The Effects of Atorvastatin Therapy on Rheological Characteristics of Erythrocyte Membrane, Serum Lipid Profile and Oxidative Status in Patients with Dyslipidemia

The statins, most commonly used in the treatment of hyperlipidemia, have certain beneficial effects including improved endothelial function, plaque stability and decreased oxidative stress and inflammation, beyond their lipid-lowering effect in plasma. We evaluated the pleiotropic impact of atorvastatin on erythrocyte structural/mechanical properties and lipid peroxidation in dyslipidemics. The study group included 44 patients with dyslipidemia and was divided into subgroups according to triglyceride and cholesterol levels as hypercholesterolemic (n?=?29) and mixed-type hyperlipidemic (n?=?15). Subjects were given 10?mg atorvastatin per day for 12?weeks. Changes in serum lipid composition, lipid contents, Na⁺/K⁺-ATPase activity and osmotic fragility in erythrocytes and oxidative stress parameters of erythrocytes and plasma were studied. Atorvastatin therapy improved the serum lipid profile of both subgroups. This alteration was accompanied by a decreased level of cholesterol in erythrocyte membranes. Moreover, enhanced activity of Na⁺/K⁺-ATPase in erythrocytes reflected the improvements in membrane lipids of both subgroups. However, a significant change was observed in osmotic fragility values of the mixed-typed dyslipidemic group. This treatment lowered the lipid peroxidation in plasma and erythrocytes and increased plasma total antioxidant capacity in all groups. The present study shows that the use of atorvastatin reversed the structural and functional features of erythrocyte membranes in dyslipidemic subjects. Also, hypolipidemic therapy had a beneficial impact on a balance between oxidant and antioxidant systems.     

Atherogenic Dyslipidemia in Children: Evaluation of Clinical,Biochemical and Genetic Aspects

The precursors of atherogenic dyslipidemia (AD) are not well defined. Therefore, we investigated 62 non-obese, non-diabetic AD and 221 normolipemic children. Anthropometric parameters, blood pressure and biochemical measures were obtained in index children, their parents and all available siblings. The heritability (h²) of anthropometric and biochemical traits was estimated by SOLAR. Rare and common variants in APOA1 and LPL genes were screened by re-sequencing. Compared to normolipemic, AD children showed increased body mass index, waist circumference, plasma glucose, insulin, ApoB, HOMA-IR, hs-CRP and lower adiponectin (p<0.001 for all). Metabolic syndrome was present in 40% of AD while absent in controls. All traits (except adiponectin and hs-CRP) showed a strong familial aggregation, with plasma glucose having the highest heritability (89%). Overall, 4 LPL loss-of-function mutations were detected (p.Asp9Asn, p.Ser45Asn, p.Asn291Ser, p.Leu365Val) and their cumulative prevalence was higher in AD than in control children (0.073 vs. 0.026; P=0.038). The LPL p.S447* gain-of-function mutation, resulted to be less frequent in AD than in control children (0.064 vs. 0.126; P=0.082). No variant in the APOA1 gene was found. Our data indicate that AD is a rather common dyslipidemia in childhood; it associates with metabolic abnormalities typical of insulin resistant state and shows a strong familial aggregation. LPL variants may contribute to the development of AD phenotype.     

Reactivity of Phospholipid Hydroperoxide Glutathione Peroxidase with Membrane and Lipoprotein Lipid Hydroperoxides

A comparative study has been carried out on the general reactivity of lipid hydroperoxides in liposornes, biological membranes and lipoproteins with two Se-dependent peroxidases: Glutathione Peroxidase (GPX) and Phospholipid Hydroperoxide Glutathione Peroxidase (PHGPX). While PHGPX reduces all hydroperoxides derived from phospholipids, cholesterol and cholesterol esters, GPX reduces only fatty acid hydroperoxides released after treatment of phospholipid hydroperoxides with phospholipase A,. These findings highlight the role of PHGPX in protecting biomembranes from peroxidative damage and add new insight into how cholesterol hydroperoxides are detossified in cells.     

