Showing papers in "Current Opinion in Lipidology in 1999"

Peroxisome proliferator-activated receptor-alpha activators regulate genes governing lipoprotein metabolism, vascular inflammation and atherosclerosis.

Abstract: The peroxisome proliferator-activated receptors (PPARs) [alpha, delta (beta) and gamma] form a subfamily of the nuclear receptor gene family. All PPARs are, albeit to different extents, activated by fatty acids and derivatives; PPAR-alpha binds the hypolipidemic fibrates whereas antidiabetic glitazo

Apolipoprotein E: from atherosclerosis to Alzheimer's disease and beyond.

Abstract: Apolipoprotein E is a key regulator of plasma lipid levels. Our appreciation of its role continues to expand as additional aspects of its function are discovered. Apolipoprotein E affects the levels of all lipoproteins, either directly or indirectly by modulating their receptor-mediated clearance or lipolytic processing and the production of hepatic very low density lipoproteins. Furthermore, it plays a critical role in neurobiology. The apolipoprotein E4 allele is the major susceptibility gene related to the occurrence and early age of onset of Alzheimer's disease. It is probable that one of the major functions of apolipoprotein E in the central nervous system is to mediate neuronal repair, remodeling, and protection, with apolipoprotein E4 being less effective than the E3 and E2 alleles. The isoform-specific effects of apolipoprotein E are currently being unraveled through detailed structure and function studies of this protein.

Sterol regulatory element-binding proteins: activators of cholesterol and fatty acid biosynthesis.

Abstract: A family of transcription factors designated sterol regulatory element-binding proteins (SREBPs) mediates the previously described end-product feedback regulation of cholesterol biosynthesis. In addition, SREBPs are emerging as important regulators of fatty acid synthesis. The current review focuses on the in-vivo regulation of SREBPs in liver and the coordinate regulation of SREBP-activated target genes.

Peroxisome proliferator-activated receptor alpha in metabolic disease, inflammation, atherosclerosis and aging

Abstract: Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors which are activated by fatty acids and derivatives. The PPARα form has been shown to mediate the action of the hypolipidemic drugs of the fibrate class on lipid and lipoprotein metabolism. PPARα activators furthermore improve

Low-density lipoprotein-independent effects of statins.

Abstract: Statins have pleiotropic properties that complement their cholesterol-lowering effects. These properties may partly account for their established benefit in the prevention of coronary artery disease beyond the reduction of LDL-cholesterol levels. The most widely recognized properties are reviewed here. They include: (i) nitric oxide-mediated improvement of endothelial dysfunction and upregulation of endothelin-1 expression; (ii) antioxidant effects; (iii) anti-inflammatory properties; (iv) inhibition of cell proliferation with anticarcinogenic actions in animals; (v) stabilization of atherosclerotic plaques; (vi) anticoagulant effects; and (vii) inhibition of graft rejection after heart and kidney transplantation. As advances are made in our knowledge, new properties are steadily being uncovered. Pleiotropic effects are currently being given consideration when instituting combination therapy for patients at high cardiovascular risk. Some pleiotropic effects are negative, and may account for occasional untoward drug interactions. For many of these new properties, the clinical relevance has not been established. The challenge for the future will be to design and carry out appropriate clinical trials to establish their relative importance in the prevention of coronary artery disease.

Pathology of in-stent restenosis.

Abstract: The process of in-stent restenosis parallels wound healing responses. Stent deployment results in early thrombus deposition and acute inflammation, granulation tissue development, and ultimately smooth muscle cell proliferation and extracellular matrix synthesis. The severity of arterial injury during stent placement correlates with increased inflammation and late neointimal growth. These pathological findings provide useful targets for therapies aimed at reducing the incidence of in-stent restenosis.

The assembly and secretion of apolipoprotein B-containing lipoproteins.

