novo synthesized cholesterol can lipidate apoA-I intracellularly. We also showed the interaction between apoA-I and ABCA1 in ER and Golgi fractions. In hepatocytes lacking ABCA1, lipidation by low density lipoprotein-cholesterol was significantly reduced at the plasma membrane, phospholipidation and lipidation by de novo synthesized sterols were both reduced in Golgi compartments, whereas ER lipidation remained mostly unchanged. Therefore, the early lipidation in ER is ABCA1 independent, but in contrast, the lipidation of apoA-I in Golgi and at the plasma membrane requires ABCA1. Thus, we demonstrated that apoA-I phospholipidation starts early in the ER and is partially dependent on ABCA1, with the bulk of lipidation by phospholipids and cholesterol occurring in the Golgi and at the plasma membrane, respectively. Finally, we showed that the previously reported association of newly synthesized apoA-I and apoB (Zheng, H., Kiss, R. S., Franklin, V., Wang, M. D., Haidar, B., and Marcel, Y. L. (2005) J. Biol. Chem. 280, 21612-21621) occurs after secretion at the cell surface.

The release of cholesterol from choroid plexus epithelial cells (CPE) plays an important role in cholesterol homeostasis in the CSF. The purpose of this study was to clarify the molecules involved in cholesterol release in CPE and the regulation mechanisms of the cholesterol release by the liver X receptor (LXR) using a conditionally immortalized CPE line (TR-CSFB3). The mRNA expression of LXRalpha, LXRbeta and their target genes, ATP-binding cassette transporter (ABC)A1, ABCG1, ABCG4 and ABCG5, were detected in rat choroid plexus. ABCA1 and ABCG1 protein were detected in the plasma membrane of TR-CSFB3 cells. Following treatment with 24S-hydroxycholesterol, an endogenous LXR ligand, the expression of ABCA1 and ABCG1 were induced in TR-CSFB3 cells. Moreover, apolipoprotein (apo)AI- and high-density lipoprotein (HDL)-mediated cholesterol release to the apical side of TR-CSFB3 cells was facilitated by this treatment, whereas that to the basal side was not affected. Following 24S-hydroxycholesterol treatment, apoE3-dependent cholesterol release from TR-CSFB3 cells was enhanced more than the apoE4-dependent release. These results suggest that LXR activation facilitates cholesterol release into the CSF from CPE through the functional induction of ABCA1 and ABCG1. The difference between apoE3 and apoE4 suggests that the cholesterol release from CPE is related to the development of neurodegenerative diseases.

OBJECTIVE

To compare within the same cohort the association of a large panel of lipids with the risk of incident coronary heart disease (CHD) and ischemic stroke events in participants of the Prospective Epidemiological Study of Myocardial Infarction.

METHODS

In this binational (Northern Ireland and France) prospective cohort, we considered 9,711 men aged 50-59 years free of CHD and stroke at baseline (1991-1993). The hazard ratios of each lipid marker for CHD and ischemic stroke events were estimated in separate Cox proportional hazard models adjusted for age, study center, systolic blood pressure, antihypertensive treatment, current smoking status, body mass index and diabetes.

RESULTS

After 10 years of follow-up, 635 men had a first CHD and 98 a first ischemic stroke event. Total cholesterol (total-C), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), non-HDL-C, triglycerides, apolipoprotein (Apo) A1 and Apo B100, their ratios and lipoprotein (a) [Lp(a)] were all significantly predictive of future CHD. Associations with ischemic stroke followed the same trend as for CHD, but with lower strength, and none were statistically significant. However, none of the differences between the hazard ratios for CHD and for ischemic stroke were statistically significant.

CONCLUSIONS

In healthy, middle-aged men, total-C, HDL-C, LDL-C, non-HDL-C, triglycerides, Apo A1 and Apo B100, their ratios and Lp(a) are, if anything, weak predictors of ischemic stroke events over a 10-year period.

Human glutathione transferase A1-1 is a well studied enzyme, but despite a wealth of structural and biochemical data a number of aspects of its catalytic function are still poorly understood. Here, five new crystal structures of this enzyme are described that provide several insights. Firstly, the structure of a complex of the wild-type human enzyme with glutathione was determined for the first time at 2.0 angstroms resolution. This reveals that glutathione binds in the G site in a very similar fashion as the glutathione portion of substrate analogues in other structures and also that glutathione binding alone is sufficient to stabilize the C-terminal helix of the protein. Secondly, we have studied the complex with a decarboxylated glutathione conjugate that is known to dramatically decrease the activity of the enzyme. The T68E mutant of human glutathione transferase A1-1 recovers some of the activity that is lost with the decarboxylated glutathione, but our structures of this mutant show that none of the earlier explanations of this phenomenon are likely to be correct. Thirdly, and serendipitously, the apo structures also reveal the conformation of the crucial C-terminal region that is disordered in all previous apo structures. The C-terminal region can adopt an ordered helix-like structure even in the apo state, but shows a strong tendency to unwind. Different conformations of the C-terminal regions were observed in the apo states of the two monomers, which suggests that cooperativity could play a role in the activity of the enzyme.

OBJECTIVE

The purpose of the present study was to assess the impact of Mg + Zn, Vitamins C + E, and combination of these micronutrients on serum lipid and lipoprotein profiles in type 2 diabetic patients.