从人和动物血浆及红细胞膜脂肪酸谱探讨脂质代谢实验模型动物选取

目的比较大鼠、家兔和人血浆及红细胞膜脂肪酸谱的异同,为脂质代谢模型动物的选取提供可靠依据。方法采用氯仿-甲醇快速提取大鼠、家兔和人血浆及细胞膜中的脂肪,并用碱法甲基化,经薄层层析纯化的甲基酯用100 mm×0.25 mm气相色谱毛细管柱测定脂肪酸组成。结果血浆中总MUFA、9c18：1、9c12c18：2 n-6和α-18：3 n-3等脂肪酸含量较高;而红细胞膜中总PUFA、AA、22：4n-6、DPA和DHA等脂肪酸含量较高;人和大鼠16：0、18：0、18：1、α-18：3n-3、AA、EPA、DHA、MUFA、n-3PUFA和n-6/n-3值均较为接近,但和家兔存在显著差异。结论与家兔相比,大鼠和人血浆及红细胞膜脂肪酸谱较接近,因此,在选取脂质代谢实验动物时,应优先考虑大鼠为模型动物,以得到与人体实际更接近的结果。     

Effect of Sesamin on Cholesterol Synthesis and on the Distribution of Incorporated Linoleic Acid in Lipid Subfractions in Cultured Rat Cells

Since sesamin influences the metabolism of essential fatty acids, its effects on cholesterol metabolism and on the incorporation of linoleic acid were studied by using cultured rat artery smooth muscle cells (SMCs) and primary cultured rat hepatocytes. Cholesterol synthesis from acetate was inhibited by sesamin in SMCs, and the distribution of incorporated linoleic acid in the lipid and phospholipid subfractions was altered by sesamin in rat hepatocytes.     

Localization of Cholesterol and Fatty Acid in a Model Lipid Membrane: A Neutron Diffraction Approach

The intercellular lipid matrix of the skin’s stratum corneum serves to protect the body against desiccation and simultaneously limits the passage of drugs and other xenobiotics into the body. The matrix is made up of ceramides, free fatty acids, and cholesterol, which are organized as two coexisting crystalline lamellar phases. In studies reported here, we sought to use the technique of neutron diffraction, together with the device of isotopic (H/D) substitution, to determine the molecular architecture of the lamellar phase having a repeat distance of 53.9 ± 0.3 Å. Using hydrogenous samples as well as samples incorporating perdeuterated (C24:0) fatty acids and selectively deuterated cholesterol, the diffraction data obtained were used to construct neutron scattering length density profiles. By this means, the locations within the unit cell were determined for the cholesterol and fatty acids. The cholesterol headgroup was found to lie slightly inward from the unit cell boundary and the tail of the molecule located 6.2 ± 0.2 Å from the unit cell center. The fatty acid headgroups were located at the unit cell boundary with their acyl chains straddling the unit cell center. Based on these results, a molecular model is proposed for the arrangement of the lipids within the unit cell.     

Acute Coronary Syndrome Remodels the Protein Cargo and Functions of High-Density Lipoprotein Subfractions

Objectives

This study examined alterations in the functions and proteome of high-density lipoprotein (HDL) subfractions (HDL2 and HDL3) isolated from patients with acute coronary syndrome (ACS) compared with control subjects.

Methods

We measured HDL subfraction cholesterol efflux capacity, inflammatory index (HII), paraoxonase-1 (PON1) activity, and lipid hydroperoxide (LOOH) levels in both male age-matched controls and the ACS group (n = 40/group). Additionally, proteomic analysis was used to monitor changes in the HDL subfraction proteome between controls and ACS subjects.