Abstract: The assembly of lipoproteins containing apolipoprotein B is a complex process that occurs in the lumen of the secretory pathway. The process consists of two relatively well-identified steps. In the first step, two VLDL precursors are formed simultaneously and independently: an apolipoprotein B-containing VLDL precursor (a partially lipidated apolipoprotein B) and a VLDL-sized lipid droplet that lacks apolipoprotein B. In the second step, these two precursors fuse to form a mature VLDL particle. The apolipoprotein B-containing VLDL precursor is formed during the translation and concomitant translocation of the protein to the lumen of the endoplasmic reticulum. The VLDL precursor is completed shortly after the protein is fully synthesized. The process is dependent on the microsomal triglyceride transfer protein (MTP). Although the mechanism by which the lipid droplets are formed is unknown, recent observations indicate that the process is dependent on MTP. The fusion of the two precursors is not dependent on MTP, but the mechanism remains to be elucidated. The conversion of the apolipoprotein B-containing precursor to VLDL seems to be dependent on the ADP ribosylation factor 1 (ARF 1) and its activation of phospholipase D. During their assembly, nascent apolipoprotein B chains undergo quality control and are sorted to degradation. Such sorting, which occurs cotranslationally during the formation of the apolipoprotein B-containing precursor, involves cytosolic chaperons and ubiquitination that targets apolipoprotein B to proteasomal degradation. Other levels of sorting occur in the secretory pathway. Thus, lysosomal enzymes are involved as well as the LDL receptor.

Fatty acid transport proteins

Abstract: A family of fatty acid transport proteins (FATPs) mediate transport of long chain fatty acids (LCFAs) across cell membranes into cells. These proteins exhibit different expression patterns among the organs of mammals. Nucleic acids encoding FATPs of this family, vectors comprising these nucleic acids, as well as the production of FATP proteins in host cells are described. Also described are methods to test FATPs for fatty acid transport function, and methods to identify inhibitors or enhancers of transport function. The altering of LCFA uptake by administering to the mammal an inhibitor or enhancer of FATP transport function of a FATP in the small intestine can decrease or increase calories available as fats, and can decrease or increase circulating fatty acids. The organ specificity of FATP distribution can be exploited in methods to direct drugs, diagnostic indicators and so forth to an organ such as the heart.

Scavenger receptor BI and cholesterol trafficking.

Abstract: Scavenger receptor BI (SR-BI) mediates the selective uptake of HDL cholesteryl ester into steroidogenic cells and the liver and is a major determinant of the plasma HDL concentration in the mouse. Recent studies indicate that SR-BI also alters the metabolism of apolipoprotein B-containing particles and influences the development of atherosclerosis in several animal models. These results and the similar pattern of SR-BI expression in humans emphasize that it is important to learn how this receptor influences lipoprotein metabolism and atherosclerosis in people.

Lipoprotein(a): intrigues and insights.

Abstract: Lipoprotein(a) is an atherogenic, cholesterol ester-rich lipoprotein of unknown physiological function. The unusual species distribution of lipoprotein(a) and the extreme polymorphic nature of its distinguishing apolipoprotein component, apolipoprotein(a), have provided unique challenges for the investigation of its biochemistry, genetics, metabolism and atherogenicity. Some fundamental questions regarding this enigmatic lipoprotein have escaped elucidation, as will be highlighted in this review.

Homocysteine and atherosclerosis.

Abstract: Elevated plasma total homocysteine is an independent risk factor for atherosclerotic vascular disease. Risk rises continuously across the spectrum of homocysteine concentrations and may become appreciable at levels greater than 10 mumol/l. A compelling case can be made for screening all individuals with atherosclerotic disease or at high risk. A reasonable, but unproven, goal for treatment is a plasma total homocysteine concentration less than 10 mumol/l. Folic acid is the mainstay of treatment, but vitamins B12 and B6 may have added benefit in selected patients. The results of ongoing randomized placebo-controlled trials will not be available for several years, but will help determine whether homocysteine lowering reduces the risk of cardiovascular disease.

Hepatic lipase: new insights from genetic and metabolic studies.

Abstract: Hepatic lipase catalyses the hydrolysis of triglycerides and phospholipids in all major classes of lipoproteins. Genetic deficiency of this enzyme is associated with a unique plasma lipoprotein profile, characterized by hypertriglyceridemia and elevated concentrations of intermediate density lipopro

Fibrates, dyslipoproteinaemia and cardiovascular disease.

Abstract: Recent epidemiological data have reaffirmed that elevated plasma triglyceride and low HDL-cholesterol levels are important risk factors for atherosclerotic vascular disease. The rationale for the clinical use of fibric acid derivatives, which are designed to correct this metabolic nexus, is now on f

Inflammation markers and coronary heart disease.

