April 24, 2017
IS ATHEROSCLEROSIS A CHOLESTEROL OR AN IMMUNE DISEASE?
Lale TokgözoğluAnkara, Turkey
S. Lale Tokgözoğlu, M.D., F.A.C.C., F.E.S.C. was born in 1959 in Ankara, Turkey. She graduated from the Hacettepe University Faculty of Medicine in 1982 on the honor roll. After finishing the Internal Medicine Residency program in the Hacettepe University Faculty of Medicine Department of Internal Medicine on 1988, she completed a fellowship program on Cardiology and Atherosclerosis at the Baylor College of Medicine in Houston, Texas. Dr. Tokgözoğlu returned to the Hacettepe University in 1991 to become Associate Professor of Cardiology, and later Professor of Cardiology in 1998.
Prof. Tokgözoğlu has served on the Executive Committee of the European Society of Atherosclerosis as member between 2003 and 2005 ,as Secretary between 2005-2009 and as Vice President of the European Atherosclerosis Society between 2009-2013. She is currently President-elect of the European Atherosclerosis Society. She was the President of the 77th European Atherosclerosis Society meeting in İstanbul.
She also served as the President of the ‘Atherosclerosis and Vascular Biology Working Group of the European Society of Cardiology’ between 2008 and 2010. She has served for 2 years on board of the European Society of Cardiology Fellowship and Training Committee and for 2 years on the board of the Education Committee. She has also served first as Member-at-Large (Europe) of the Executive Committee of the International Society of Atherosclerosis, then as President of the European Federation of the International Atherosclerosis Society followed by the post of Secretary of the International Society of Atherosclerosis. She is still serving on their executive committee.
Prof. Tokgözoğlu has served on the Board of the Prevention Association of the European Society of Cardiology since 2011. She will be the chair of the Europrevent Congress in 2016 in İstanbul. Prof Tokgözoğlu has founded and chaired the Istanbul Consortium Chapter of the American College of Cardiology in 2010 which is a consortium of 16 countries. She was elected to be the European representative of the American College of Cardiology Assembly of International Governors Steering Committee in 2015.
She has been serving on the Scientific Program Committee of European Society of Cardiology since 1995. She has been a member of the young investigator award committees of the International Atherosclerosis Society in Stockholm 2000, European Atherosclerosis Society in Prague in 2005 and European Society of Cardiology in 2009, 2010 and 2015. Prof. Tokgözoğlu is currently a Fellow of the American College of Cardiology and European Society of Cardiology.
Prof. Tokgözoğlu has been elected to the ‘Science Academy in Turkey’ in 2014. Prof. Tokgözoğlu has served as the Secretary of the Lipid Working Group of the Turkish Society of Cardiology between 1994 and 1996, as President of the Lipid Working Group of the Turkish Society of Cardiology between 1998 and 2000. She has been on the Executive Committee of the Turkish Society of Cardiology for 6 years between 2000 and 2006 and as Vice President between 2008 and 2010 and is currently the President of the Turkish Society of Cardiology.
She has chaired the ‘Research Committee of the Turkish Society of Cardiology’ for 4 years. She is the founding member of the Atherosclerosis Research and Education Society in Turkey. Prof Tokgözoğlu is one of the authors of the ‘National Heart Health Policy’ for Turkey.
Prof Tokgözoğlu initiated the academic collaboration between Cornell-Weill Medical College and Hacettepe Universities in 2013 and is the Coordinator for the Cornell-Weill Medical College affairs in Hacettepe University.
Prof Tokgözoğlu has more than 200 publications, has authored 3 books and several book chapters. Prof. Tokgözoğlu is on the Editorial Board for European Heart Journal, Atherosclerosis, Anatolian Journal of Cardiology and Archives of the Turkish Society of Cardiology. She has won the “Prof. Dr. Şeref Zileli “Resident of the Year” Award in 1987; the Sandoz Scientific Award in 1989 and the “Young Investigator Award” of the Turkish Society of Cardiology in 1994 and second runner up in the Pfizer Cardiology Scientific Award in 1999.
Prof Tokgözoğlu works and publishes on atherosclerotic vascular disease, clinical lipidology, imaging ,hypertension and pulmonary hypertension.
Michal VrablíkPrague, Czech Republic
Michal Vrablik M.D., Ph.D. is currently an Associate Professor of Internal Medicine at the 1st Faculty of Medicine, Charles University in Prague, the Czech Republic. His main interests include preventive cardiology, clinical lipidology and genetics of lipoprotein metabolism disorders.
After graduating from the 1st Faculty of Medicine of Charles University in Prague in 1997 he obtained his PhD in 2001 (thesis on “Familial Dyslipidemias – Clinical and Genetic Aspects”). In 2011 he successfully defended his habilitation work and was appointed an Associate Professor in Internal Medicine. He is most recently involved in studying cardiovascular prevention strategies in different population groups and pharmacogenetic studies.
He is the chairman of the Czech Atherosclerosis Society, a member of the Executive Committee of the European Atherosclerosis Society and, also, a member of the board of the Czech Society of Internal Medicine and the board of the Working group of preventive cardiology of the Czech Society of Cardiology. He participates in the FH screening MedPed program being a leader of the project’s national center. He has served as a principal investigator and investigator in more than thirty research projects on familial dyslipidemias and cardiovascular disease risk and has participated in a number of international clinical trials.
Dr. Vrablik regularly presents at national as well as international scientific meetings and he is also involved in the “Speakers Bureau” for IAS- European Federation. Dr. Vrablik served as a lecturer at the EAS Summer School between 2007 and 2009. Since 2010 he has worked as a co-organizer of International Atherosclerosis Research School endorsed by the EAS and IAS. He was a member of organizing committees of the 75th EAS congress in Prague in 2005 and the 12th Congress of European Federation of Internal Medicine in 2013. He is the Congress Chair of the 85th Congress of European Atherosclerosis Society to be held in Prague in 2017.
In 2005-6 he received a research grant from the Czech Society of Cardiology and joined Healthy Heart Program of St. Paul´s Hospital, Vancouver, Canada. He worked at Cardiovascular Risk Reduction and Metabolic Syndrome Clinics with prof. Jiri Frohlich.
Dr. Vrablik has authored and co-authored more than 100 papers in peer-reviewed scientific journals. He is the sole author of two monographs and of fifteen book chapters. He is also a member of editorial board as well as a reviewer for several national and international journals.
