Alteration of the lipid profile is the foundation of both primary and secondary prevention of coronary artery disease. Statins have become the gold standard for lowering LDL-cholesterol levels; however, an increasing number of studies have shown the benefit and importance of increasing HDL-cholesterol levels. Extended-release (ER) niacin (Niaspan (R)) is a safe and effective treatment for raising HDL levels. In addition to its effects on lipids, emerging data suggest that ER niacin has other beneficial roles on the vasculature, likely due to its antioxidant properties and lowering of prothrombotic factors. A large multicenter, 4-year follow-up clinical study, the Atherothrombosis Intervention in Metabolic Syndrome in Low HDL/High Triglycerides and Impact on Global Health Outcomes (AIM-HIGH) study is currently being conducted in the USA and Canada to further evaluate the benefits of adding ER niacin to statins in patients with atherogenic dyslipidemia. The current review describes the importance of HDL-raising therapy and the role of ER niacin in the present-day management of dyslipidemia.
The apolipoprotein APOA5 gene, a member of the gene cluster on chromosome 11q23 that includes APOA1, APOC3 and APOA4, has gained considerable interest as it encodes ApoAV, a key determinant of circulating levels of potentially atherogenic triglyceride-rich lipoproteins (TRL). Indeed, strong associations between genetic variants of the APOA5 gene sequence and elevated triglyceride (TG) levels have been established. This apolipoprotein may potentiate lipolysis of TRL through facilitation of lipoprotein interaction with lipoprotein lipase. In addition, ApoAV may enhance clearance of remnant lipoproteins by mediating their interaction with the LDL receptor-related protein (LRP)1. The implication of ApoAV in intravascular TRL metabolism is further supported by studies that have demonstrated upregulation of APOA5 gene expression by nuclear receptors (PPAR alpha, FXR and HNF4 alpha) and hormones (thyroxine) involved in hypotriglyceridemic pathways. APOA4 expression may equally be modulated by nutritional status and, more specifically, by stimulation of lipogenesis through transcriptional regulation mediated by insulin and SREBP-1c. However, despite the fact that studies in mice have clearly revealed that plasma levels of ApoAV are inversely correlated with plasma TG levels, the relationship between ApoAV and metabolism of TRL remains controversial in man. Indeed, positive correlations between ApoAV and TG levels have recently been observed in patients with hypertriglyceridemia and Type 2 diabetes. The question as to whether ApoAV is a key determinant of TG levels in humans therefore remains conjectural.
The dyslipidemia of insulin resistance is characterized by elevated levels of triglycerides (TGs), low HDL-cholesterol and small dense LDL particles. Many of these features are affected by the reduction In insulin sensitivity, with a central role played by abnormalities in assembly and secretion of VLDL. Postprandial hyperlipidemia is common in insulin-resistant individuals, probably owing to reduced lipolysis of nascent chylomicrons. Increased exchange of HDL cholesteryl esters for TGs Is associated with lipolysis of HDL-TG by hepatic lipase and this produces dysfuntional particles that are less stable than normal particles and contribute to decreased reverse cholesterol transport, On the other hand, TG accumulation has been described as dangerous for several tissues, the so-called lipotoxicity, particularly for pancreatic P-cells where It results in impairment of glucose-stimulated insulin secretion and accelerated apoptosis. Recently, islet dysfunction and loss of insulin secretion have also been associated with alterations of plasma and Islet cholesterol levels. A more comprehensive appreciation of reciprocal effects of insulin resistance and atherogenic dyslipidemia should guide the physician in a more conscious therapeutic decision.
It is increasingly clear that nongenetic elements play a crucial role in the pathogenesis of Parkinson's disease (PD), yet no modifiable environmental risk factor has been clearly identified. Recent work in animal models of PID supports the contention that n-3 polyunsaturated fatty acids (PUFA) found in fatty fish are neuroprotective in PD. Moreover, a few epidemiological reports suggest that a high intake of fish (and n-3 PUFA) is associated with a lower risk of developing PD, The question remains whether docosahexenoic or eicosapentenoic acid is the brain n-3 PUFA responsible for the observed neuroprotective effect. Despite these encouraging data, the development of n-3 PUFA as drugs is hindered by the fact that they are nonpatentable compounds, at least in their natural form. Nevertheless, owing to their favorable safety profile, it should be a high priority to pursue preclinical and clinical studies on the nutraceutical properties of n-3 PUFA in PD.
