Journal Of Lipid Research Research Articles

The Cholesterol Wars: The Cholesterol Skeptics vs the Preponderance of Evidence

Daniel Steinberg 227 pages. New York, NY: Academic Press; 2007. $69.95. ISBN 978-0123739797 I consider The Cholesterol Wars by Daniel Steinberg to be required reading for every serious student of atherosclerosis and lipidology. It is written in an authoritative, scholarly, yet readable style. Steinberg has carefully reviewed the material for which he previously laid the groundwork with a series of articles in the Journal of Lipid Research . His subject is one about which he knows a great deal and in which he himself played a major role over the last 5 decades. I remember first hearing him speak about the subject matter of the book during the 2001 Drugs Affecting Lipid Metabolism meeting during a dinner at the Russian Tea Room in New York the night before 9/11. Everyone present that night remembers both the scintillating talk as well as where they were on that particular occasion. I will make a few comments, observations, and an occasional critical remark that is not intended to detract from the quality of this publication. First, Steinberg begins by discussing the early cholesterol-feeding experiments of Nikolai Anitschkow and rightly points out that they followed studies on the toxicity of feeding large amounts of protein to rabbits. I believe that part of the failure to accept the cholesterol hypothesis on the basis of Anitschkow’s work is related to the extreme conditions of the experiment and to the very high levels of cholesterol obtained in the blood, which raised doubts about its relevance to humans. We now know with the benefit of hindsight that one can develop atherosclerosis even with lesser degrees of cholesterol elevation, but many also suspected that the cholesterol-feeding experiments might have induced an inflammatory response that was separate …

The Influence of the Regulatory T Lymphocytes on Atherosclerosis

Atherosclerosis is complex inflammatory disease of the arterial wall, in which T lymphocytes play a significant role.1 Since the recognition that T lymphocytes are present in human atherosclerotic plaque nearly 2 decades ago,2 research has focused on the functional importance of these cells in the atherosclerotic process. The majority of T lymphocytes in atherosclerotic lesions are CD4+ T-helper cells with a phenotype characteristic of the proinflammatory T-helper 1 (Th1) subset. These cells recognize specifically antigens that are produced in relative abundance in hypercholesterolemic individuals or in plaques including oxidatively modified LDL (Ox-LDL) and HSP60/65. The T cells are activated when macrophage or dendritic cells present these antigens to the T cells in plaques or lymphoid tissues. The Th1 cells produce inflammatory cytokines IFN-γ, tumor necrosis factor (TNF)-α, and membrane CD40-ligand, which amplify the immune response through activation of macrophages, vascular smooth muscle cells, and endothelial cells.1 See page 2691 Many mechanisms have evolved to maintain immunologic self-tolerance and to limit responses to foreign antigens. One of these mechanisms involves regulatory T cells (Treg) that actively suppress responses of effector T cells. The best- characterized Treg are the natural CD4+CD25+ Treg that mature in the thymus and comprise 5% to 10% of peripheral CD4+ T cells.3 Other surface markers expressed by Treg include CTLA-4 and GITR. FoxP3, a forkhead family transcription factor, is a lineage specification factor for Treg and plays a crucial role in their suppressive function.4 Natural Treg are generated during thymic development, but Treg are also induced in peripheral tissues during immune responses. Treg express antigen receptors typical of effector T cells and are presumably activated by peptide antigens presented by APCs. They also require interleukin (IL)-2 for development and survival. Once activated, Treg may suppress other T …

Multiphoton Microscopy for 3-Dimensional Imaging of Lymphocyte Recruitment Into Apolipoprotein-E–Deficient Mouse Carotid Artery

Two recent elegant studies have shown that in apolipoprotein-E–deficient mice, the lamina adventitia is a major site of arterial wall inflammation associated with lymphocyte infiltration into atherosclerotic arteries and with formation of adventitial lymphoid-like tissues.1,2 These results suggest that lymphocyte responses in the lamina adventitia may play a crucial role in atherosclerosis development.1,2 However, in both studies, the detection of immune cells within the artery was limited to conventional analysis systems (flow cytometry, immunohistochemistry), which require the removal, disruption, and processing of tissue at defined time points to give a “snapshot” of the immune response to vascular damage in vivo. For evaluation of atherosclerotic processes and their relationship to immune activation, imaging of 3-dimensional structures in intact vascular tissues and functional aspects of the diseased artery (eg, details of the interactions of immune cell with vessel wall structures) are required. A potential solution to this problem is offered by the development of multiphoton laser-scanning microscopy,3 with the ability to penetrate directly into tissues at sufficient depths to image tissues in situ in the absence of significant phototoxicity. By moving the focal point axially, …