Kathryn MooreNew York, USA
Kathryn Moore is the Jean and David Blechman Professor of Cardiology, and Professor of Cell Biology at New York University School of Medicine. Her research focuses on the mechanisms of metabolic dysfunction and chronic inflammation in atherosclerosis and obesity, with an emphasis on understanding maladaptive macrophage-driven inflammatory responses. She has been the recipient of numerous awards including the Claflin Distinguished Scholar Award, the Ellison Foundation New Scholar in Aging Award, and the American Heart Association’s Jeffrey Hoeg Arteriosclerosis Award for Basic Science and Clinical Research. Dr. Moore is a member of the editorial board of Arteriosclerosis, Thrombosis and Vascular Biology.
Role of non-coding RNA for cholesterol homeostasis and atherogenesis
There is accumulating evidence that non-coding RNAs play a key role in atherosclerosis. The best characterized to date are microRNAs (miRNAs), small, ~22 nucleotide sequences, which influence gene expression at the post-transcriptional level. miRNAs have been shown to modulate endothelial cell, vascular smooth cell, and macrophage functions, as well as lipoprotein metabolism. Notably, miR-33, located within the genes coding for sterol regulatory element-binding protein-2 (SREBP-2), a transcription factor known to regulate cholesterol levels, is an important regulator of cellular cholesterol efflux, fatty acid beta oxidation, as well as high-density lipoprotein metabolism.
Recent research has also identified the involvement of long non-coding RNAs in regulation of gene expression in a number of molecular contexts. One such long non-coding RNA, linc-OSBPL6, has received attention given that it appears to act as a binding hub for both miR-27b and miR-33a/b, and thus, indirectly, influences expression of their target genes. Overexpression of this long non-coding RNA increases cholesterol efflux, while RNA-silencing reduced cholesterol efflux from hepatocytes and macrophages.
These findings focus attention on noncoding RNAs as critical regulators of signalling pathways influencing lipid homeostasis, and thus the balance of atherosclerotic plaque progression and regression. Such understanding may offer future therapeutic potential.
Feinberg MW; Moore KJ. MicroRNA Regulation of atherosclerosis. Circ Res 2016;118:703-20.
Ouimet M, Ediriweera HN, Gundra UM, Sheedy FJ, Ramkhelawon B, Hutchison SB, Rinehold K, van Solingen C, Fullerton MD, Cecchini K, Rayner KJ, Steinberg GR, Zamore PD, Fisher EA, Loke P, Moore KJ. MicroRNA-33-dependent regulation of macrophage metabolism directs immune cell polarization in atherosclerosis. J Clin Invest 2015;125:4334-48.
Ouimet M, Hennessy EJ, van Solingen C, Koelwyn GJ, Hussein MA, Ramkhelawon B, Rayner KJ, Temel RE, Perisic L, Hedin U, Maegdefessel L, Garabedian MJ, Holdt LM, Teupser D, Moore KJ. miRNA targeting of Oxysterol-Binding Protein-Like 6 regulates cholesterol trafficking and efflux. Arterioscler Thromb Vasc Biol 2016;36:942-51.
Mihai G. NeteaNijmegen, Netherlands
Mihai Netea is Professor, Department of Internal Medicine, Nijmegen University Medical Center, Radboud University Nijmegen, The Netherlands. Mihai Netea was born and studied medicine in Cluj-Napoca, Romania. He completed his PhD at the Radboud University Nijmegen, The Netherlands, on studies investigating the cytokine network in sepsis. After working as a post-doc at the University of Colorado, he returned to Nijmegen where he finished his clinical training as an infectious diseases specialist, and where he currently heads the division of Experimental Medicine, Department of Internal Medicine, Nijmegen University Nijmegen Medical Center. His main research interests are sepsis and immunoparalysis, pattern recognition of fungal pathogens, primary immunodeficiencies in innate immune system, and the study of the memory traits of innate immunity. His laboratory has been a key contributor to the elucidation of mechanisms responsible for inflammasome activation in various cells types Professor Netea is the recipient of numerous awards, including the Radboud Science Award (2011), European Society for Clinical Investigation Award for Translational Research (2103) and the NWO Spinoza Prize (2016).
Innate immune response drives atherosclerosis
Atherosclerosis is characterized by persistent inflammation in the arterial wall. Monocyte-derived macrophages, the most abundant immune cells in atherosclerotic plaques, are the key effector cell of the innate immune response. Macrophages express receptors that recognize a broad range of molecular patterns foreign to the mammalian organism but commonly found on pathogens. Activation of these receptors stimulates the release of cytokines that regulate processes involved in the initiation and progression of atherosclerosis.
Research indicates that this innate immune response is not static. Indeed, there is accumulating evidence for innate immune memory, which can enhance the proinflammatory state in the long-term and result in increased production of proatherogenic cytokines. Thus, ‘trained immunity’, involving epigenetic reprogramming of monocytes due to persistent inflammatory stimulation, may exacerbate vascular wall inflammation and drive accelerated atherosclerosis, especially in the concomitant presence of other risk factors. For example, in the setting of diabetes, hyperglycemia may induce long-term activation of monocytes and macrophages and therefore exacerbate plaque development and cardiovascular complications. Understanding of the underlying molecular mechanisms may offer future potential for novel therapeutic approaches for the prevention of atherosclerosis and its associated cardiovascular complications.
Netea MG, Joosten LA, Latz E, Mills KH, Natoli G, Stunnenberg HG, O’Neill LA, Xavier RJ. Trained immunity: A program of innate immune memory in health and disease. Science 2016;352:aaf1098.
Netea MG, van de Veerdonk FL, van der Meer JW, Dinarello CA, Joosten LA. Inflammasome-independent regulation of IL-1-family cytokines. Annu Rev Immunol 2015;33:49-77.
van Diepen JA, Thiem K, Stienstra R, Riksen NP, Tack CJ, Netea MG. Diabetes propels the risk for cardiovascular disease: sweet monocytes becoming aggressive? Cell Mol Life Sci 2016 [Epub ahead of print]
Peter Libby, Boston, USA
Peter LibbyBoston, USA
Dr. Peter Libby is a cardiovascular medicine specialist at Brigham and Women’s Hospital (BWH) and the Mallinckrodt Professor of Medicine at Harvard Medical School (HMS).