Most of the previous work on the sphingolipid ceramide has been devoted to its function as an apoptosis inducer. Recent studies, however, have shown that in stem cells, ceramide has additional nonapoptotic functions. In this article, ceramide signaling will be reviewed in light of 'systems interface biology': as an interconnection of sphingolipid metabolism, membrane biophysics and cell signaling. The focus will be on the metabolic interconversion of ceramide and sphingomyelin or sphingosine-1-phosphate. Lipid rafts and sphingolipid-induced protein scaffolds will be discussed as a membrane interface for lipid-controlled cell signaling. Ceramide/sphingomyelin and ceramide/sphingosine-1-phosphate-interdependent cell-signaling pathways are significant for the regulation of cell polarity, apoptosis and/or proliferation, and as novel pharmacologic targets in cancer and stem cells.
Gpihbp1-deficient mice exhibit severe chylomicronemia, even on a low-fat diet, with grossly lipemic plasma and plasma triglyceride levels as high as 5000 mg/dl. GPIHBP1 is expressed on the luminal surface of endothelial cells of heart, muscle and fat, precisely where the lipolytic processing of triglyceride-rich lipoproteins occurs. When GPIHBP1 is expressed in cultured cells, it confers upon those cells the capacity to bind both chylomicrons and lipoprotein lipase, suggesting that GPIHBP1 is a key platform for the lipolytic processing of chylomicrons in capillaries. These cell culture and mouse studies suggested the possibility that some cases of hypertriglyceridemia in humans might be caused by defects in GPIHBP1. In a recent study, the exons of GPIHBP1 were sequenced in 160 patients with severe hypertriglyceridemia, and a homozygous G56R mutation was identified in two siblings with chylomicronemia. This mutation was not encountered in 600 normolipidemic Caucasian control subjects or 610 Caucasian patients with hyperlipidemia. Although the finding of a homozygous GPIHBP1 mutation in two siblings was intriguing, recent cell culture studies have suggested that the G56R mutation may not alter GPIHBP1 function. Additional sequencing 1 efforts in diverse populations will be required to understand the relevance of GPIHBP1 I mutations to human hypertriglyceridemia.
Metabolic syndrome (MS) is associated with increased risk of coronary heart disease, stroke and cardiovascular mortality. However, little data exist on the relationship between MS and operative mortality following coronary revascularization. This retrospective study found that MS in patients undergoing coronary artery bypass graft (CABG) surgery is a significant independent predictor of an increased risk of post-operative mortality. Thus, MS may be an important and novel patient risk factor for CABG surgery.
As in Western populations, the prevalence of obesity has been increasing rapidly in Chinese populations in recent years, but if the same criteria to define obesity are used, it is still much less common in Chinese than in Caucasians. For BMI greater or equal to 30 kg/m2, recent estimates suggest the prevalence ranges from 3 to 6% in different adult Chinese populations compared with figures of approximately 33% in the USA. However, it is generally accepted that the Chinese and other Asian populations have a greater amount of body fat than Caucasians at the same level of BMI or waist circumference, and that the prevalence of metabolic risk factors for cardiovascular disease and cardiovascular events start to increase at lower values of the obesity indices in Asians compared with Western people. Therefore, lower cut-off criteria have been proposed to define obesity in Chinese populations and if the cut-off value for BMI greater than or equal to 25 kg/m2 is adopted, the overall prevalence of obesity in Chines...
Recent evidence from prospective epidemiological large-scale studies have provided convincing proof for the role of nonfasting triglycerides, carried in VLDL and chylomicrons, as an independent risk factor for cardiovascular disease and death. Overproduction of large VLDL1 by the liver on one hand, and accumulation of apoB 48-containing triglyceride-rich lipoproteins (TRLs) on the other hand are present before overt hyperglycemia, highlighting the role of insulin resistance as an early pathogenic defect. Multiple insulin action sites demonstrate insulin resistance in the liver, adipose tissue and muscle, as well as in the intestine. Together, these perturbations of insulin action contribute to the overproduction of atherogenic VLDL and chylomicron remnant particles. Consequently, the vascular wall endothelium is exposed to exaggerated cholesterol influx resulting in endothelial dysfunction, oxidative stress and prothrombotic state during subsequent meals over the 24-h period. This overview summarizes current understanding of diabetic postprandial 'dysmetabolism' and reviews recent data on TRL secretion and intravascular processing and removal accumulated during this decade. Various therapeutic strategies and future opportunities are also discussed.