Vitamin D Supplementation and Cardiovascular Disease Risk

Many studies,1,2 but not all, have shown that low bone density is associated with increased cardiovascular disease (CVD) risk. Vitamin D deficiency is common in the elderly and is associated with osteoporosis; however, the association of endogenous 25-OH vitamin D (25-OH D) levels with CVD events is controversial.3,4 CVD rates are higher during winter seasons and at increased geographic latitudes where average serum vitamin D levels are lowest.5 Low 25-OH D levels have been found in stroke6 and heart failure patients.7 Moreover, 25-OH D deficiency is associated with hypertension, obesity,8 glucose intolerance,8 and the metabolic syndrome,9 which may be responsible, at least in part, for its association with increased CVD risk. Article p 846 Although vitamin D supplementation improves bone strength, elevated serum vitamin D levels may be associated with lower levels of vascular calcification. In subjects at moderately high risk for coronary heart disease, endogenous serum vitamin D levels were inversely correlated with the extent of coronary artery calcification as determined by cardiac computed tomography.10 Vitamin D also has intriguing antiinflammatory properties11 that have potential therapeutic benefit in several autoimmune diseases and allograft rejection. In 2 small clinical trials,12,13 vitamin D supplementation lowered C-reactive protein levels. Additionally, 1,25(OH)2D induces relaxation of vascular smooth muscle cells …

Circulating Platelet-Derived Microparticles Are Associated With Atherothrombotic Events

Platelet-derived microparticles (PDMP) are first observed as vesicles released from platelets after adhesion to vessels walls.1–3 Circulating PDMP can therefore be thought of as a marker of in vivo platelet activity.4 In these studies, flow-cytometory was applied to measure PDMP. As a result, the clinical significance of PDMP remains unresolved. In this study, we investigate the usefulness of PDMP that could vary the vulnerability for thrombotic events using newly developed ELISA kit.5 Our population consisted of 66 ACS patients with or without ST segment elevation (the ACS group) and 126 patients with stable angina (the SAP group). A further 26 noncardiac chest-pain syndrome patients were selected as a control group. Circulating PDMP levels were assayed using the ELISA method5 (supplement I, available online at http://atvb.ahajournals.org). …

Improvement of a solid phase extraction method for separation of animal muscle phospholipid classes

The solid phase extraction (SPE) method used by Banni et al. (2001) [Banni, S., Carta, G., Angioni, E., Muru, E., Scanu, P., Melis, M. P., et al. (2001). Distribution of conjugated linoleic acid and metabolites in different lipid fraction in the rat liver. Journal of Lipid Research, 42, 1056–1061] for fractionation of liver phospholipids (PLs) into phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylinositol (PI) was modified to improve its separation efficiency. A mixture of PL standards, containing PC, PE, PS and PI, was separated into individual classes by using aminopropyl minicolumns, following the method of Banni et al. (2001). The obtained eluted fractions were further analysed by thin layer chromatography (TLC) and PL classes were identified. TLC revealed the co-elution of PC and PE, that of PE with PS and no elution of PI. The SPE method was subsequently modified in order to obtain a correct PL fractionation into PC, PE, PS and PI. The principal modifications consisted of increased solvent volumes for PC, PE and PS elution, and a different solvent mixture to allow PI elution. The effectiveness of the modified SPE method was checked by TLC, using both standards and muscle samples, showing a correct elution of PC, PE, PS and PI.

Longitudinal Differences in Familial Combined Hyperlipidemia Quantitative Trait Loci

To the Editor: Familial combined hyperlipidemia (FCHL), associated with premature cardiovascular disease, is the most common genetic hyperlipidemia with an estimated prevalence of 1%.1 The complex genetic background of FCHL is slowly being dissected through genome screens and positional candidate association studies.2–6 However, it has also been argued that although numerous studies have been conducted and reported, there are many conflicting results and a true understanding of the genetics remains largely unknown.7 Previously in this journal, we reported 4 quantitative trait loci (QTL) for apolipoprotein B (apoB), cholesterol, and triglycerides with P <0.001 in 22 FCHL pedigrees from Maastricht, in The Netherlands.8 The original QTL study was based on the premise that because FCHL is defined by increased serum levels of cholesterol, apoB, and triglycerides in families, QTL analyses of these quantitative traits in FCHL families might identify important genetic loci for this disorder. This letter reports QTL analyses of 5-year follow-up data in the same individuals. Longitudinal studies show that the lipid …

Lipoprotein(a)