Dr. Libby received his medical degree from the University of California, San Diego School of Medicine. He completed a residency in internal medicine and a fellowship in cardiovascular disease at Peter Bent Brigham Hospital (now BWH). He also completed a research fellowship in cellular physiology at HMS and an honorary doctorate from the University of Lille, France Dr. Libby is board certified in internal medicine and cardiovascular disease.
Dr. Libby’s clinical and research interests include vascular biology, atherosclerosis and preventive cardiology. Dr. Libby’s research laboratory studies the messengers created by the body that may produce arterial plaque and blockages, as well as normal and abnormal function of smooth muscle and endothelial cells.
Dr. Libby has received numerous awards and recognitions for his research accomplishments, including most recently the Gold Medal of the European Society of Cardiology (2011), the Basic Research Prize of the American Heart Association (2011), the Anitschkow Prize in Atherosclerosis Research of the European Atherosclerosis Society (2013), and the Special Award of the Heart Failure Association of the European Society of Cardiology (2014). He has received a number of lifetime achievement awards various organizations. Dr. Libby was selected as Consulting Editor of the year by Circulation Research in 2015, and received a 2015 High Citation Award as an editorial board member of Arteriosclerosis Thrombosis, and Vascular Biology. He was awarded the Ernst Jung Gold Medal for Medicine for 2016.
Dr. Libby has published extensively in medical journals including Circulation, Journal of Clinical Investigation, Proceedings of the National Academy of Sciences, New England Journal of Medicine, and Nature.
He is an Editor of Braunwald’s Heart Disease, having served as the Editor-in Chief of the 8th Edition. Dr. Libby has also contributed chapters on the pathogenesis, treatment, and prevention of atherosclerosis to many editions of Harrison’s Principles of Internal Medicine. He has held numerous visiting professorships and delivered more than 80 major named or keynote lectures throughout the world.
The case for immune cells: An expanded cardiovascular continuum
Atherosclerosis is now established as an inflammatory condition, with immune cells playing a key role in driving the atherogenic process and mechanisms underlying the associated cardiovascular complications. Indeed, foam cells – lipid-laden macrophages- derive from mononuclear phagocytes. While it has been previously thought that these represent a homogeneous population, recent evidence supports a role for different subsets of mononuclear phagocytes in mediating local inflammatory responses in the atherosclerotic plaque. Additionally, leukocytes are important contributors to both acute injury and subsequent healing of the myocardium in acute coronary syndromes, with the initial wave of proinflammatory mononuclear phagocytes in the infarct followed by a second wave of less inflammatory monocytes with reparative functions.
More recently, experimental insights have expanded the role of immune cells via inflammatory signaling networks that link the brain, autonomic nervous system, bone marrow, and spleen to atherosclerotic plaque and ischaemic heart disease. Thus, the interplay between pain perception and stress in the central nervous system, adrenergic signaling in the sympathetic nervous system and subsequent release of progenitor cells and leukocytes from the bone marrow to sites of extramedullary hematopoiesis or local inflammation has been shown to contribute to the complications of atherosclerosis. Imaging studies also provide support for the “splenocardiac” axis in the biology of atherosclerosis and ischaemic disease.
Taken together, there is now a strong rationale for expanding the traditional ‘cardiovascular continuum’ to include the nervous system, the spleen, and the bone marrow, with immune cells playing a key role via integrative inflammatory signaling networks. From a clinical perspective, this interplay of pathways may offer novel therapeutic targets with potential for fine-tuning the inflammatory responses during atherosclerosis and acute myocardial injury.
Libby P, Nahrendorf M, Swirski FK. Leukocytes link local and systemic inflammation in ischemic cardiovascular disease: an expanded “Cardiovascular Continuum”. J Am Coll Cardiol 2016;67:1091-103.
Libby P, Bornfeldt KE, Tall AR. Atherosclerosis: Successes, surprises, and future challenges. Circ Res 2016;118:531-4.
De Caterina R, D’Ugo E, Libby P. Inflammation and thrombosis – testing the hypothesis with anti-inflammatory drug trials. Thromb Haemost 2016;116:1012-21.
Chris J. PackardGlasgow, United Kingdom
Chris Packard is the Research and Development Director of NHS Greater Glasgow & Clyde, Scotland, UK. He holds an Honorary Professorship of Vascular Biochemistry at the University of Glasgow, and is also a Consultant Clinical Scientist for NHS Greater Glasgow & Clyde Biochemistry and founding Chairman of NEXXUS. Professor Packard received the Scottish Enterprise Special Recognition Award for his contribution to the Life Sciences industry in Scotland in February 2014 and was appointed Commander of the Order of the British Empire (CBE) in June 2014.
His research has focused on two key aspects: lipoprotein metabolism and how it is affected by diets and drugs, and large scale clinical trials of lipid lowering agents. Key contributions include evaluation of the role of the low-density lipoprotein (LDL) receptor in vivo, the discovery of metabolic channelling in the apolipoprotein B lipoprotein delipidation cascade, and the formulation of models to explain the generation of small, dense LDL. More recently his field of research has widened to include investigations of emerging risk factors, and the consequences of social deprivation on health and wellbeing.
Lowering LDL-C for cardiovascular disease
A causal relationship between low-density lipoprotein cholesterol (LDL-C) plasma levels and the risk of coronary atherosclerosis is now established. Indeed, the Cholesterol Treatment Trialists’ Collaboration showed reduction in the risk of major cardiovascular events by about one fifth per mmol/L LDL-C reduction (1). Long term follow-up from major statin trials indicate a potential lifetime benefit from LDL-lowering therapy. In the West of Scotland Coronary Prevention Study, a primary prevention trial, 20-year follow-up indicated a legacy effect associated with 5 years’ treatment with a statin, resulting in improved survival and reduction in major cardiovascular disease events (2); however, such findings were not consistently shown across all major statin trials. This may relate to the extent of disease at baseline; lowering LDL-C levels earlier rather than later in the atherosclerotic disease process may delay the development of atherosclerosis, resulting in improved clinical benefit over the trajectory of the disease.
