马尾松树皮提取物预防apoE基因敲除小鼠肝脏脂肪变性

目的探究马尾松树皮提取物(Pinus massoniana bark extract, PMBE)对载脂蛋白E(ApoE)基因敲除小鼠肝脏脂肪变性的影响。方法给8只ApoE KO雄性小鼠每天口服PMBE(30 mg/kg)2周,然后喂养高胆固醇及高脂饮食8周后,与普通饮食(NC)组及高脂饮食(HCD)组进行对比,取各组小鼠肝脏组织进行油红染色及Real-time PCR试验,检测脂质代谢相关基因的表达。结果经PMBE治疗后的小鼠肝细胞中脂质沉积减少,肝脏脂质含量减低;随后检测脂质代谢相关基因,发现PMBE通过减少脂质合成和增加脂解作用显著抑制了肝脏脂肪的蓄积。结论 PMBE可以预防肝脏脂肪变性的发生和发展。     

microRNAs——脂质代谢调控新机制

综述了近年来microRNAs,尤其是miR-33在脂质代谢调控方面的功能研究进展.脂质代谢在细胞水平进行有规律的调控,主要参与者有肝X受体(LXRs)和固醇调节元件结合蛋白(SREBPs)等.最近研究发现,非编码RNAs家族成员microRNAs在转录后水平调节脂质代谢相关基因表达,参与胆固醇、甘油三酯和脂肪酸代谢.其中miR-33可靶向沉默三磷酸脂苷结合盒(ABC)转运体家族成员ABCA1和ABCG1,抑制胆固醇流出和高密度脂蛋白(HDL)合成;通过靶向沉默脂肪酸β-氧化相关基因,如CPT1A、CROT和HADHB表达,抑制脂肪酸氧化;还可沉默AMPK和RIP140的表达,影响甘油三酯代谢.其他microRNAs如miR-122、miR-370、miR-125a-5p、miR-27、miR-320等,也参与调控胆固醇、甘油三脂、脂肪酸代谢及脂肪细胞分化.     

肝脂酶基因多态性与冠心病的关系

肝脂酶 (hepaticlipase,HL)对血浆脂蛋白的代谢起重要作用 ,它影响着血浆中高密度脂蛋白 (HDL)的水平以及低密度脂蛋白 (LDL)的种类 ,因此肝脂酶的活性与冠心病的发生具有相关性。肝脂酶基因的单核苷酸多态性 (SNP)与酶的活性相关 ,并影响血浆脂蛋白水平以及冠心病的发生。为研究肝脂酶基因的单核苷酸多态性与中国汉族冠心病的相关性 ,采用聚合酶链反应、变性高效液相色谱及DNA测序等技术对 10 2例经冠状动脉造影确诊的冠心病患者和 84例正常对照的肝脂酶基因 (包括启动子区以及所有外显子 )的SNP进行了研究 ,结果在肝脂酶基因启动子区发现了一未见文献报道的多态位点 ,即- 2T→C转换。经检验 ,对照组和病例组基因型频率的分布符合Hardy Weinberg平衡。冠心病患者组中 - 2C等位基因的携带者 (基因型为TC或CC)显著高于对照组 (5 7.9%versus 4 2 .7% ,χ2 =4 .181,df=2 ,P =0 .0 4 1) ,且冠心病组中 - 2C等位基因的频率显著高于对照组 (χ2 =3.988,df =1,P =0 .0 4 6 ,OR =1.5 8,95 %CI =1.0 1～ 2 .4 7) ;在冠心病组中进一步发现 -2C等位基因与高密度脂蛋白胆固醇水平升高相关 (P <0 .0 5 )。这提示肝脂酶基因的 - 2T→C多态性可能与血浆高密度脂蛋白胆固醇的水平以及冠心病的发生具有相关性。     

CD36调控脂质代谢作用及机制

脂质代谢是机体的重要代谢过程,其紊乱会导致众多疾病的发生。人类白细胞分化抗原36(cluster of differentiation 36,CD36)是一种在单核细胞、巨噬细胞、平滑肌细胞以及脂肪细胞高度表达的清道夫受体,是识别氧化低密度脂蛋白及长链脂肪酸的主要受体和转运蛋白,在脂质代谢过程中发挥着重要作用。本文综述了CD36基因及蛋白的结构和生理功能,阐述了清道夫受体CD36在脂质代谢过程中发挥的作用,并系统地总结了其级联AMPK、mTOR和MAPK信号通路参与脂质代谢过程的分子机制,为相关生物学研究提供了理论基础。     