METHODS

In a randomized, double-blind, placebo controlled clinical trial, 69 type 2 diabetic patients were randomly divided into four groups, each group receiving one of the following daily supplement for 3 months; group M: 200 mg Mg and 30 mg Zn (n = 16), group V: 200mg Vitamin C and 150 mg Vitamin E (n = 18), group MV: minerals plus vitamins (n = 17), group P: placebo (n = 18). Fasting blood and urine samples were collected at the beginning and at the end of the trial. Serum triglyceride, total cholesterol, high density lipoprotein cholesterol (HDL-c) and low density lipoprotein cholesterol (LDL-c) were measured enzymatically. Apolipoproteins (apo) A1 and B were measured by immunoturbidimetric method. Adjustment for differences in baselines covariates and changes in variables during study were performed by analysis of covariance using general linear models.

RESULTS

Results indicate that after 3 months of supplementation mean serum levels of HDL-c and apo A1 increased significantly in the MV group by 24% (50.4 +/-19.3 mg/dl versus 40.6 +/- 10.8 mg/dl) and 8.8% (169.8 +/- 33.8 mg/dl versus 156.1+ /- 23.9 mg/dl), respectively (P < 0.01). There were no significant changes in the levels of these parameters in the other three groups. Serum levels of total cholesterol, LDL-c, triglyceride, and apo B were not altered after supplementation in all four groups.

CONCLUSIONS

It is concluded that since co-supplementation of Mg, Zn, Vitamins C and E significantly increases HDL-c and apo A1, supplementation of these micronutrients could be recommended for the type 2 diabetic patients based on their daily requirements.

BACKGROUND

Moderate-to-severe psoriasis is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD); however, the link is poorly understood.

METHODS

Skin and serum from patients with psoriasis were evaluated to understand if there was evidence of dysregulation in a targeted group of inflammatory and lipid genes related to ASCVD. Microarray analyses of expression of targeted ASCVD genes from skin in 89 patients with moderate-to-severe psoriasis from the ACCEPT trial were compared with non-diseased skin from healthy controls (n = 25). Serum (n = 149) was tested at baseline for monocyte chemoattractant protein-1 (MCP-1), macrophage-derived chemokine (MDC), and apolipoprotein-A1 (Apo-A1) comparing to healthy controls (n=162).

RESULTS

An increase in skin gene expression for MCP-1 (7.98-fold) and MDC (6.66-fold) (p < 0.001 each) was observed in lesional versus healthy skin. Significant decreases in liver X receptor-alpha (LXR-α) (-5.94-fold), a protective lipoprotein metabolism gene, and in peroxisome proliferator-activated receptor-alpha (PPAR-α) (-7.58-fold), a protective anti-inflammatory and lipid modulating gene, were observed in lesional versus healthy skin (p < 0.001 each). Serum analyses revealed that MCP-1 (502 vs. 141 pg/mL) and MDC (1240 vs. 409 pg/mL) levels were significantly elevated in psoriasis compared with healthy controls (p < 0.001 each). Dysregulated lipid metabolism was also evident in the serum, as Apo-A1, a protein product related to PPAR-α activation, was significantly decreased in patients with psoriasis compared with healthy controls (25.2 vs. 38.9 mg/dL; p < 0.001).

CONCLUSIONS

Analyses of targeted genes and their products known to be associated with ASCVD revealed dysregulation of inflammatory (MCP-1 and MDC) and lipid metabolism (LXR-α, PPAR-α) genes in psoriasis. These findings provide evidence of a potential shared pathophysiology linking psoriasis to cardiometabolic diseases.

Objective: In vitro and animal studies suggest that purified anthocyanins have favorable effects on metabolic profiles, but clinical trials have reported inconsistent findings. Furthermore, no study has been specifically conducted among individuals with prediabetes. The aim of this study was to investigate whether purified anthocyanins could improve cardiometabolic risk factors in Chinese adults with early untreated hyperglycemia. Research Design and Methods: This was a 12-week randomized, double-blind, placebo-controlled trial. A total of 160 participants aged 40-75 years with prediabetes or early untreated diabetes were randomly allocated to receive either purified anthocyanins (320 mg/day, n = 80) or placebo (n = 80) of identical appearance. A three-hour oral glucose tolerance test (OGTT) was performed, and cardiometabolic biomarkers (glycated hemoglobin A1c (HbA1c), fasting and postprandial glucose, insulin, C-peptide, and lipids) were measured at baseline and at the end of the trial. Results: A total of 138 subjects completed the protocol. Compared with placebo, purified anthocyanins moderately reduced HbA1c (-0.14%, 95% CI: -0.23~-0.04%; p = 0.005), low-density lipoprotein-c (LDL-c) (-0.2 mmol/L, 95% CI: -0.38~-0.01, p = 0.04), apolipoprotein A-1 (apo A1) (0.09 g/L, 95% CI: 0.02~0.17; p = 0.02), and apolipoprotein B (apo B) (-0.07 g/L, 95% CI: -0.13~-0.01; p = 0.01) according to intention-to-treat analysis. Subgroup analyses suggested that purified anthocyanins were more effective at improving glycemic control, insulin sensitivity, and lipids among patients with elevated metabolic markers. Conclusions: The 12-week randomized controlled trials (RCT) in Chinese adults with prediabetes or early untreated diabetes indicated that purified anthocyanins favorably affected glycemic control and lipid profile. Future studies of a longer duration that explore the dose-response relationship among patients with cardiometabolic disorders are needed to confirm our findings.