Results

Both HDL2 and HDL3 from ACS patients had greater HII and LOOH levels compared with controls (P<0.001); PON1 activity and cholesterol efflux capacity in both HDL2 and HDL3 from the ACS group were significantly less than those of controls (P<0.001). Using proteomic analysis, we demonstrated that, compared with the control group, nine proteins were selectively enriched in HDL3 from subjects with ACS, and ras-related protein Rab-7b was decreased in HDL3. Additionally, in the ACS subjects, 12 proteins were decreased in HDL2 and 4 proteins were increased in HDL2.

Conclusions

Functional HDL subfractions shifted to dysfunctional HDL subfractions during ACS, and the functional impairment was linked to remodeled protein cargo in HDL subfractions from ACS patients.     

Contemporary Management and Attainment of Cholesterol Targets for Patients with Dyslipidemia in China

Aims

It is well-established that lipid disorder is an important cardiovascular risk factor, and failure to reach optimal lipid levels significantly contributes to the residual cardiovascular risks. However, limited information is available on the management and the attainment of recommended cholesterol targets in real-world practice in China.

Methods and Results

A nationally representative sample of 12,040 patients with dyslipidemia from 19 provinces and 84 hospitals across China were consecutively enrolled in this survey. Risk stratification and individual cholesterol target was established for all participants. This survey identified a high-risk cohort, with over 50% of patients had hypertension, 37.5% had coronary artery disease, and more than 30% had peripheral artery disease. Thirty-nine percent of all participants received lipid lowering medications. And the majority of them (94.5%) had statins (42.5% with atorvastatin, 29.0% with simvastatin, and 15.2% with rosuvastatin). However, the overall attainment for low-density lipoprotein cholesterol (LDL-C) target is low (25.8%), especially, in female (22.2%), and in patients with increased body mass index (BMI) (38.3% for BMI<18.5, 28.1% for BMI 18.5–24.9, 26.0% for BMI 25.0–29.9, and 17.4% for BMI≥30, P<0.0001). Subgroup analysis also showed the attainment is significantly lower in patients who were stratified into high (19.9%) and very high (21.1%) risk category. In logistic regression analysis, eight factors (BMI, gender, coronary artery disease, systolic and diastolic blood pressure, hypertension, family history of premature coronary artery disease and current smoking) were identified as independent predictors of LDL-C attainment.

Conclusions

Despite the proven benefits of lipid-lowering therapies, current management of dyslipidemia continues to be unsatisfied. A considerable proportion of patients failed to achieve guideline-recommended targets in China, and this apparent treatment gap was more pronounced among patients with increased BMI, higher risk stratification and women.     

Mitochondrial GWA Analysis of Lipid Profile Identifies Genetic Variants to Be Associated with HDL Cholesterol and Triglyceride Levels

It has been suggested that mitochondrial dysfunction has an influence on lipid metabolism. The fact that mitochondrial defects can be accumulated over time as a normal part of aging may explain why cholesterol levels often are altered with age. To test the hypothesis whether mitochondrial variants are associated with lipid profile (total cholesterol, LDL, HDL, and triglycerides) we analyzed a total number of 978 mitochondrial single nucleotide polymorphisms (mtSNPs) in a sample of 2,815 individuals participating in the population-based KORA F4 study. To assess mtSNP association while taking the presence of heteroplasmy into account we used the raw signal intensity values measured on the microarray and applied linear regression. Ten mtSNPs (mt3285, mt3336, mt5285, mt6591, mt6671, mt9163, mt13855, mt13958, mt14000, and mt14580) were significantly associated with HDL cholesterol and one mtSNP (mt15074) with triglycerides levels. These results highlight the importance of the mitochondrial genome among the factors that contribute to the regulation of lipid levels. Focusing on mitochondrial variants may lead to further insights regarding the underlying physiological mechanisms, or even to the development of innovative treatments. Since this is the first mitochondrial genome-wide association analysis (mtGWAS) for lipid profile, further analyses are needed to follow up on the present findings.     