The plethora of evidence demonstrating the relationship between LDL-C lowering and improved cardiovascular outcomes has been a key driver for the development of novel treatments that lower LDL‑C levels substantially beyond the effects observed with statins. The first of the PCSK9 inhibitor outcomes trials are expected in early 2017. If the magnitude of clinical benefit from these treatments is consistent with the regression line for LDL-C lowering observed with statins (and ezetimibe) even in patients with low LDL-C levels at baseline, this will reinforce the critical importance of lowering LDL-C to reduce absolute cardiovascular risk.
- Baigent C, Keech A, Kearney PM et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78.
- Ford I, Murray H, McCowan C, Packard CJ. Long-term safety and efficacy of lowering low-density lipoprotein cholesterol with statin therapy: 20-year follow-up of West of Scotland Coronary Prevention Study. Circulation 2016;133:1073-80.
Packard CJ, Ford I. Long-term follow-up of lipid-lowering trials. Curr Opin Lipidol 2015;26:572-9.
Packard CJ, Weintraub WS, Laufs U. New metrics needed to visualize the long-term impact of early LDL-C lowering on the cardiovascular disease trajectory. Vascul Pharmacol 2015;71:37-9.
Laufs U, Descamps OS, Catapano AL, Packard CJ. Understanding IMPROVE-IT and the cardinal role of LDL-C lowering in CVD prevention. Eur Heart J 2014;35:1996-2000.
April 25, 2017
THE BIOLOGY OF TRIGLYCERIDES REVISITED
Alberico L. CatapanoMilan, Italy
Alberico L. Catapano was born in Milano in 1952. Received degree from the University of Milano in 1975 and a specialization in Clinical Pharmacology in 1979. From 1972 been involved in the field of Atherosclerosis, Lipids, Lipoproteins and genetic dislypidaemias. From the scientific standpoint Prof. Catapano has made landmark observations regarding the role of HSP’s and of Petranxins in Atherogenesis and on the role of HDL in the modulation of the immune response. Alberico Catapano is Full Professor of Pharmacology at the University of Milano, Director of the Laboratory for the study of Lipoproteins and Atherosclerosis and of the Center for the Study of Atherosclerosis of the Italian Society of Atherosclerosis (S.I.S.A.) at the “Bassini” Hospital. He is also the Director of Center of Epidemiology and Preventive Pharmacology of the University of Milano (SEFAP).
Professor Catapano is Past President of the European Atherosclerosis Society (EAS), the Chairman of EAS Educational, Guidelines & Corporate Activities Committees and the Chairman of the EAS/ESC guidelines for the treatment of dyslipoproteinemias. He holds board positions in several learned Scientific Societies including the Italian Society for the Study of Atherosclerosis ; he is also President of the Italian Society of Clinical and Experimental Therapy (SITeCS) and General Director of the SISA Foundation.
He has authored more than 340 scientific papers in peer reviewed journals and of several books in the area of the Atherosclerosis, Lipoproteins and Lipid Metabolism. He is the editor of Atherosclerosis Supplements and also co editor of “Atherosclerosis” and associate editor of other scientific journals.
Henry N. GinsbergNew York, USA
The EAS is delighted to announce that one of the two Keynote Lectures at the 2017 EAS Congress in Prague will be given by Henry N. Ginsberg, MD, the Irving Professor of Medicine and Director Emeritus of the Irving Institute for Clinical and Translational Research at Columbia University Medical Center.
Professor Ginsberg’s research interests have centered on regulation of the metabolism of apolipoprotein B–containing lipoproteins in cells, mice, and humans. His present work focuses on the interaction between the secretion of very low-density lipoproteins by the liver and hepatic steatosis, as well as human mutations affecting hepatic lipid and lipoprotein metabolism. He recently received an Outstanding Investigator Award from NIH.
Professor Ginsberg has been a key contributor to the success of EAS as Co-Chair, with Professor John Chapman (Pitié-Salpetriere University Hospital, Paris, France), of the EAS Consensus Panel. Since its inception in 2009, the EAS Consensus Panel has addressed topical questions in key areas of cardiovascular disease research. The EAS Consensus Panel has helped to raise awareness of familial hypercholesterolaemia, establish lipoprotein(a) as a cardiovascular risk factor, as well as focus on the appropriate management of statin-associated muscle symptoms (SAMS). Full details are available at: http://www.eas-society.org/?page=sams_consensus
Robert Farese, JrBoston, USA
Dr. Robert Farese, Jr., studied chemistry at the University of Florida and medicine at Vanderbilt University. He then completed a residency and chief residency in internal medicine at the University of Colorado. In 1989, Dr. Farese moved to the University of California San Francisco to train in endocrinology and metabolism and did his postdoctoral research training with Dr. Stephen Young at the Gladstone Institutes, where he became an expert in gene targeting in murine embryonic stem cells and studied lipoprotein and cholesterol metabolism. In 1994, Dr. Farese established his laboratory at the Gladstone and UCSF where he studied neutral lipid metabolism, focusing on the pathways of lipid synthesis and storage. His laboratory cloned many of the important enzymes of neutral lipid synthesis, including the DGAT enzymes, which mediate triglyceride (TG) synthesis. Excessive accumulation of TGs underlies obesity, diabetes, fatty liver, and other metabolic diseases. Dr. Farese and co-workers discovered the DGAT enzymes and defined their molecular functions in lipid biochemistry, physiology, identified human disease mutations, and laid the groundwork for development of DGAT inhibitors.
In 2005, Dr. Farese took a sabbatical with Dr. Peter Walther, where he began working with Dr. Tobias Walther on the cell biology of lipid droplets. They collaborated closely for many years and established a joint laboratory at Harvard in 2014. They have focused on unraveling the molecular mechanisms of LD formation, protein targeting to LDs, and the role that LDs play in disease.
In 2007, Dr. Farese co-founded the Consortium for Frontotemporal Dementia (FTD) Research (CFR), a UCSF-based, multi-investigator collaborative effort whose goal is to find cures for FTD by studying progranulin biology. Dr. Farese and co-workers have generated murine and iPS models for progranulin-deficient FTD, and he co-directs the Basic Research for the CFR.
Dr. Farese has received numerous honors, among them election to the American Society for Clinical Investigation and the Association of American Physicians, a “Freedom to Discover Award” from Bristol-Myers Squibb, and the Avanti Lipid research award.
