Lipoprotein metabolism and atherogenesis: implications for therapy.

The causes of atherosclerosis are numerous, but disturbances in lipid and lipoprotein (LP) metabolism undoubtedly play a key role. Although there exist multiple forms of genetic and secondary hyperlipoproteinemias linked with premature vascular diseases there are only a few LP that need to be considered: low-density LP, beta-very-low-density LP, chylomicron remnants and LP(a). In addition, low HDL levels have been found to represent an independent risk factor. Prolonged residence times of these LP lead to chemical modification and interaction with platelets, smooth muscle cells, endothelial cells and macrophages. Atherogenesis is thus a concerted action. Knowledge of the metabolic pathways of most of these LP is necessary in order to be able to specifically influence hyperlipoproteinemia with dietary measures or, ultimately, with lipid-lowering drugs.     

Atherosclerosis, Inflammation, Genetics, and Stem Cells: 2012 Update

Atherosclerosis is a peculiar form of inflammation triggered by cholesterol-rich lipoproteins and other noxious factors such as cigarette smoke, diabetes mellitus, and hypertension. Genetics also play an important role in the disease, accounting for about 40% of the risk. Of surprise in recent years of post-human genome sequencing, atherosclerosis-relevant genes discovered by non-biased techniques (ie, genome-wide association studies), did not rehash previously suspected pathways of lipid metabolism, diabetes, or hypertension. Instead these studies highlighted genes relevant to mechanisms of inflammation and stem cell biology. Only a minority of implicated genes were linked to lipid and other cardiac risk factor genes. Although such findings do not contradict the fact that atherosclerosis is triggered and exacerbated by elevated lipids, atherosclerosis "new genes" suggest that the mechanism responsible for the development of arterial lesions is more complex than a simple response to injury, where injury is necessary, but perhaps not sufficient, for disease progression.     

Genetic variants, cardiovascular risk and genome-wide association studies

Genome-wide association studies have shown an association between single nucleotide polymorphisms (SNPs) and coronary artery disease and myocardial infarction in new chromosomal regions: 1p13.1, 2q36.3, 9p21 and 10q11.21. The SNPs from the 9p21 region constitute a risk haplotype due to the strong linkage disequilibrium in this area. These SNPs have been extensively replicated in several European and Asian populations, and are associated with other pathologies such as abdominal aortic and intracranial aneurysms, and with intermediate phenotypes such as arterial stiffness and coronary calcium. The risk haplotype of 9p21 is located in a region without annotated genes, near CDKN2A and CDKN2B, known tumor suppressor genes encoding for inhibitors of cell cycle kinases. In the remaining regions the SNPs are located in genes with known roles in atherosclerosis as well as others with new roles. It has been shown that the incorporation of genetic information in the form of SNPs slightly improves the prediction of long-term cardiovascular risk estimated by the Framingham function, allowing the reclassification of individuals into more precise categories. Gene expression studies have found that expression levels of CDKN2A/CDKN2B/ANRIL are co-regulated and associated with the risk haplotype and atherosclerosis severity.Full English text available from: www.revespcardiol.org     

The potential role of genes in nonalcoholic fatty liver disease

Although most people with obesity and type 2 diabetes will have steatosis, only a minority will ever develop nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Family studies suggest that genetic factors are important in disease progression, although dissecting genetic factors playing a role in NASH and fibrosis from those influencing the development established risk factors is difficult.Several approaches can be used to look for genetic factors playing a role in nonalcoholic fatty liver disease (NAFLD). In the future, genome-wide single nucleotide polymorphism (SNP) scanning of cases and controls may become feasible. To date, however,studies have relied on candidate gene, case control, allele association methodology. Recent, and as yet preliminary, studies have reported associations between steatosis severity, NASH, and fibrosis with genes whose products are involved in lipid metabolism,oxidative stress, and endotoxin-cytokine interactions. If confirmed,these associations will enhance understanding of disease pathogenesis,and accordingly, the ability to design effective therapies.     