睡眠呼吸暂停综合征患者血脂水平的研究

目的:了解阻塞性睡眠呼吸暂停低通气综合征(OSAHS)患者血浆脂质代谢情况。方法:分别检测健康对照组、睡眠呼吸暂停综合征患者组甘油三酯、总胆固醇、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、载脂蛋白A、载脂蛋白B、脂蛋白a、载脂蛋白E含量。进行统计学对比及分析。结果:睡眠呼吸暂停综合征患者的甘油三酯、总胆固醇、高密度脂蛋白、总胆固醇/高密度脂蛋白、载脂蛋白A、载脂蛋白B及载脂蛋白E与健康对照组比较有显著差异,且与其睡眠监测指标有明显相关。结论:OSAHS可导致血浆脂质代谢紊乱,与动脉粥样硬化发生及发展的存在重要的相关性,是独立于年龄、体重、饮食、遗传等原因的冠心病、高血压、脑卒中等心脑血管疾病的发病因素之一。因此,提高对OSAHS的警惕是非常重要的。     

载脂蛋白C3-高脂血症与内皮细胞功能障碍的重要分子

载脂蛋白C3(APOC3)是一个多功能蛋白质,与甘油三酯(TG)水平成正相关关系,是预测冠心病(CAD)发生发展的一个独立风险因子。近年来的研究表明,它不仅可调节富甘油三酯脂蛋白(TRL)代谢,而且是内皮功能的一个重要调节者,它可以同时诱导内皮功能紊乱和脂质代谢紊乱,从而参加诱发动脉粥样硬化(AS)、增加发生CAD的风险以及其它相关疾病。APOC3基因多态性也与疾病发生密切相关。     

银灵通胶囊调节实验性高脂饮食大鼠血脂的研究

目的:探究银灵通胶囊对脂质代谢的影响及其机制。方法:建立大鼠高脂模型,用药后检测其血脂、丙二醛(MDA)、超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GSH-Px)的活性,检测肝脏组织的高密度脂蛋白受体SR-BI、低密度脂蛋白受体(LDLR)、氧化低密度脂蛋白(ox-LDH)受体CD36蛋白表达的mRNA表达水平,检测血管组织学变化。结果:高脂饮食明显升高大鼠血清中总胆固醇(CH)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)和动脉硬化指数(AI值),银灵通胶囊组可降低上述指标,且呈一定的浓度依赖;高脂饮食可增加肝脏中SR-BI及CD36表达,降低LDLR表达,银灵通胶囊引起SR-BI的过度表达,使LDLR表达增加,CD36表达下降。高脂饮食使血清中MDA的含量增加,给予银灵通胶囊后,明显降低血清MDA的含量。结论:银灵通胶囊具有调节脂质代谢,抗动脉粥样硬化(AS)及抗脂质过氧化作用。其机制与银灵通胶囊能引起肝脏中SR-BI的过度表达及LDLR表达增加,降低肝脏中CD36表达和血清MDA含量有关。     

动脉粥样硬化基因工程小鼠模型

建立可靠的动脉粥样硬化动物模型对于探明其病因、发病机制及防治药物的开发均具有重要的意义。本文介绍了载脂蛋白、脂质代谢有关的受体、脂质代谢有关的酶和转运蛋白等十几种动脉粥样硬化相关基因的基因工程小鼠模型的特点及应用。     

脂代谢异常对肾病的影响

肾脏疾病发展为慢性肾衰竭是个不可逆的过程,脂质代谢的异常,对肾病患者具有重要的影响。多项实验已经证实,即使在肾病的早期阶段,也会出现不同程度的脂质及脂类代谢的异常,高密度脂蛋白(HDL)、低密度脂蛋白(LDL)、脂联素、瘦素等脂类代谢相关物质发生改变,不仅对血浆脂代谢产生影响,对于肾小球及肾小管的结构及功能也会有一定的损伤作用。肾病患者,如肾病综合征、慢性肾衰竭等疾病,多数有肾小球及肾小管间质的损伤,肾脏的脂毒性加重肾单位的破坏。随着人们对于慢性肾脏病认识的逐渐深入,降脂治疗的普遍应用,人们普遍认为改善血浆中脂类的水平,对于肾病的治疗,尤其对于慢性肾衰竭的预防具有重要作用。     