Balancing the fat: lipid droplets and human disease
The most efficient way that cells store energy is in the form of fat, particularly triacylglycerols, which are packaged into lipid droplets, compact cytosolic organelles that also store precursors for membrane and hormone synthesis. When energy is in short supply, lipids are mobilized. Thus, lipid droplets are dynamic, either growing or shrinking in cells to maintain lipid levels and meet metabolic demands. Yet despite being discovered over a century ago, the mechanisms that underlie lipid droplet formation and response to metabolic demands have yet to be fully elucidated. Studies into these lipid storage mechanisms using mouse models of obesity and metabolic disease may offer important insights into lifestyle-related diseases, such as obesity, hepatic steatosis and liver disease, and cardiovascular disease.
Balancing fat storage in the lipid droplet is therefore critical for health. Recent research has provided insights into the molecular processes underlying lipid storage, notably identification of key proteins and genes involved in the regulation of lipid storage. For example, key surfactant proteins at the surface of the lipid droplet have been shown to have an important structural role, in packaging lipid in smaller units, protecting lipid droplets against endogenous lipases, and facilitating triglyceride formation. In addition, lipid droplets may integrate lipid metabolism, inflammatory mediator production, membrane trafficking, and intracellular signaling, in response to supply and demand for lipid. Improved understanding of these mechanisms may offer future therapeutic potential, especially in the management of metabolic disease.
Kory N, Farese RV Jr, Walther TC. Targeting fat: mechanisms of protein localization to lipid droplets. Trends Cell Biol 2016;26:535-46.
Wang H, Becuwe M, Housden BE, Chitraju C, Porras AJ, Graham MM, Liu XN, Thiam AR, Savage DB, Agarwal AK, Garg A, Olarte MJ, Lin Q, Fröhlich F, Hannibal-Bach HK, Upadhyayula S, Perrimon N, Kirchhausen T, Ejsing CS, Walther TC, Farese RV. Seipin is required for converting nascent to mature lipid droplets. Elife 2016; doi: 10.7554/eLife.16582.
Kory N, Thiam AR, Farese RV Jr, Walther TC. Protein crowding is a determinant of lipid droplet protein composition. Dev Cell 2015;34:351-63.
Gary F. LewisToronto, Canada
Dr. Gary Lewis completed his medical training in 1982 at the University of Witwatersrand in South Africa, followed by specialty training in Internal Medicine and then Endocrinology at the University of Chicago. He joined the staff of the Toronto General Hospital in 1990, was appointed Head of the Division of Endocrinology at University Health Network and Mount Sinai Hospitals in 2001, Director of the University of Toronto Division of Endocrinology and Metabolism in 2008 and Director of the Banting and Best Diabetes Centre, U of T, in 2011. He is a Full Professor in the Departments of Medicine and Physiology, University of Toronto and he holds the Sun Life Financial Chair in Diabetes and the Drucker Family Chair in Diabetes Research. Dr. Lewis’ research focuses on elucidating the mechanisms of blood fat abnormalities in diabetes and prediabetic states.
Regulation of lipid mobilization and lipoprotein secretion by the intestine
Individuals with type 2 diabetes typically exhibit a dyslipidaemia characterized by high plasma triglyceride levels, carried mainly in triglyceride-rich lipoproteins (TRLs) such as chylomicrons and very low-density lipoproteins, decreased high-density lipoprotein cholesterol levels and qualitative changes in lipoproteins, as well as an abnormal postprandial lipid response. Both impaired clearance of TRLs from the circulation, as well as increased production of both hepatic and intestinal TRLs underpin the development of this dyslipidaemia.
Recent evidence indicates that the incretin hormones glucagon-like protein-1 (GLP-1) and a glucagon-like protein-2 (GLP-2) also affect intestinal lipid uptake and lipoprotein secretion via effects on multiple target organs. GLP-1 been shown to directly influence triglyceride homeostasis by inhibiting intestinal lipoprotein production, thus lowering plasma triglycerides. In contrast, GLP-2 promotes the release of chylomicrons into the circulation, thereby increasing plasma triglycerides. The net effect of these opposing actions has yet to be fully elucidated. There is also emerging evidence to implicate central regulation of triglyceride homeostasis. Thus, hypothalamic glucose-sensing mechanisms have been shown to regulate liver, but not intestinal, very low-density lipoprotein-triglyceride production. Further understanding of the regulation of triglyceride homeostasis by the gut-liver-brain axis may offer future therapeutic potential for the management of dyslipidaemia and prevention of atherosclerosis.
Xiao C, Dash S, Morgantini C, Hegele RA, Lewis GF. Pharmacological targeting of the atherogenic dyslipidemia complex: the next frontier in CVD prevention beyond lowering LDL cholesterol. Diabetes 2016;65:1767-78.
Lewis GF, Xiao C, Hegele RA. Hypertriglyceridemia in the genomic era: a new paradigm. Endocr Rev 2015;36:131-47.
Xiao C, Dash S, Morgantini C, Adeli K, Lewis GF. Gut peptides are novel regulators of intestinal lipoprotein secretion: experimental and pharmacological manipulation of lipoprotein metabolism. Diabetes 2015;64:2310-8.
Marja-Riitta TaskinenHelsinki, Finland
Marja-Riitta Taskinen is Emerita Professor of Medicine at the Cardiovascular Research Group, Heart and Lung Centre, at Helsinki University Central Hospital. Her research team, which focuses on lipoprotein kinetics in health and lipid disorders and the genetics of familial dyslipidemias, is a member of the Research Program Unit, Diabetes & Obesity Research program at the University of Helsinki. Professor Taskinen is the recipient of numerous awards including the Claude Bernard Award (2002), Edwin Bierman Award (2004), Novartis Award (2006), the Grand Award of the Finnish Foundation for Cardiovascular Research (2011), and the Pohjola and Suomi Mutual Medical Award of the Finnish Medical Foundation (2012). She has been a key player in the European Atherosclerosis Society (President, 2006-2008), International Atherosclerosis Society, European Association for the Study of Diabetes, and the International Diabetes Federation.
Hepatic lipid and lipoprotein metabolism
Triglyceride-rich very low-density lipoprotein 1 (VLDL1) particles are responsible for carrying most of the circulating triglycerides. The balance between synthesis of VLDL1-triglyceride in the liver and intestine, and subsequent removal by lipoprotein lipase (LPL) is a key determinant of circulating levels of plasma triglycerides. In individuals with abdominal obesity and dyslipidemia, VLDL1-triglyceride clearance predominates over increased secretion of VLDL1 particles.