Membrane Organization and Regulation of Cellular Cholesterol Homeostasis

An excess of intracellular free cholesterol (Chol) is cytotoxic, and its homeostasis is crucial for cell viability. Apolipoprotein A-I (apoA-I) is a highly efficient Chol acceptor because it activates complex cellular pathways that tend to mobilize and export Chol from cellular depots. We hypothesize that membrane composition and/or organization is strongly involved in Chol homeostasis. To test this hypothesis, we constructed a cell line overexpressing stearoyl coenzyme A (CoA) desaturase (SCD cells), which modifies plasma membrane (PM) composition by the enrichment of monounsaturated fatty acids, and determined this effect on membrane properties, cell viability, and Chol homeostasis. PM in SCD cells has a higher ratio of phospholipids to sphingomyelin and is slightly enriched in Chol. These cells showed an increase in the ratio of cholesteryl esters to free Chol; they were more resistant to Chol toxicity, and they exported more caveolin than control cells. The data suggest that cell functionality is preserved by regulating membrane fluidity and Chol exportation and storage.     

红细胞膜带4.2蛋白的结构与功能

带4.2蛋白是一种重要的红细胞膜蛋白,与红细胞的形态、可变形性及携氧功能有至关重要的联系。它通过与带3蛋白(阴离子通道蛋白)、锚蛋白结合,稳定的连接在细胞膜的内表面,连接着膜骨架网架结构与细胞膜,是膜骨架与脂质双分子层连接的重要纽带。带4.2蛋白的缺失会引起球形或椭圆形红细胞增多症及不同程度的溶血性贫血,严重的情况需要摘除脾脏来进行治疗。近年来研究认为,带4.2蛋白在维持细胞膜骨架的完整性和稳定性方面扮演了重要角色。现对带4.2蛋白结构及功能的研究状况进行综述。     

血脂异常及动脉粥样硬化中医研究进展

“血脂异常”及“动脉粥样硬化”是现代医学病名,古代医书中虽无此病名记载,但却不乏与之相关的论述.现代中医根据其临床表现将其归属于“眩晕”、“胸痹”、“中风”、“痰浊”、“血瘀”、“脉痹”、“血痹”、“脱疽”等病症范畴.现代中医学者对血脂异常、动脉粥样硬化的中医病名认识、病因病机探讨及二者之间的联系进行了大量的理论和实验研究,对血脂异常和动脉粥样硬化有了新的认识.动脉粥样硬化是引起心脑血管疾病的首要原因,也是其发病的病理基础,而血脂异常又是动脉粥样硬化发病的主要因素之一.故对血脂异常和动脉粥样硬化发病机制及防治策略的研究,不仅是西医研究的热点,同时也是中医中药研究重点,值得我们一生探索.     

Interplay between Membrane Curvature and Cholesterol: Role of Palmitoylated Caveolin-1

Caveolin-1 (cav-1) is an important player in cell signaling and endocytosis that has been shown to colocalize with cholesterol-rich membrane domains. Experimental studies with varying cav-1 constructs have suggested that it can induce both cholesterol clustering and membrane curvature. Here, we probe the molecular origin of membrane curvature and cholesterol clustering by cav-1 by using coarse-grain molecular dynamics simulations. We have performed a series of simulations of a functionally important cav-1 construct, comprising the membrane-interacting domains and a C-terminal palmitoyl tail. Our results suggest that cav-1 is able to induce cholesterol clustering in the membrane leaflet to which it is bound as well as the opposing leaflet. A positive membrane curvature is observed upon cav-1 binding in cholesterol-containing bilayers. Interestingly, we observe an interplay between cholesterol clustering and membrane curvature such that cav-1 is able to induce higher membrane curvature in cholesterol-rich membranes. The role of the cav-1 palmitoyl tail is less clear and appears to increase the membrane contacts. Further, we address the importance of the secondary structure of cav-1 domains and show that it could play an important role in membrane curvature and cholesterol clustering. Our work is an important step toward a molecular picture of caveolae and vesicular endocytosis.     