In this issue of Stroke , the Atherosclerosis Risk in Communities (ARIC) study provides evidence that lipoprotein(a) [Lp(a)] is a significant predictor of stroke.1 This is an important finding, because ARIC is both large and prospective. Over 14 000 patients were enrolled in 1987 to 1989, and during 13.5 years of follow-up, they experienced 496 ischemic strokes. Lp(a) remained a significant predictor of stroke after adjustment for age, race, systolic blood pressure, antihypertensive medication, smoking status, use of postmenopausal hormone therapy, diabetes, LDL cholesterol, HDL cholesterol, fibrinogen, and von Willebrand factor. It thus seems likely that Lp(a) is potentially an important treatable risk factor. But what is Lp(a), and how does it relate to atherosclerosis and cardiovascular events? A meta-analysis of prospective studies of coronary events2 seems to establish that Lp(a) is also a predictor of myocardial infarction, but numerous studies indicate that it does not seem to predict the burden of atherosclerosis as assessed by intima-media thickness,3,4 except perhaps in patients with renal …

COX-2 in Cardiovascular Disease

Prostanoids are a large family of lipid mediators derived from the arachidonic acid metabolites of the cyclooxygenase (COX) enzymes. Therapeutically, COX is the target of the nonsteroid antiinflammatory drugs (NSAIDs), a chemically diverse group that includes ibuprofen, naproxen, and diclofenac, among dozens of others. Inhibition of prostanoid production by traditional NSAIDs accounts for all their major therapeutic effects, such as the dampening down of inflammation and the reduction of fever, and their potentially severe adverse side effects, most commonly within the gastrointestinal tract.1,2 See page 1137 Since the early 1990’s it has been clear there are two distinct enzymes responsible for the production of prostanoids: a constitutive COX-1 found in all tissues and an inflammation-associated enzyme COX-2.1,2 COX-2 is constitutively expressed in only a few sites, such as parts of the kidney and central nervous system, but is highly upregulated and active at sites of inflammation. These findings led to the hypothesis that selective COX-2 inhibitors could be antiinflammatory without the major side effects associated with traditional NSAIDs. Against this background several COX-2–selective inhibitors have been produced and brought to market, the first two being celecoxib (Celebrex) and rofecoxib (Vioxx). Preclinical studies of these COX-2–selective inhibitors were extremely promising. In animal models, for example, they were demonstrated to be as efficacious as traditional NSAIDs but to be lacking their toxic actions on the gastrointestinal tract. Clinical trials have, however, been marred by controversy. The CLASS trial for celecoxib, a 12-month osteoarthritis study of celecoxib, demonstrated celecoxib to have improved safety relative to ibuprofen but not …

Prevalence and Pathology of Amyloid in Atherosclerotic Arteries

To the Editor: Apolipoprotein AI (AApoAI)–associated amyloidosis is characterized by the deposition of apolipoprotein AI (apoAI) and occurs as a hereditary and a nonhereditary form. Hereditary AApoAI amyloidosis is a systemic disease leading to the deposition of amyloid in various organs and tissues and is caused by germline mutations in the APOA1 gene. Nonhereditary AApoAI amyloid is far more prevalent and characterized by deposits of nonvariant protein in atherosclerotic arteries.1–3 Despite being linked to the most common cause of morbidity and mortality in Western societies, nonhereditary AApoAI amyloid has achieved only little attention.1–4 It shares several striking similarities with secondary or reactive AA amyloidosis. Nonhereditary AApoAI amyloid occurs in the background of a local chronic inflammatory reaction, it originates from an apolipoprotein that largely associates with high-density lipoproteins (HDLs), and apoAI-containing HDL is endocytosed and retroendocytosed by macrophages, which, in themselves, are able to form amyloid in vitro. Finally, AApoAI amyloidosis is characterized by the deposition of proteolytic fragments of the precursor protein, leading us to speculate that proteolysis is involved in the pathogenesis of AApoAI amyloid.1,3 The aim of this study was to gain further insights into the pathology of nonhereditary AApoAI amyloid. See cover The prevalence and spatial distribution of amyloid, macrophages, cathepsin B (CathB), cathepsin K (CathK), cathepsin L (CathL), and carboxy methyl lysine (CML) was studied using carotid artery specimens obtained from a consecutive series of all 225 patients undergoing carotid endarterectomy with polyester patch angioplasty (Table I, available online at http://atvb.ahajournals.org) during the period from 1997 to 2003. All patients were scheduled for elective therapeutic endarterectomy and gave written informed consent in the surgical procedure. Patient characteristics were retrieved from hospital records. This study was in accordance with the guidelines of the ethics committee of the University of Magdeburg. Tissue samples were …