Regulation of LPL is a key factor influencing triglyceride turnover. Post-transcriptionally, this is controlled by both liver-derived apolipoproteins, as well as angiopoietin-like proteins, specifically the products of the ANGPTL3, ANGPTL4 and ANGPTL8 genes. LPL is activated by apolipoprotein (apo)C-II and inhibited by apoC-III. ApoC III inhibits TRL remnant uptake by hepatic lipoprotein receptors, and hepatic assembly and secretion of VLDL apoC-III, and therefore plays a critical role in the development of hypertriglyceridaemia. ANGPTL3 and ANGPTL4 impair triglyceride clearance by inhibiting LPL. ANGPTL3 is expressed in the liver and regulated by the liver X receptor, whereas expression of ANGPTL4 is more widespread and controlled by the peroxisome proliferator-activated receptor (PPAR) family and fatty acids. But even before regulation by these proteins, LPL secretion and delivery is also influenced by other intermediaries, such as the products of LMF1 and GPIHBP1 genes. Further insights into the regulation of triglyceride turnover may offer future therapeutic potential.
Vergès B, Adiels M, Boren J, Barrett PH, Watts GF, Chan D, Duvillard L, Söderlund S, Matikainen N, Kahri J, Lundbom N, Lundbom J, Hakkarainen A, Aho S, Simoneau-Robin I, Taskinen MR. ApoA-II HDL catabolism and its relationships with the kinetics of ApoA-I HDL and of VLDL1, in abdominal obesity. J Clin Endocrinol Metab 2016;101:1398-406.
Borén J, Watts GF, Adiels M, Söderlund S, Chan DC, Hakkarainen A, Lundbom N, Matikainen N, Kahri J, Vergès B, Barrett PH, Taskinen MR. Kinetic and related determinants of plasma triglyceride concentration in abdominal obesity: multicenter tracer kinetic study. Arterioscler Thromb Vasc Biol 2015;35:2218-24.
Taskinen MR, Borén J. New insights into the pathophysiology of dyslipidemia in type 2 diabetes. Atherosclerosis 2015;239:483-95.
Anne Tybjaerg-HansenCopenhagen, Denmark
Anne Tybjærg-Hansen MD DMSc, Professor, Chief Physician.
Chief Physician at the Department of Clinical Biochemistry, Section for Molecular Genetics, at Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark (from Nov. 1999).
Professor of Clinical Biochemistry with Focus on Translational Molecular Cardiology at the University of Copenhagen, Copenhagen, Denmark (from Dec. 2009).
Graduated as a medical doctor from the University of Copenhagen in 1981. Scientific education included 1 year at the University of Copenhagen and the Lipid Clinic at Righospitalet, 3 years at Hagedorn Research Laboratory, Gentofte, Denmark; and 3 years (87-89) at British Heart Foundation’s Molecular Biology Research Group, London, UK.
Member of the steering committees of the Copenhagen City Heart Study and the Copenhagen General Population Study. Current chairman European Lipoprotein Club.
Demystifying the management of hypertriglyceridaemia
April 26, 2017
CARDIOMETABOLIC RISK FACTORS BEYOND LIPIDS
Kausik RayLondon, United Kingdom
Kausik Ray is Professor of Public Heath, and Honorary Consultant Cardiologist at Imperial College London. Professor Ray received his medical education at the University of Birmingham Medical, his MD thesis at the University of Sheffield, a postdoctoral fellowship at Harvard Medical School and his MPhil in epidemiology from the University of Cambridge.A Fellow of the ACC, ESC, AHA, and the RCP (London and Edinburgh).
His research interests have focused on the prevention of CVD from large scale observational studies to clinical trials. His work has influenced international guidelines and received more than 12 000 citations.
Professor Ray leads the EAS FH Studies collaboration involving around 60 countries currently and serves on the Executive Committee of several ongoing trials in cardiovascular disease.
Stephen NichollsAdelaide, Australia
Stephen Nicholls is Deputy Director and Heart Health Theme Leader at the South Australian Health and Medical Research Institute (SAHMRI). He is Professor of Cardiology at the University of Adelaide, Consultant Cardiologist at the Royal Adelaide Hospital and Principal Research Fellow of the National Health and Medical Research Council of Australia. He completed his medical training in Adelaide, cardiology training in Newcastle and his PhD at the Heart Research Institute, focusing on the anti-inflammatory properties of high-density lipoproteins (HDL, the good form of cholesterol). After a postdoctoral fellowship in plaque imaging, he was appointed to faculty at the Cleveland Clinic, where he served as the Medical Director of the Atherosclerosis Imaging Core Laboratory and Cardiovascular Director of the Cleveland Clinic Coordinating Center for Clinical Research. He returned to Australia in 2012 to take up his current positions in Adelaide.
Professor Nicholls has published more than 600 original manuscripts, conference proceedings and book chapters, including in the New England Journal of Medicine, Lancet, Journal of the American Medical Association and Nature Medicine and is frequently invited to talk on a range of topics in cardiovascular disease at national and international conferences. He is currently a Past President of the Australian Atherosclerosis Society and Treasurer of the Cardiac Society of Australia and New Zealand and an inaugural Fellow of the Australian Academy of Health and Medical Sciences.
Stephen Nicholls major research interests include studying the impact of metabolic factors influencing heart disease, development of novel plaque imaging modalities in clinical practice and performing large scale clinical trials of novel cardioprotective therapies.
Sarah LewingtonOxford, United Kingdom
Sarah Lewington is Associate Professor, MRC Population Health Research Unit, Director of Graduate Studies, Nuffield Department of Population Health, and Research Fellow, Green Templeton College, Oxford UK. Professor Lewington’s main research interest is in major risk factors for premature adult mortality, with a particular focus on tobacco, alcohol, blood pressure and obesity, and she is the Oxford-based principal investigator for studies conducted in Russia, Cuba and India. She leads a team of epidemiologists, statisticians and statistical programmers that forms the CTSU’s Population Studies Group and is the MRC Programme Leader Track, Statistical Epidemiology. Sarah is also a Scientific Director for the MSc in Global Health Science, with responsibility for the planning, development, delivery and management of all aspects of the fully revised MSc degree course.