脂肪细胞型脂肪酸结合蛋白与动脉粥样硬化的研究进展

脂肪细胞型脂肪酸结合蛋白是脂肪酸结合蛋白家族成员之一,与体重、糖脂代谢紊乱、高血压关系密切,有助于代谢综合征的诊断及预测。近年来逐渐成为动脉粥样硬化的标记物,并为动脉粥样硬化的治疗提供了新的靶点。     

The canine copper toxicosis gene MURR1 is not implicated in the pathogenesis of Wilson disease

Background It has recently been demonstrated that the Wilson disease (WD) protein directly interacts with the human homolog of the MURR1 protein in vitro and in vivo, and that this interaction is specific for the copper transporter. The aim of the present study was to clarify the role of MURR1 in the pathogenesis of WD as well as in other WD-like disorders of hepatic copper metabolism of unknown origin. Methods Using the single-strand conformation polymorphism (SSCP) method followed by sequencing, we analyzed the 5′ untranslated region (UTR) and three exons of the MURR1 gene in three groups of patients: 19 wd patients in whom no mutations were detected in the ATP7B gene, 53 wd patients in whom only one mutation in the ATP7B gene was found, and 34 patients in whom clinical and laboratory data suggested a WD-like disorder of hepatic copper metabolism of unknown origin. Results We  detected in these patients six rare nucleotide substitutions, namely one splice-site consensus sequence and one missense and four silent nucleotide substitutions. All substitutions except one were found in the heterozygous state. No difference in the frequencies of the various substitutions was observed between patients and controls. Conclusions These data suggest that the MURR1 gene and its protein product are unlikely to play a primary role in the pathogenesis of Wilson disease. More extensive studies with larger numbers of clinically homogeneous patients should be carried out to establish whether nucleotide alterations in the MURR1 gene may have a role in causing WD or WD-like disorders or act as modifying factors in the phenotype variability in WD.     

Mouse models of atherosclerosis

Atherosclerosis is a complex disease in which progressive cellular changes occur for decades before the acute manifestation of cardiovascular disease. Definition of atherogenic mechanisms in humans is hindered by the complexity and chronicity of the disease process, combined with the inability to sequentially characterize lesions in an individual patient because of shortcomings in noninvasive detection modalities. Therefore, there has been a reliance on animal models of the disease to define mechanistic pathways. Over the last decade, the mouse has become the predominant species used to create models of atherosclerosis. The initial interest was based on the great diversity of inbred strains with defined genetic backgrounds that provides a means of linking genes to the development of atherosclerosis. More recently, the ability to genetically modify mice to over or under express specific genes has facilitated the definition of pathways in the atherogenic process. All of the current mouse models of atherosclerosis are based on perturbations of lipoprotein metabolism through dietary and/or genetic manipulations. Although hyperlipidemia is necessary for the development of atherosclerosis, mouse models have demonstrated that many nonlipid factors can influence the severity and characteristics of lesions. This review selectively highlights some of the most commonly used mouse models of atherosclerosis and compare their lesions to those formed in the human disease.     

Orphan nuclear receptors find a home in the arterial wall

Orphan nuclear receptors of the peroxisome proliferator activated receptor (PPAR) and liver X receptor (LXR) subfamilies have been shown to play critical roles in both local and systemic lipid metabolism. The PPARs control fatty acid metabolism in various cell types, including adipocytes, liver, and macrophages. The LXRs have been implicated in the regulation of cholesterol metabolism in the liver, intestines, and macrophages. The importance of these receptors in physiologic lipid metabolism suggests that they may influence the development of metabolic disorders such as obesity, diabetes, and atherosclerosis. Furthermore, the ability of these receptors to be modulated pharmacologically makes them attractive therapeutic targets. This review focuses on the role of PPAR and LXR signaling pathways in macrophage lipid metabolism and the potential of these pathways to modulate the development of atherosclerosis.     

Effects of calcium antagonists on lipids and atherosclerosis

The arterial accumulation of cholesterol and calcium is a hallmark of atherosclerosis. Calcium antagonists (CAs) lessen the severity of experimentally induced atherosclerosis in cholesterol-fed animals. The reduction of aortic cholesterol is one of the most striking findings. This effect is achieved without a reduction of plasma lipid or blood pressure, and is probably related to an interference of CAs with lipid metabolism in the arterial wall. To what extent these properties of CAs are due to their ability to block calcium channels still remains to be addressed. This report briefly discusses the available in vivo and in vitro evidence for the antiatherosclerotic properties of CAs, and outlines the possible mechanisms by which these compounds affect cellular lipid metabolism.     