干预GPR1通路对实验性小鼠脂肪累积的影响

一直以来,肥胖是令人担忧和烦恼的健康问题,可导致包括2型糖尿病在内的代谢综合征发生.与肥胖相关疾病的发病机制是多因子影响的结果,但是,越来越多的证据表明,脂肪组织分泌的细胞因子(脂联素、瘦素、TNF-α等)的改变,以及局部的炎症反应对于这些疾病的发生具有重要作用.Chemerin(也被称为他扎罗汀诱导基因2或者视黄酸受体反应子2),是近年来发现的一种脂肪细胞因子,是G蛋白偶联受体1(GPR1)的配体,在调节代谢、先天免疫等方面具有重要的作用.为了研究Chemerin及其受体GPR1对小鼠脂肪累积的影响,本课题组通过高脂饲料喂养,成功建立小鼠肥胖模型,利用si RNA干扰技术沉默小鼠和分化前3T3-L1细胞中Chemerin或GPR1基因的表达发现:a.Chemerin及其受体GPR1在高脂饲料喂养小鼠的腹股沟脂肪以及肩胛下脂肪中的表达高于正常饲料组;b.沉默C57BL/6小鼠体内Chemerin或GPR1基因的表达后,肝脏以及腹股沟脂肪组织中脂质的累积受到抑制;c.3T3-L1细胞在体外分化成熟过程中,Chemerin和GPR1也呈高表达的趋势,沉默分化前3T3-L1细胞中Chemerin或GPR1基因的表达后,3T3-L1细胞向脂肪细胞的分化受到影响,降低了脂肪细胞中脂质的累积以及与脂质代谢相关基因的表达,改变了成熟脂肪细胞中新陈代谢功能.这些结果提示,Chemerin及其受体GPR1可能在小鼠脂肪累积中具有调控作用.综上所述,Chemerin/GPR1可能是一种调节脂肪组织中脂质累积的潜在信号通路,为肥胖症等代谢紊乱疾病的治疗提供了可能的作用靶点.     

Postprandial lipoprotein metabolism, genes and risk of cardiovascular disease

PURPOSE OF REVIEW: Several lines of evidence suggest that postprandial lipemia increases the risk of atherogenesis, and in each of the systems involved in postprandial metabolism the roles of many genes have been explored in order to establish the possible implications of their variability in coronary heart disease risk. RECENT FINDINGS: This report focuses on recent results pertaining to postprandial lipoprotein metabolism and genes, their variability and their relationship with intermediate phenotypes and coronary heart disease. The postprandial lipid response was modified by polymorphisms within the genes for apolipoprotein AI, apolipoprotein E, apolipoprotein B, apolipoprotein CI, apolipoprotein CIII, apolipoprotein AIV, apolipoprotein AV, lipoprotein lipase, hepatic lipase, fatty acid-binding protein-2, the fatty acid transport proteins, microsomal triglyceride transfer protein and scavenger receptor class B type I. We also discuss recent advances in the effects of gene regulation using knockdown animal models on postprandial lipoprotein metabolism. SUMMARY: The review discusses several of these factors as well as the potential impact of gene polymorphism on the variability of postprandial lipoprotein metabolism as intermediate phenotypes for coronary heart disease. The variability in postprandial lipid response is highly complex. Future studies will need to be large if they are to assess the effects of multiple polymorphisms.     

Familial hypercholesterolaemia

Familial hypercholesterolaemia (FH), defined as the heritable occurrence of severe hypercholesterolaemia with cholesterol deposits in tendons and premature heart disease, is caused by at least four genes in sterol and lipoprotein pathways and displays varying gene-dose effects. The genes are the low-density lipoprotein (LDL) receptor, apolipoprotein (apo) B, proprotein convertase subtilisin/kexin 9, and the autosomal recessive hypercholesterolaemia (ARH) adaptor protein. All of these disorders have in common defective clearance of LDL within a complex system of lipid and lipoprotein metabolism and regulation. Normal cellular cholesterol and lipoprotein metabolism is reviewed before describing the disorders, their metabolic derangements and their clinical effects. FH is classified as two simplified phenotypes of disease according to the severity of the metabolic derangement. The dominantly inherited heterozygous phenotype comprises defects in the LDL receptor, apoB100, and neural apoptosis regulatory cleavage protein. The homozygous phenotype is co-dominant in defects of the LDL receptor, and occurs also as the ARH of adapter protein mutations. Defective binding of apoB100 does not result in a significant gene dose effect, but enhances the severity of heterozygotes for LDL receptor mutations. The genetic diagnosis of FH has provided greater accuracy in definition and detection of disease and exposes information about migration of populations. All of these disorders pose a high risk of atherosclerosis, especially in the homozygous phenotype. Studies of influences on the phenotype and responses to treatment are also discussed in the context of the metabolic derangements.     