Abstract: Evidence supports the position that the chronic atherothrombotic process is intimately associated with what has classically been called 'inflammation'. Proteins that are part of the acute phase response (e.g. fibrinogen, C-reactive protein) are sensitive markers of low-level inflammation, and in population studies, inflammation marker levels at the upper end of the healthy reference range are associated with the presence of subclinical atherothrombotic disease (e.g. carotid wall thickness) and, prospectively, with future cardiovascular disease events. While there are plausible mechanisms for most of these markers, it remains to be demonstrated whether the markers actually participate in cardiovascular disease, or simply reflect the underlying disease process. This point is important, since marker-specific interventions might be useful if the former position is correct. Recent work suggests that inflammation markers may represent different aspects of the atherothrombotic process at different points in the natural history of the disease. This has implications for the interpretation of marker levels and the timing of the future events that they predict.

Removal of cholesterol from extrahepatic sources by oxidative mechanisms.

Abstract: Sterol 27-hydroxylase is an evolutionarily old cytochrome P450 species that is critical for oxidation of the side chain of cholesterol in connection with bile acid biosynthesis in the liver. The wide tissue and organ distribution of the enzyme suggests that it may also have other functions. It was recently shown that some cells (e.g. macrophages) have a high capacity to convert cholesterol into both 27-hydroxycholesterol and cholestenoic acid and that there is a significant flux of these steroids from extrahepatic sources to the liver where they are further oxidized into bile acids. The magnitude of this flux is such that it may be of importance for overall homeostasis of cholesterol. Very recently it was shown that the brain utilizes a similar mechanism for removal of cholesterol. A unique brain-specific 24S-hydroxylase converts cholesterol into 24S-hydroxycholesterol that is transported over the blood-brain barrier much more rapidly than unmetabolized cholestero. When 24S-hydroxycholesterol has reached the circulation it is taken up by the liver and further metabolized, most probably into bile acids. This flux is likely to be of importance for cholesterol homeostasis in the brain. This review summarizes our current knowledge regarding oxidative mechanisms for removal of extrahepatic cholesterol. It is evident that some cells utilize these mechanisms as alternatives or complements to the classical HDL-dependent reverse cholesterol transport.

Regulation of cholesterol metabolism by dietary plant sterols.

Abstract: Renewal has occurred in the use of plant sterols for the treatment of hypercholesterolemias. A novel development was to convert plant sterols to corresponding stanols and esterify them to fat soluble form. In contrast to the crystalline plant sterols or stanols, plant stanol esters can be easily consumed during normal food intake in soluble form in different fat-containing food constituents when they have a potent cholesterol-lowering effect, shown in normo- and hypercholesterolemic men and women without or with coronary heart disease, children and diabetes. Cholesterol lowering is approximately 10% for total and 15% for LDL cholesterol, with the respective values for stanol ester margarine (2-3 g/day stanols) being 15% and 20%. Stanol esters reduce cholesterol absorption efficiency by up to 65%, increase cholesterol elimination in feces as cholesterol itself, usually not as bile acids, and stimulate cholesterol synthesis. Serum beta-carotene level is lowered, but no fat malabsorption or lowering of serum fat soluble vitamins have been observed. In contrast to plant sterols, stanols and their esters are minimally absorbed and they reduce serum plant sterol concentrations, also preventing statin-induced increase of plant sterols. Stanol ester margarine has been included in dietary treatment of hypercholesterolemia followed by the addition of drug treatment in resistant cases.

Intestinal cholesterol absorption.

Abstract: The strong association between intestinal cholesterol absorption and total plasma cholesterol level has renewed interest in the absorptive process and stimulated the generation of new animal models. Increasingly, new studies suggest that cholesterol absorption is genetically controlled and supports a protein-mediated mechanism for cholesterol uptake into the intestinal mucosal cell. Insights into potential mechanisms are predicted to lead to novel pharmacological approaches to inhibit cholesterol absorption.

Dietary and pharmacological antioxidants in atherosclerosis.

Abstract: Antioxidants that inhibit LDL oxidation are thought to be potential anti-atherogenic compounds. The results of major human randomized trials with antioxidants have, however, been disappointing, except for probucol, which consistently inhibits restenosis. Similarly, animal intervention studies show that antioxidants do not generally inhibit atherosclerosis, although some compounds provide protection. Direct evidence for the oxidation of LDL causing atherosclerosis is needed. This article summarizes results from antioxidant intervention studies, and highlights some of the key issues that need to be addressed to link biochemical changes in the arterial wall more directly to the oxidation theory of atherosclerosis.