SREBPs信号转导途径与动脉粥样硬化研究进展

固醇调节元件结合蛋白对细胞内胆固醇的稳态调节有重要作用,近几年研究发现固醇调节元件结合蛋白广泛参与了动脉粥样硬化危险因素如吸烟、高血糖、脂代谢障碍、肥胖、高血压等的促动脉粥样硬化作用,现就固醇调节元件结合蛋白在动脉粥样硬化中作用的最新进展做一综述,有助于对动脉粥样硬化的发病机理有更新、更全面的认识。     

Impact of alcohol intake on measures of lipid metabolism depends on context defined by gender,body mass index,cigarette smoking,and apolipoprotein E genotype

Hyperlipidemia, smoking, and obesity are well-known risk factors for cardiovascular disease. Conversely, moderate alcohol intake is associated with lower atherosclerosis risk. However, the influence of taking alcohol on the interrelationships of these factors in a particular context has not been thoroughly investigated. In this study, we asked whether the association between plasma measures of lipid metabolism and alcohol intake is dependent on context defined by gender, age, body mass index (BMI), smoking, and apolipoprotein E (APOE) genotype. Data were obtained in a sample of 869 women and 824 men who participated in the Quebec Heart Health Survey. There was no evidence that variation among APOE genotypes influenced the association between LDL cholesterol (LDL-C) or HDL cholesterol (HDL)-C and alcohol, after adjustment for age and BMI. Further, the positive (LDL-C and BMI) and the negative (HDL-C and BMI) associations that were observed in men and women with the epsilon3/2 and epsilon3/3 genotypes were not modified by alcohol intake. However, in women with the epsilon4/3 genotype only, we found a significant influence of an alcohol by BMI interaction on the prediction of total cholesterol, LDL-C, HDL-C, apoA-I, and apoB, and this interaction was influenced by the status of smoking. Whereas the influence of an alcohol by BMI interaction on total cholesterol and LDL-C was significant in smokers, its influence on HDL-C was significant only in non-smokers. This study emphasizes the context dependency of the influence of alcohol on lipid metabolism and demonstrates how biological, environmental, and genetic factors interact to determine cardiovascular disease risk.     

Genetics and dyslipidemias

The intense search which has developed around understanding the pathological mechanisms of atherosclerosis has underlined the complexity of a process which involves very many proteins, the products of genetic information. This observation, combined with genetic epidemiological data, has introduced the notion of familial susceptibility applicable to atherogenic dyslipidaemia. This susceptibility relies on the presence of mutations, more or less frequent in the population, affecting the key genes in plasmatic lipid transport. The mutations which are currently the best documented concern the genes involved in the metabolism of atherogenic lipoproteins: LDL-receptor, apo B or apo E. Nevertheless, a better understanding of the inverse transport of cholesterol would allow progressive demonstration of the mutations affecting HDL metabolism. The aim of such work encompasses the characterisation of the most relevant mutations for defining coronary risk, and a better understanding of the interactions of these mutations with conventional environmental risk factors.     

The magic and mystery of microRNA-27 in atherosclerosis

Atherosclerosis (As) is now widely appreciated to represent a chronic inflammatory reaction of the vascular wall in response to dyslipidemia and endothelial distress involving the inflammatory recruitment of leukocytes and the activation of resident vascular cells. MicroRNAs (miRNAs) are a group of endogenous, small (~22 nucleotides in length) non-coding RNA molecules, which function specifically by base pairing with mRNA of genes, thereby induce translation repressions of the genes within metazoan cells. Recently, the function of miR-27, one of the miRNAs, in the initiation and progression of atherosclerosis has been identified. In vivo and in vitro studies suggest that miR-27 may serve as a diagnostic and prognostic marker for atherosclerosis. More recently, studies have identified important roles for miR-27 in angiogenesis, adipogenesis, inflammation, lipid metabolism, oxidative stress, insulin resistance and type 2 diabetes, etc. In this review, we focus on the role of miR-27 in the development of vulnerable atherosclerotic plaques, potential as a disease biomarker and novel therapeutic target in atherosclerosis.