Large-scale epidemiology assessment of the main determinants of cardiovascular disease
Cardiovascular disease is a leading cause of death and disability worldwide. While observational epidemiologic studies can provide useful insights into associations between biomarkers and cardiovascular disease, it is only with large-scale epidemiology assessment involving the use of meta-analysis that such associations can be conclusively established. Although not without limitations, meta-analysis of observational studies, especially individual subject data, has provided robust evidence to support the causal relevance of several major risk factors including smoking, adiposity, blood pressure, blood cholesterol, and diabetes mellitus to cardiovascular disease. This information has been critical for defining health policy targeting behavior, as well as use of pharmacotherapy, which has contributed to dramatic declines in cardiovascular disease mortality in developed regions over the last half of the 20th century. Recent insights from the Global Burden of Disease 2010 Study has, however, shown that the decline in mortality rates for both ischaemic heart disease and stroke between 1990 and 2010 in developed countries is not matched by that in developing regions, thus highlighting the need for further efforts to reduce cardiovascular disease globally.
Despite these advances, the established major risk factors may explain only part of cardiovascular disease risk, thus highlighting the need for further research to detect “novel” or “emerging” risk or biomarkers for cardiovascular disease. Large-scale epidemiology assessment will play a key role here in identifying whether such novel biomarkers are truly causal for cardiovascular risk.
Herrington W, Lacey B, Sherliker P, Armitage J, Lewington S. Epidemiology of atherosclerosis and the potential to reduce the global burden of atherothrombotic disease. Circ Res 2016;118:535-46.
Global BMI Mortality Collaboration, Di Angelantonio E, Bhupathiraju ShN, Wormser D, Gao P, Kaptoge S, Berrington de Gonzalez A, Cairns BJ, Huxley R, Jackson ChL, Joshy G, Lewington S, Manson JE, Murphy N, Patel AV, Samet JM, Woodward M, Zheng W, Zhou M, Bansal N, Barricarte A, Carter B, Cerhan JR, Smith GD, Fang X, Franco OH, Green J, Halsey J, Hildebrand JS, Jung KJ, Korda RJ, McLerran DF, Moore SC, O’Keeffe LM, Paige E, Ramond A, Reeves GK, Rolland B, Sacerdote C, Sattar N, Sofianopoulou E, Stevens J, Thun M, Ueshima H, Yang L, Yun YD, Willeit P, Banks E, Beral V, Chen Zh, Gapstur SM, Gunter MJ, Hartge P, Jee SH, Lam TH, Peto R, Potter JD, Willett WC, Thompson SG, Danesh J, Hu FB. Body-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. Lancet 2016;388:776-86.
Lewington S, Lacey B, Clarke R, Guo Y, Kong XL, Yang L, Chen Y, Bian Z, Chen J, Meng J, Xiong Y, He T, Pang Z, Zhang S, Collins R, Peto R, Li L, Chen Z; China Kadoorie Biobank Consortium. The burden of hypertension and associated risk for cardiovascular mortality in China. JAMA Intern Med 2016;176:524-32.
Qi SunBoston, USA
Qi Sun is Assistant Professor in the Department of Nutrition, Harvard T.H. Chan School of Public Health and Assistant Professor of Medicine at Brigham and Women’s Hospital and Harvard Medical School, Boston, USA. Dr. Sun’s primary research interests are focused on identifying biomedical risk factors, including dietary biomarkers, in relation to type 2 diabetes, obesity, and cardiovascular disease. His research is primarily based on a few large-scale cohort studies including the Nurses’ Health Study I and II and the Health Professionals Follow-up Study. In addition, Dr. Sun is interested in the role of environmental pollutants, especially those from dietary sources, in the aetiology of obesity and type 2 diabetes.
Diet and cardiometabolic health
Cardiometabolic disease is an important cause of morbidity and mortality worldwide, fueled by escalating rates of obesity and type 2 diabetes. Diet is a key modifiable lifestyle factor that can be targeted to reduce disease-risk profiles, and is therefore fundamental to lifestyle approaches to prevent cardiometabolic disease. Diet involves multidimensional exposure, given that it is a combination of different foods and nutrients, and thus quantitative and qualitative components of the diet, such as fat, warrant consideration.
Such thinking has prompted a shift towards consideration of overall dietary patterns, such as the Mediterranean diet, rather than focusing on individual nutrients and/or foods. Indeed, pivotal studies such as PREDIMED, show that the Mediterranean diet favourably impacts cardiometabolic risk factors and reduces cardiovascular events. Consideration of diet quality has now been incorporated into recent guidelines, notably the 2016 Joint ESC/EAS Guidelines for Management of Dyslipidaemia, and the 2016 Joint Task Force Guidelines for Prevention of Cardiovascular Disease. These also allow for adaptations to take account of personal and cultural food preferences.
Yet the reduction in risk of cardiometabolic disease with improvement in overall diet quality is only partly explained by changes in body weight, implying the contribution of other factors. Ongoing research has highlighted the relevance of interactions between diet and an individual’s genetic make-up (nutrigenetics) to both the initiation and progression of cardiometabolic disease. Worldwide collaborative efforts have identified common genetic variants associated with type 2 diabetes, as well as contributed to understanding of gene-environment interactions that may modify the cardiovascular risk phenotype. Additionally, experimental studies indicate that exercise and dietary intervention may play a key role in improving insulin resistance by alleviating oxidative stress. Such approaches provide new potential to addressing the major global challenge of cardiometabolic disease.
Ley SH, Pan A, Li Y, Manson JE, Willett WC, Sun Q, Hu FB. Changes in overall diet quality and subsequent type 2 diabetes risk: Three U.S. prospective cohorts. Diabetes Care 2016. pii: dc160574. [Epub ahead of print]
Ley SH, Ardisson Korat AV, Sun Q, Tobias DK, Zhang C, Qi L, Willett WC, Manson JE, Hu FB. Contribution of the Nurses’ Health Studies to uncovering risk factors for type 2 diabetes: diet, lifestyle, biomarkers, and genetics. Am J Public Health 2016;106:1624-30.
Yu E, Rimm E, Qi L, Rexrode K, Albert CM, Sun Q, Willett WC, Hu FB, Manson JE. Diet, lifestyle, biomarkers, genetic factors, and risk of cardiovascular disease in the Nurses’ Health Studies. Am J Public Health 2016;106:1616-23.