Diabetic dyslipidaemia

PURPOSE OF REVIEW: Diabetic dyslipidaemia is a cluster of plasma lipid and lipoprotein abnormalities that are metabolically interrelated. The increase of large type 1 very low density lipoprotein particles in type 2 diabetes initiates a sequence of events that generates atherogenic remnants, small dense low-density lipoprotein and small dense high-density lipoprotein particles. Thus, it is of great importance to elucidate the mechanisms behind the overproduction of large very low density lipoprotein particles in diabetic dyslipidaemia. This review discusses the pathophysiology of very low density lipoprotein metabolism in type 2 diabetes and recent concepts of lipid management of diabetic dyslipidaemia. RECENT FINDINGS: Results indicate that triglyceride and apolipoprotein B production in types 1 and 2 very low density lipoprotein are significantly correlated, suggesting a coupling of the two processes governing the metabolism of these lipoprotein subpopulations. Insulin resistance, hyperglycaemia, and liver fat were associated with excess hepatic production of type 1 but not type 2 very low density lipoprotein particles. These data provide support for the independent regulation of types 1 and 2 very low density lipoprotein apolipoprotein B production. SUMMARY: Recent data suggest that the assembly of very low density lipoprotein is fundamentally altered in type 2 diabetes, explaining the overproduction of large type 1 very low density lipoprotein as well as the inability of insulin to suppress production of type 1 very low density lipoprotein in type 2 diabetes. Future discoveries hopefully will delineate the regulatory steps to allow more targeted treatment of diabetic dyslipidaemia.     

Clinical significance of apolipoprotein A5

PURPOSE OF REVIEW: We have examined the evidence from recent human studies examining the role of apolipoprotein A-V in triglyceride-rich lipoprotein metabolism and cardiovascular disease risk. Special emphasis was placed on the evidence emerging from the association between genetic variability at the apolipoprotein A5 locus, lipid phenotypes and disease outcomes. Moreover, we address recent reports evaluating apolipoprotein A5 gene-environment interactions in relation to cardiovascular disease and its common risk factors. RECENT FINDINGS: Several genetic association studies have continued to strengthen the position of APOA5 as a major gene that is involved in triglyceride metabolism and modulated by dietary factors and pharmacological therapies. Moreover, genetic variants at this locus have been significantly associated with both coronary disease and stroke risks. SUMMARY: Apolipoprotein A-V has an important role in lipid metabolism, specifically for triglyceride-rich lipoproteins. However, its mechanism of action is still poorly understood. Clinical significance at present comes largely from genetic studies showing a consistent association with plasma triglyceride concentrations. Moreover, the effects of common genetic variants on triglyceride concentrations and disease risk are further modulated by other factors such as diet, pharmacological interventions and BMI. Therefore, these genetic variants could be potentially used to predict cardiovascular disease risk and individualize therapeutic options to decrease cardiovascular disease risk.     

Abnormal apolipoprotein composition in alcoholic hepatitis

Alcoholic hepatitis leads to major derangements in lipoprotein metabolism. This study defines the characteristics of the abnormal high density lipoprotein and very low density lipoprotein in relation to the severity of the disease. In severely affected subjects very low density lipoprotein apolipoproteins were deficient in apolipoprotein E and apolipoprotein C. The concentration of high density lipoprotein was markedly reduced, although the proportion of high density lipoprotein 1 was substantially elevated when compared to normal subjects. High density lipoproteins were deficient in apolipoprotein AI and apolipoprotein AII but enriched in apolipoprotein E, apolipoprotein E complexes and apolipoprotein C, and contained a mixture of particles. The high density lipoprotein of subjects with alcoholic hepatitis contained a high proportion of material which bound to heparin affinity columns. This bound fraction contained a group of particles rich in apolipoprotein E, apolipoprotein E complexes and apolipoprotein C and was deficient in apolipoprotein AI and apolipoprotein AII. Examination by electron microscopy showed the presence of both discoidal and spherical particles, which varied in concentration according to the severity of the disease. Another fraction of high density lipoprotein, not bound to heparin, contained reduced amounts of apolipoprotein AI and apolipoprotein AII, consisted of disc-shaped particles and showed a higher esterified: free cholesterol ratio than the other high density lipoprotein fraction.     