Konstantinos Kantartzis, Hans-Ulrich Haring & Norbert Stefan† †Author for correspondence University of Tubingen, Department of Internal Medicine, Otfried-Muller-Str 10, D-72076 Tubingen, Germany Tel.: +49 7071 298 0390; Fax: +49 7071 295 974; norbert.stefan@ med.uni-tuebingen.de ‘...fatty liver directly, and/or by inducing insulin resistance, contributes to an atherogenic serum lipid profile and may also play a role in the regulation of the quality of HDL.’
Phospholipids are important structural and functional components of all biological membranes. The mitochondrial phospholipid, cardiolipin, comprises approximately 15% of the entire phospholipid mass of the heart. Cardiolipin plays an important role in the regulation of various mitochondrial processes, including ATP generation, apoptosis, electron transport and mitochondrial lipid and protein import. Alterations in the content and fatty acid composition of phospholipids within the heart are linked to sustained differences in myocardial electrical activity. Reduced levels of cardiolipin are an underlying biochemical cause of the Barth syndrome, a rare X-linked genetic disease that is associated with cardiomyopathy and heart failure. This article focuses on the synthesis of cardiolipin, the regulation of cardiolipin synthesis and the implications of heart failure on cardiac cardiolipin and its synthesis.
Three papers published in the year 2008 from my laboratory reported experiments and data indicating the therapeutic potential of phosphoethanolamine-bound C-reactive protein (PEt-bound CRP) in atherosclerosis. The small-molecule compound PEt, which binds to CRP, could in itself be of therapeutic value. The first paper described the capability of PEt-bound CRP to capture native low-density lipoprotein (LDL) cholesterol in human serum [1]. The second paper described the potency of PEt-bound CRP to bind to a modified form of LDL called enzymatically-modified LDL (E-LDL). Although CRP alone could bind to E-LDL, the PEt-bound CRP was much more potent than unbound CRP in binding to E-LDL [2]. This paper also reported a previously unknown function of CRP. CRP, once bound to E-LDL, prevented the formation of E-LDL-loaded macrophage foam cells. The third paper further emphasized the importance of PEt-bound CRP and presented a review of the literature on the connection between CRP and atherosclerosis [3]. CRP, also known as high-sensitivity CRP or hsCRP, is a serum protein which is used as a marker of systemic inflammation [see CRP reviews 3-7, and the references cited in 3, 4]. CRP is associated with risk of atherosclerosis; however, recent data suggest that the association of CRP with atherosclerosis may not be causal [8]. In 1982, it was shown that under certain experimental conditions CRP interacted with LDL [9]. Since then CRP was suspected to play a role in atherosclerosis. CRP was also found deposited and co-localized with LDL and macrophages in human atherosclerotic lesions. Discovering the functions of CRP in atherosclerosis quickly became a hot subject for research. Atherosclerosis is a heart disease caused by the deposition and subsequent modification of LDL in artery walls. Atherogenic LDL, which includes modified forms of LDL produced by oxidation and proteolysis of LDL, enters macrophages to form foam cells. The LDL-loaded macrophage foam cells contribute to the development of atherosclerosis which leads to myocardial infarction. To prevent atherosclerosis, LDL can be targeted therapeutically at two locations: the native LDL found mostly in the circulation and the atherogenic LDL located mostly in the artery walls.