Fredrik BäckhedGothenburg, Sweden
Professor Fredrik Bäckhed combines clinical oriented research with gnotobiotic mouse models to address the role of the normal gut microbiota in metabolic diseases. Fredrik Bäckhed holds a PhD from the Karolinska Institute, and performed postdoctoral training at Washington University, St Louis where he identified the gut microbiota as an environmental factor that regulates adiposity and obesity. Dr Bäckhed is professor at University of Gothenburg and Director of the Wallenberg Laboratory (www.wlab.gu.se) for cardiovascular research. He is also Professor at Copenhagen University and has been guest Professor at University of Oslo. His research aims to identify novel therapeutic and diagnostic targets for the metabolic syndrome by focusing on the role of the gut microbiota. His team uses an interdisciplinary research approach to delineate the mechanisms by which the gut microbiota modulates host physiology and metabolism. Professor Bäckhed has co-authored more than 80 papers in international peer-reviewed journals, including Nature, Science, Cell and Proceedings of National Academy of Sciences.
Microbiome and cardiometabolic disease
New therapeutic targets are critical to combat the pandemic of obesity. The microbiome, which plays a key role in modulating host physiology and metabolism, has become a focus for research, given that it lies at the intersection of diet and metabolic health. Translational animal models and studies in humans have identified mechanisms that link the gut microbiota with obesity and thus cardiometabolic disease. Such studies have shown the relevance of dietary factors and macronutrients, which act as substrates for many microbially produced metabolites, such as short-chain fatty acids and bile acids, in modulating host metabolism. Changes in the gut ecology influence the inflammatory and metabolic properties of the gut microbiota and hence host physiology, and thus impact metabolic risk.
Despite accumulating evidence for a link between the gut microbiome and cardiometabolic health, few studies have validated causality in humans and the underlying mechanisms are yet to be fully elucidated. Greater understanding of alterations in the gut microbiota in combination with dietary patterns, as well as identification of novel signaling pathways, may provide insights into how the gut microbiota contributes to cardiometabolic disease progression. Indeed, recent findings have implicated a link between reduced levels of butyrate-producing bacteria and possible causality for type 2 diabetes, whereas the reverse has been found for levels of Lactobacillus species. Ultimately, the aim is to exploit such findings to enable the development of novel diagnostic and therapeutic targets directed to the microbiome for prevention of cardiometabolic disease.
Sonnenburg JL, Bäckhed F. Diet-microbiota interactions as moderators of human metabolism. Nature 2016; 535:56-64.
Schroeder BO, Bäckhed F. Signals from the gut microbiota to distant organs in physiology and disease. Nat Med 2016;22:1079-89.
Greiner TU, Bäckhed F. Microbial regulation of GLP-1 and L-cell biology. Mol Metab 2016;5:753-8.
Patrick SchrauwenMaastricht, Netherlands
Patrick Schrauwen, PhD is Professor of Metabolic aspects of Type 2 Diabetes Mellitus at the Maastricht University Medical Center (MUMC). The lab of Professor Schrauwen performs human translational research on insulin resistance, lipotoxicity, mitochondrial dysfunction and brown adipose tissue with special emphasis on type 2 diabetes mellitus. Professor Schrauwen was awarded the ‘Silver Medal Award’ from the Nutrition Society’ in 2006, the ‘Rising Star Award’ from the European Association for the Study of Diabetes (EASD) in 2008 and the Minkowski Award of the EASD in 2016. He received the prestigious Corona-Gallina Award for excellence in diabetes research in 2013. Professor Schrauwen has published over 200 publications, and is in the editorial boards of ‘Scientific Reports’ and ‘Diabetologia’. His main fields of interest include insulin resistance, lipotoxicity and mitochondrial dysfunction, with a special emphasis on type 2 diabetes.
Importance of physical activity in metabolic and cardiovascular health and the influence of obesity and diabetes
Accumulating evidence suggests that physical inactivity may be as important a factor as being overweight for the development of insulin resistance, type 2 diabetes and potentially fatty liver disease. Physical activity can improve several metabolic risk factors associated with cardiovascular disease. Skeletal muscle plays an important role in maintaining whole body energy and substrate metabolism and is responsible for ~80% of postprandial glucose uptake in humans. Exercise training has been shown to have beneficial effects on skeletal muscle metabolism, and there is also emerging evidence to suggest a benefit on liver metabolism, most likely by reducing hepatic fat availability and synthesis, and increasing hepatic triacylglycerol oxidation. Research efforts have therefore focused on understanding the underlying mechanisms influencing metabolic homeostasis. Studies have shown that physical exercise can promote selective induction of angiopoietin-like 4 (ANGPTL4) in non-exercising muscle and reduce local fatty acid uptake, while at the same time directing fatty acids to the active skeletal muscle, thus implying a key role for ANGPTL4 in regulation of lipid homeostasis during exercise.
Exercise also has a favourable impact on both the number and function/efficiency of mitochrondria. Exercise training has been shown to promote mitochondrial function and insulin sensitivity, which may underlie its role in the prevention and treatment of type 2 diabetes. Ongoing research has led to the emergence of novel targets for boosting mitochondrial function, many of which appear to be regulated by factors such as nutrition, ambient temperature and circadian rhythms. Carnitine acetyltransferase, a mitochondrial matrix enzyme, has attracted attention as a potential therapeutic target, given evidence suggesting a role in regulation of total body glucose tolerance and glucose oxidation. Studies have implicated carnitine insufficiency and reduced carnitine acetyltransferase activity as reversible components of the metabolic syndrome. Such insights may provide a basis for nonpharmacological strategies for prevention of type 2 diabetes.
Brouwers B, Hesselink MK, Schrauwen P, Schrauwen-Hinderling VB. Effects of exercise training on intrahepatic lipid content in humans. Diabetologia 2016;59:2068-79.
Combatting type 2 diabetes by turning up the heat. Schrauwen P, van Marken Lichtenbelt WD. Diabetologia 2016;59:2269-79.
Hansen J, Timmers S, Moonen-Kornips E, Duez H, Staels B, Hesselink MK, Schrauwen P. Synchronized human skeletal myotubes of lean, obese and type 2 diabetic patients maintain circadian oscillation of clock genes. Sci Rep 2016;6:35047.