Investigating the genetic regulation of the expression of 63 lipid metabolism genes in the pig skeletal muscle

A comprehensive and systematic view of the genetic regulation of lipid metabolism genes is still lacking in pigs. Herewith, we have investigated the genetic regulation of 63 porcine genes with crucial roles in the uptake, transport, synthesis and catabolism of lipids. With this aim, we have performed an expression QTL (eQTL) scan in 104 pigs with available genotypes for the Illumina Porcine SNP60 chip and microarray measurements of gene expression in the gluteus medius muscle. Analysis of the data with gemma software revealed 13 cis‐ and 18 trans‐eQTL modulating the expression of 19 loci. Genes regulated by eQTL participated in a wide array of lipid metabolism pathways such as the β‐oxidation of fatty acids, lipid biosynthesis and lipolysis, fatty acid activation and desaturation, lipoprotein uptake, apolipoprotein assembly and cholesterol trafficking. These data provide a first picture of the genetic regulation of loci involved in porcine lipid metabolism.     

Highly polymorphic apolipoprotein A-IV locus in the baboon

Apolipoprotein A-IV is found in mesenteric lymph chylomicrons, very low density lipoprotein particles, high density lipoprotein particles, and in the lipoprotein-free fraction of plasma. Apolipoprotein A-IV is polymorphic in a variety of species including human, dog, and horse. Efforts to estimate the impact of apolipoprotein A-IV structural variation on quantitative lipid levels in humans have been limited by the low frequency of the less common alleles. In the baboon, Papio hamadryas anubis, we have found apolipoprotein A-IV to be highly variable at the protein level with five alleles appearing at polymorphic frequency. We have confirmed the autosomal codominant inheritance of these five alleles in pedigreed baboons. The baboon has been shown to be a suitable animal model for the study of atherosclerosis, and the existence of a common, multi-allele apolipoprotein A-IV polymorphism in the baboon may be useful in elucidating the role of apolipoprotein A-IV in lipid metabolism.     

Defective receptor binding of low density lipoprotein from pigs possessing mutant apolipoprotein B alleles

We previously identified a defect in the in vivo catabolism of low density lipoprotein (LDL) from hypercholesterolemic pigs carrying a mutant apolipoprotein B allele. In the present studies, we examined the in vitro metabolism of mutant LDL in cultured pig fibroblasts. A 3-fold higher concentration of mutant LDL (compared to control) was needed to displace 50% of control 125I-LDL binding. Mutant LDL had a 6-fold higher dissociation constant than control LDL. Scatchard plots of the binding data were concave upward, suggesting multiple classes of binding sites or negative cooperativity. The mutant LDL degradation rate was reduced by 40%; this decrease could be attributed to a dense LDL subspecies. Mutant and control buoyant LDL subspecies were degraded more slowly than the corresponding dense LDL subspecies. Together, these studies show that diminished LDL receptor binding can result from mutations in apolipoprotein B and from changes in the lipid composition of LDL particles.     

A common VLDLR polymorphism interacts with APOE genotype in the prediction of carotid artery disease risk

The genetic factors associated with carotid artery disease (CAAD) are not fully known. Because of its role in lipid metabolism, we hypothesized that common genetic variation in the very low density lipoprotein receptor (VLDLR) gene is associated with severe CAAD (>80% stenosis), body mass index (BMI), and lipid traits in humans. VLDLR was resequenced for variation discovery in 92 subjects, and single nucleotide polymorphisms (tagSNPs) were chosen for genotyping in a larger cohort (n = 1,027). Of the 17 tagSNPs genotyped, one tagSNP (SNP 1226; rs1454626) located in the 5' flanking region of VLDLR was associated with CAAD, BMI, and LDL-associated apolipoprotein B (apoB). We also identified receptor-ligand genetic interactions between VLDLR 1226 and APOE genotype for predicting CAAD case status. These findings may further our understanding of VLDLR function, its ligand APOE, and ultimately the pathogenesis of CAAD in the general population.