‘The NCEP guidelines remain valid and appropriate LDL goals should still be attempted to be achieved. Statin therapy should remain the primary therapeutic intervention.’ The lipid hypothesis was originally proposed as a theory to explain the central role of dyslipidemia in the initiation and progression of atherosclerosis. The lipid hypothesis was supported by epidemiologic, pathologic and genetic observations. However, definitive proof of concept would require prospective clinical trial evidence that demonstrates that optimization of dyslipidemia would result in a reduction in risk from the complications of atherosclerosis. Epidemiologic studies that demonstrate a statistical correlation between dyslipidemia and atherosclerosis do not necessarily imply that pharmacologic modification of the lipid profile will alter the natural history of atherosclerosis. Early clinical trials that
Overweight and obesity are independent risk factors for cardiovascular disease. Many cardiovascular disease risk factors are elevated in overweight and obese individuals, including dyslipidemia and inflammation, among others. Current dietary recommendations focus on achieving a healthy body weight and lowering intake of trans and saturated fat, and cholesterol to reduce total cholesterol and LDL-C. Recent advances in our knowledge of lipid responses to specific macronutrient(s) means that it is now possible to individualize diet 'prescriptions' on the basis of the presenting clinical lipid/lipoprotein profile. However, these diets may be less effective in overweight, obese individuals who are 'inflamed' and insulin resistant. Consequently, there is great interest in identifying strategies for decreasing inflammation and increasing insulin sensitivity to realize the full benefits of a blood cholesterol-lowering diet in overweight or obese individuals.
‘Compartmental descriptions can be as diverse as organisms within an ecosystem or small molecules within a subcellular organelle.’ Oxidative stress is frequently invoked to explain biological injury, but the lack of a clear definition for this term may mask underlying mechanisms rather than contribute to its understanding. The diverse and complex phenomena related to oxidative stress contribute to the problem of definition. Our goals are to review basic concepts of oxidation and introduce a qualitative compartmental kinetic model in an effort to help to clarify this definition and provide a framework for exploring the myriad inter-relationships. While oxidation and reduction formally refer
The 49th meeting of the International Conference for the Bioscience of Lipids (ICBL) was convened at the end of August 2008 in the historic city of Maastricht in The Netherlands. The meeting organizers (Jan Glatz, Joost Luiken and Edouard Bevers) crafted a program directed at bridging an atmosphere of intense science with the ambitious goal of exploring translational scientific themes. Hence, the title of the conference – Lipidology: Bridge Between Basic Science and Clinical Pathology. The purpose of the meeting was to present the most recent advances on lipid bioscience, as these relate to human health and disease, from both the basic science and the clinical perspectives. In regards to this goal, the meeting was an unqualified success. The seven scientific sessions of the conference ranged from ‘Cell Membrane Organization and Dynamics’ to ‘Lipid Droplets as Multifunctional Organelles’, from ‘Lipids and their Dynamics in Intracellular Transport’ to ‘Fatty Acids, Lipids and the Metabolic Syndrome’, and fr...
Phospholipid transfer protein (PLTP) plays an essential role in lipoprotein metabolism. Deficiency or overexpression of PUP in animal models results in modulation of the atherosclerotic process. Moreover, PUP has also been implicated in obesity and diabetes, underscoring its versatile nature and its central role in the pathophysiology of these tightly connected disease states. The purpose of this article is to assess the current evidence on the role of PUP in all these conditions. This evidence strongly suggests that PUP may become a therapeutic target.
Enhancing reverse cholesterol transport from macrophages in the arterial wall to the liver for biliary excretion has been identified as a potential therapeutic strategy to reduce and eventually regress atherogenesis. In addition to HDL-raising therapies, modulating macrophage cholesterol efflux pathways might be an interesting new approach in the treatment of atherosclerosis. Recently, two ATP-binding cassette transporters, ABCA1 and ABCG1, have been indentified to play a critical role in the efflux of cholesterol from macrophages, suggesting a function in maintaining normal cellular cholesterol homeostasis and the prevention of atherogenesis. This review focuses on the recent findings on the role of macrophage ABCA1 and ABCG1 in atherosclerotic lesion development and highlights the complex regulatory mechanisms and possible consequences of therapeutic upregulation of these transporters.
Stearoyl-CoA desaturase (SCD) is a highly conserved Delta-9 desaturase that converts saturated fatty acids into monounsaturated fatty acids. Mice lacking the Scd1 gene are characterized by decreased adiposity and increased lipid oxidation and insulin sensitivity in liver and skeletal muscle. Two isoforms of SCD have also been identified in humans, and there appears to be an association between SCD expression and adiposity. This review will provide a brief update of recent progress in understanding the role of SCID in mediating the progression of disease in human populations, with a special emphasis on metabolic disease.