A comprehensive classification system for lipids

AbstractLipids are produced, transported, and recognized by the concerted actions of numerous enzymes, binding proteins, and receptors. A comprehensive analysis of lipid molecules, “lipidomics,” in the context of genomics and proteomics is crucial to understanding cellular physiology and pathology; consequently, lipid biology has become a major research target of the postgenomic revolution and systems biology. To facilitate international communication about lipids, a comprehensive classification of lipids with a common platform that is compatible with informatics requirements has been developed to deal with the massive amounts of data that will be generated by our lipid community. As an initial step in this development, we divide lipids into eight categories (fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, sterol lipids, prenol lipids, saccharolipids, and polyketides) containing distinct classes and subclasses of molecules, devise a common manner of representing the chemical structures of individual lipids and their derivatives, and provide a 12 digit identifier for each unique lipid molecule. The lipid classification scheme is chemically based and driven by the distinct hydrophobic and hydrophilic elements that compose the lipid. This structured vocabulary will facilitate the systematization of lipid biology and enable the cataloging of lipids and their properties in a way that is compatible with other macromolecular databases.[Reprinted with copyright permission from the Journal of Lipid Research. 2005. 46: 839–861.]

Cardioprotective Effects of High-Density Lipoproteins

The fact that a low level of high-density lipoprotein (HDL) cholesterol is highly predictive of future cardiovascular events has been established in population studies beyond all reasonable doubt. Furthermore, the evidence is overwhelming that the relationship is one of cause and effect rather than an epiphenomenon, with numerous studies in animals demonstrating that HDL-raising interventions translate into profound reductions in atherosclerosis. Such interventions have included the infusion of both native and reconstituted HDLs into rabbit models of atherosclerosis, the overexpression of apolipoprotein (apo) A-I (the major HDL protein) in transgenic mice and rabbits, and the inhibition of cholesteryl ester transfer protein (CETP) in rabbits. See pages 1325 and 1426 Evidence that raising the level of HDLs is also antiatherogenic in humans is mounting, although there are still relatively few human studies that have directly tested the phenomenon. Fibrates, statins, and niacin all raise the level of HDL cholesterol, and treatment with each of these agents has been shown to be associated with a reduction in future cardiovascular events. Fibrates are especially effective in event reduction in people with insulin resistance or with other features of the metabolic syndrome, although the benefits cannot be explained in terms of the observed HDL raising.1 Statins are effective in reducing events in all subjects, but the benefits can be explained almost completely in terms of the achieved LDL lowering2; the contribution of a statin-induced elevation of HDL is difficult to evaluate. Niacin, the most effective of the currently available HDL-raising agents, has also been shown to reduce cardiovascular events, especially when coadministered with a statin3; but again, other properties of niacin may …

Arteriosclerosis, Thrombosis, and Vascular Biology , 2005

The purpose of this editorial is to provide for our readers the annual update of the status of the journal. Goals of our editorship, which began in 1999, were to publish high-quality papers, provide authors with timely review and publication of their manuscripts, and to publish papers of interest to our readers. We will summarize data related to each of these goals, some changes and plans for the journal, and thank several people for their help. There is no perfect approach to evaluate journals and the quality of papers published in journals. Impact factor is one measure of quality of papers. In some Universities, decisions about promotion and tenure are based in part on impact factor of journals in which papers are published. Thus, impact factor may be important, in relation to selection of journals in which authors wish to publish their work. The impact factor for ATVB again increased this past year, to 6.8 (Figure 1). The impact factor of the journal has increased more than 70% during the past few years. The large increase in 1999 was determined by decisions during the editorship of Dr Alan Fogelman. Impact factors of other journals in this area of research have not changed consistently during the last few years (Figure 1). We believe that Arteriosclerosis, Thrombosis, and Vascular Biology is recognized as an appropriate forum for publication of excellent papers related to atherosclerosis, lipoproteins, vascular biology, and thrombosis. Figure 1. Impact factor of ATVB , JBC ( Journal of Biological Chemistry ), T&H ( Thrombosis & Hemostatsis ), JLR ( Journal of Lipid Research ), Athero ( Atherosclerosis ) and AJP ( American Journal of Physiology – Heart and Circulation ) Immediacy index provides information about the frequency of references to articles during the first year of their publication. The immediacy index for ATVB has increased substantially in the past …

Physiological and molecular mechanisms involved in nutritional regulation of fatty acid synthesis

Physiological and molecular mechanisms involved in nutritional regulation of fatty acid synthesis

Physiological actions of taurine

Physiological actions of taurine

Research on adipose tissue and the first 25 years of the Journal of Lipid Research

Research on adipose tissue and the first 25 years of the Journal of Lipid Research

Journal of Lipid Research, New York

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Journal of Lipid Research, New York

Journal of Lipid Research, New York

Journal of Lipid Research, New York

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Journal of Lipid Research, New York

Journal of Lipid Research, New York