Esterified Cholesterol Is Highly Localized to Bruch's Membrane, as Revealed by Lipid Histochemistry in Wholemounts of Human Choroid

Accumulation of neutral lipids in Bruch''s membrane (BrM) is a major age change in human retina and contributes to the formation of extracellular lesions associated with age-related macular degeneration. We developed a BrM–choroid wholemounting technique suitable for reliable staining and evaluated different fluorescent lipid dyes for topographic semiquantitative analysis of BrM lipids. Thin BrM–choroid complexes with partially stripped choroid from 10 aged donor eyes were prepared with an optimized wholemounting technique. Preparation quality was monitored by examining 1-μm-thick sections of representative samples. The staining patterns of Nile Red, BODIPY 493/503, filipin for unesterified cholesterol (UC-F), filipin for esterified cholesterol (EC-F), and Oil Red O in wholemounts were compared with their staining patterns in chorioretinal sections, using wide-field epi-fluorescence microscopy. Wholemounts exhibited optimal flatness on the BrM side. Reduced tissue thickness allowed reliable dye penetration and staining of BrM. Only EC-F was with high specificity localized to BrM and demonstrated an intense and distinct granular staining pattern not previously appreciated in chorioretinal sections. All other lipid dyes also stained choroidal or retinal tissue intensely. No dye provided perfect characteristics in regard to representing all neutral lipid classes present in BrM or to fluorescence intensity. Nevertheless, only EC-F was highly localized to BrM with a specific granular pattern. Because direct assays indicate that esterified cholesterol is abundantly present in BrM, we consider EC-F the most valuable choice for analyzing neutral lipid deposits in human BrM. (J Histochem Cytochem 57:731–739, 2009)     

Serum Magnesium and Atherogenic Lipid Fractions in Type II Diabetic Patients of Lahore, Pakistan

This study was conducted to determine the prevalence of hypomagnesemia and its effect on the lipid profile of local type II diabetic patients. For this purpose, 219 diabetic patients and 100 age-matched control subjects were enrolled. Blood samples of the subjects were analyzed for fasting glucose, Mg, triglyceride, total cholesterol, HDL-cholesterol, and LDL-cholesterol. Results showed that mean serum values of these parameters were differing in diabetic patients as compared to control subjects. The reference range of serum magnesium in healthy controls was 1.2-4.4 mg/dl. Mean serum magnesium in diabetic patients was significantly lower as compared to healthy subjects (1.6 ± 0.23 mg/dl vs. 2.8 ± 0.8 mg/dl). Among diabetic patients, 143 (65.3%) had serum magnesium level below 1.7 mg/dl (hypomagnesemia). The corresponding figure for control subjects was 11 (11%). The difference was significant (p < 0.01). Diabetes mellitus patients with current hyperglycemic status had significantly lower serum Mg as compared to euglycemic patients (p = 0.05). Serum Mg in diabetic patients was correlated with all lipid parameters. Among them, HDL-cholesterol was significantly (p < 0.05) positively correlated (r = 0.34), while total cholesterol and LDL-cholesterol was negatively correlated, albeit non-significantly, with serum Mg. These results demonstrate that hypomagnesemia is accompanied by atherogenic alterations in the lipid profiles of type II diabetic patients of Lahore, Pakistan.     

脂蛋白脂酶与疾病的关系及中药对脂蛋白脂酶的作用

脂蛋白脂酶(lipoprotcin lipase,LPL)是脂质代谢的关键酶,主要水解甘油三酯,在乳糜微粒及极低密度脂蛋白的代谢中发挥重要作用.该酶的缺乏或活力异常,与血脂异常、代谢综合症、动脉粥样硬化、糖尿病、子痫前期等疾病有一定关系.一些具有调脂作用的中药能够影响脂蛋白脂酶的活力或表达.