Editorial [ Hot Topic:New Methodology and Approaches to Intracellular Lipid Transport in Atherosclerosis and Cardiovascular Disease (Guest Editors: Basil D. Roufogalis and Thomas Grewal)]

Treatment of lipid disorders commonly involves the use of cholesterol- and triglyceride lowering drugs, in particular statins and fibrates. Anion exchange resins, ezitimibe and niacin have also shown potential to reduce plasma lipid levels. Most treatments aim to reduce Low Density Lipoprotein (LDL) cholesterol and/or triglyceride-rich Very Low Density Lipopotein (VLDL) levels, and are often associated with an increase in cardioprotective High Density Lipoprotein (HDL). In fact, numerous epidemiological studies confirmed an inverse relationship of HDL, or a direct association of LDL to HDL ratio, and risk for cardiovascular disease. In particular the pharmacological induction of key molecules upregulating HDL levels or increasing HDL-induced reverse cholesterol transport from the periphery to the liver for bile secretion are promising therapeutic approaches to treat cardiovascular disease, but also diabetes and metabolic syndrome. However, despite cardioprotective effects of HDL being well documented, pharmaceutical approaches specifically targeting the anti-atherosclerotic activities of HDL are far from being fully understood or well developed. In addition, despite great advances in the field over recent years, the regulation of the key molecules controlling the removal of excess cholesterol in atherosclerotic plaque or triglycerides in fatty liver disease is still not fully understood. Several articles in this special issue aim to summarize important aspects in cholesterol and lipid transport that provide opportunity to ameliorate or reverse the formation of lipid-loaded foam cells in atherosclerosis or the accumulation of triglycerides in other diseases associated with lipid disorders, such as the metabolic syndrome. I. Zanooti et al. (in this issue) summarize current knowledge on the intracellular trafficking routes of cholesterol that influence cholesterol export (efflux) from cells, with a special emphasis on the contribution of ATP Binding Cassette A1 and G1 Transporters (ABCA1, ABCG1) and Scavenger Receptor Class B Type I (SR-BI). In particular, this review provides useful information on the currently available biochemical methodologies to examine lipid efflux from cells and the general considerations that have to be taken into account when addressing cholesterol efflux in cell culture. C. Buechler and S. Bauer (in this issue) address another aspect of lipid efflux relevant for pharmaceutical intervention against metabolic syndrome and atherosclerosis and summarize the growing list of proteins associated with ABCA1. Several of those are potentially involved in ABCA1 degradation, the prevention of which is a highly valuable target for drug development. Despite the large amount of research that has been published in the last decades to address the link between signal transduction and reverse cholesterol transport, concise reviews aiming to summarize the opportunities to enhance HDL and apolipoprotein AI (apoAI) -dependent reverse cholesterol transport are still missing. V. Mulay et al. (in this issue) provide a detailed description of the plethora of signaling cascades that promote atheroprotective cell behaviour, in particular the involvement of protein kinases and GTPases in the regulation of ABC transporters and SR-BI to promote removal of excess cholesterol from lipid-loaded macrophages. The potential of pharmaceutical intervention to modulate the activity of signaling proteins, thereby ameliorating atherosclerosis via increasing the activity of cholesterol transporters, is discussed. Despite the major advances in the understanding of cellular cholesterol transport, the knowledge of inter-compartment sterol trafficking is still limited, in part due to the experimental tools yet being insufficient to study cholesterol transport with high accuracy without simultaneously perturbing the experimental system. M. Traini and W. Jessup (in this issue) summarize the advantages of combining genomic strategies, imaging techniques and biochemistry in model organisms such as yeast and drosophila to complete missing links in intracellular sterol transport, lipid storage and metabolism. In addition, the exciting opportunities of functional genomics, but also the limitations in validating identified candidates using RNAi libraries, automated microscopy and visualization of sterols in living cells are discussed. D. Wüstner (in this issue) gives an overview of the challenges and the limitations of most experimental tools aiming to visualize and measure sterol transport and organelle cholesterol content. In addition, recent technical advances in the field to visualize and quantitate cholesterol dynamics using fluorescent analogues are described in detail. Alternatively, to study the trafficking of HDL-derived lipids in cells, C. Roehrl et al. (in this issue) describe the combined use of light and electron microscopy to follow the cellular fate of fluorescent cholesterol analogues incorporated into HDL particles. Using diaminobenzidine photooxidation to convert the fluorescent signal into electron-dense particles for electron microscopical inspection, the authors show that reconstituted HDL particles labeled with BODIPYcholesterol or BODIPY-cholesteryl oleate are an appropriate tool to investigate compartmental distribution of sterols at high resolution. Finally, two articles provide pharmaceutically and clinically relevant aspects of cholesterol and triglyceride transport that have as yet received limited attention in the field of lipoprotein research. J. Heeren and O. Bruns (in this issue) summarize the potential of nanoparticles-based imaging technologies for the non-invasive assessment of atherosclerotic lesions. Indeed, the properties of nanoparticles might offer future opportunities for quantitative measurements of lipoprotein metabolism in patients. Ultimately, nanoparticles could potentially be used to non-invasively evaluate foam cell formation, the early hallmark of atherosclerosis, lesion progression as well as regression in response to therapeutic intervention. Alternatively, nanoparticles could also be useful as carrier systems for anti-atherosclerotic drugs. In addition, M.S. Kim et al (in this issue) summarize the potential of natural medicines for the treatment of non-alcoholic fatty liver disease (NAFLD). Lipid accumulation during the development of NAFLD is characterized by the formation of triglyceride-rich lipid droplets. Given that active compounds within natural herbs that lower hepatic triglycerides are poorly characterized, medium-high throughput screening assays could provide opportunities for lead identification and drug development. The analysis of protein markers that can monitor the magnitude of LD formation have become attractive candidates to assess the efficacy of drugs aiming to reduce hepatic lipid accumulation. Additionally, the authors provide several examples that the quantification of the size and number of lipid droplets could also be developed into an automated microscopy based assay to screen compound libraries derived from natural medicines for their potential to reduce NAFLD.....