Genetic architecture and evolution of the lipoprotein(a) trait.

Abstract: Apolipoprotein(a) is coded by one of the most polymorphic genes known in humans In white and Asian populations variation in this gene is the major determinant of the plasma concentrations of the atherogenic lipoprotein(a) which varies enormously between individuals and considerably across populations Recent studies have shown that the genetic architecture of the quantitative Lp(a) trait differs among major human groups In Africans there is evidence for a transacting factor Three types of variation have been identified in the apo(a) gene: a size polymorphism in the coding region (K IV type 2 repeats), a pentanucleotide repeat polymorphism in the promoter (5'PNRP) and sequence variation in coding and non-coding regions of the gene including a C/T polymorphism at +93 which creates an additional ATG start codon but also affects transcription The causal +93 C/T effect is masked by linkage disequilibrium in white populations Analysis of apo(a) K IV 6-10 exons revealed the existence of population-specific spectra of polymorphism in this domain However further sequence variation which may provide clues for the understanding of the regulation of apo(a) concentrations still needs to be identified DNA sequencing and phylogenetic analysis have demonstrated that two types of apo(a) exist, in phylogenetically distant mammalian lineages a K IV derived primate form and a K III-derived hedgehog form which are products of convergent evolution

Functional variants in the lipoprotein lipase gene and risk of cardiovascular disease

Abstract: The current report is a quantitative review of the relationship between lipoprotein lipase gene variants and cardiovascular disease based on published population-based studies. Sixteen studies, representing 17 630 individuals, report allelic distribution for lipoprotein lipase gene variants among pa

Hormone replacement therapy and cardiovascular disease.

Abstract: A large amount of research continues to be conducted on the mechanisms of hormone replacement therapy (HRT) effects, and the first of the large clinical trials published its results during the past year. In addition to the well known effects on LDL-cholesterol, HDL-cholesterol, and triglycerides, recent studies confirmed that estrogen with or without a progestin lowers lipoprotein (a) concentrations in women (but not in men). In men, estrogen appears to have a similar effect on other lipids and lipoproteins and on plasminogen activator inhibitor-1 as in women. A comparison of estrogen with simvastatin indicated that simvastatin is better at lowering LDL-cholesterol while estrogen is better at raising HDL-cholesterol; when given in combination the additional effects were modest. Estrogen and simvastatin had similar beneficial effects on endothelial function. The estrogen effect on endothelial function may be blocked by medroxyprogesterone, but the data are inconsistent. These studies of intermediate outcomes were put in perspective by the results of a landmark secondary prevention trial of coronary heart disease (CHD). This randomized placebo-controlled trial (Heart and Estrogen/Progestin Replacement Study) of conjugated equine estrogens plus medroxyprogesterone failed to show the anticipated reduction in CHD, and at the same time the threefold increase in venous thromboembolism confirmed that HRT is procoagulant. Therefore, it is still not known whether HRT is a viable option for the prevention of CHD. The preliminary data on selective estrogen receptor modulators are not overly promising, but a definitive trial to test whether raloxifene will reduce CHD is ongoing.

Flavonoids in food and natural antioxidants in wine.

Abstract: Plant foodstuffs are an important source of a wide variety of flavonoids with protective properties on low-density lipoprotein oxidation as shown in vitro and in some human and animal experiments. Increasing information is available concerning the absorption and pharmacokinetics of these molecules,

Influence of the HDL receptor SR-BI on atherosclerosis.

Abstract: The scavenger receptor class B, type I (SR-BI) is an HDL receptor that mediates selective cholesterol uptake from HDL to cells. In rodents, SR-BI has a critical influence on plasma HDL-cholesterol concentration and structure, the delivery of cholesterol to steroidogenic tissues, female fertility, and biliary cholesterol concentration. SR-BI can also serve as a receptor for non-HDL lipoproteins and appears to play an important role in reverse cholesterol transport. Recent studies involving the manipulation of SR-BI expression in mice, either using adenovirus-mediated or transgenic hepatic overexpression or using homologous recombination for complete functional ablation, indicate that the expression of SR-BI protects against atherosclerosis. If SR-BI has a similar activity in humans, it may become an attractive target for therapeutic intervention.

Potential tissue selectivity of dietary phytoestrogens and estrogens.

Abstract: The recent discovery of a second estrogen receptor subtype, estrogen receptor-beta, may significantly advance our understanding of tissue specific effects of estrogenic compounds, both natural and synthetic. Although specific effects mediated by estrogen receptor beta in vivo remain to be elucidated

Cholesteryl ester transfer protein and its plasma regulator: lipid transfer inhibitor protein.

Abstract: The interconnections between cholesteryl ester transfer protein (CETP) expression and lipid metabolism, and the possible roles of CETP in atherogenesis are examined. The importance of lipid transfer inhibitor protein in modulating CETP activity is detailed, and the consequences of this inhibitory activity on CETP-mediated events are proposed.

Acyl-coenzyme A:cholesteryl acyltransferase 2.

Abstract: In addition to acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT1), an enzyme in the endoplasmic reticulum of cells found ubiquitously throughout the body, data recently obtained in at least three mammalian species, including nonhuman primates, mice and humans, demonstrate the presence of an additional ACAT (EC 2.1.3.26), termed ACAT2, which is localized to the endoplasmic reticulum of liver and intestine. Data suggest that ACAT2 may be the enzyme responsible for cholesteryl ester secretion into apolipoprotein B-containing lipoproteins. We have hypothesized that oversecretion of cholesteryl esters produced by the action of hepatic ACAT2 could account for the increased atherogenicity associated with cholesteryl ester-enriched LDL in nonhuman primates. In such cases, ACAT2 is an appealing target for therapy to reduce coronary heart disease.

Regulation of macrophage gene expression by peroxisome-proliferator-activated receptor gamma: implications for cardiovascular disease.

Abstract: The peroxisome-proliferator-activated receptor gamma is a member of the nuclear receptor superfamily that functions as a key transcriptional regulator of cell differentiation and lipid metabolism. In addition, peroxisome-proliferator-activated receptor gamma is now recognized to be the biological receptor for the thiazolidinedione class of antidiabetic drugs, which includes troglitazone and rosiglitazone. Recent evidence indicates that peroxisome-proliferator-activated receptor gamma is expressed at high levels in macrophages, including the foam cells of atherosclerotic lesions. Oxidized low-density lipoprotein, which plays a central role in lesion development, can activate peroxisome-proliferator-activated receptor gamma by providing the cell with oxidized fatty acid ligands of the receptor. The elucidation of a peroxisome-proliferator-activated receptor gamma signalling pathway in macrophages provides a mechanism by which oxidized lipids may directly regulate gene expression in the context of the atherosclerotic lesions. A number of potential target genes for peroxisome-proliferator-activated receptor gamma in these cells have been identified. Some, such as the type B scavenger receptor CD36 are induced by peroxisome-proliferator-activated receptor gamma ligands, whereas others, such as scavenger receptor type A, inducible nitric oxide synthetase and certain cytokines, are repressed. Given the widespread clinical use of thiazolidinediones, it is important to consider the influence of these drugs on the risk of atherosclerosis. The net effect of peroxisome-proliferator-activated receptor gamma ligands on the atherogenic process is likely to reflect a balance between local effects in the artery wall and systemic effects on lipid metabolism.

Smooth muscle cell phenotypes in atherosclerotic lesions.

Abstract: Recently, there has been a dramatic change in the way we think about the role of vascular smooth muscle cells in atherosclerosis, and it is now generally accepted that a dearth of vascular smooth muscle cells in an atherosclerotic plaque is a detrimental feature of the disease. Indeed, it is now rec

Genes, variation of cholesterol and fat intake and serum lipids.

Abstract: Several studies have examined gene-diet interactions in the response of plasma lipid concentrations to changes in dietary fat and/or cholesterol. Among the gene loci examined, APOE has been the most studied, and the current evidence suggests that this locus might be responsible for some of the interindividual variability in dietary response. Other loci, including APOA4, APOA1 and APOB have also been found to account for some of the variability in the fasting and fed states.

Understanding coronary heart disease as a consequence of defective regulation of apolipoprotein B metabolism.

Abstract: Further understanding of the causative link between plasma lipids and coronary heart disease will come from a deeper appreciation of the impact of lipoprotein heterogeneity on the processes of atherosclerosis and thrombosis. It is now widely appreciated that remnants of triglyceride-rich lipoprotein