EAS Newsletter

​​​Focus on EAS Innsbruck 2016: Plenary speakers ​​

Session I: Integrative approach in atherosclerosis​​

Helen Hobbs, USA: Fatty liver disease: ancient mutations for a common disease

 Helen Hobbs.jpgHelen H. Hobbs is Professor of Internal Medicine and Molecular Genetics, Director of the McDermott Center for Human Growth and Development, University of Texas (UT) Southwestern Medical Center, Dallas Texas, and an Investigator of the Howard Hughes Medical Institute. She is also Director of the Dallas Heart Study, a longitudinal, multi-ethnic, population-based study of Dallas County.  After obtaining her clinical and post-doctoral training at Columbia-Presbyterian Hospital and UT Southwestern Medical Center Dallas, she joined the faculty of UT Southwestern. Her research interests focus on defining the genetic determinants of plasma lipoprotein levels and cardiovascular risk, most recently genetic variations that counter susceptibility to fatty liver disease.  She is a member of the American Society for Clinical Investigation, the Association of American Physicians, the Institute of Medicine, the American Academy of Arts and Sciences and the National Academy of Sciences. She is the recipient of numerous awards including the American Heart Association Clinical Research Prize, the Heinrich Wieland Prize, the 2007 American Heart Association Distinguished Scientist Award, and the 2013 Pasarow Foundation Award in Cardiovascular Research.​

Non-alcoholic fatty liver disease encompasses a spectrum of related disorders characterised by accumulation of triglycerides in hepatocytes. While usually benign, in some individuals it can progress to non-alcoholic steatohepatitis and ultimately to cirrhosis. Genome-wide association studies have provided novel insights into the genetic determinants of hepatic steatosis. Sequence variations in two genes were shown to confer susceptibility to fatty liver disease. The patatin-like phospholipase domain-containing 3 (PNPLA3) is involved in hepatocellular lipid droplet remodelling and very low-density lipoprotein (VLDL) secretion; the I148M variant is a determinant of hepatic steatosis triggered by a number of environmental factors. Additionally, the transmembrane 6 superfamily member 2 (TM6SF2) E167K gene variant, which interferes with VLDL secretion, was shown to increase susceptibility to progressive non-alcoholic steatosis by compartmentalisation of lipids within hepatocytes. This association thus refutes the idea that long-term storage of fatty acids in hepatocytes as triglycerides is benign. Other variants, including rare mutations, involved in the regulation of hepatocellular lipid metabolism, are also being investigated.

Future challenges include elucidating the molecular mechanisms underlying the association between gene variants and progressive liver disease, as well as the impact of gene variants in risk stratification, which will hopefully offer potential novel therapeutic targets.

References

Kozlitina J, Smagris E, Stender S, Nordestgaard BG, Zhou HH, Tybjærg-Hansen A, Vogt TF, Hobbs HH, Cohen JC. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet 2014; 46:352-6.

Wang Y, Gusarova V, Banfi S, Gromada J, Cohen JC, Hobbs HH. Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion. J Lipid Res 2015;56:1296-307.

Li JZ, Huang Y, Karaman R, Ivanova PT, Brown HA, Roddy T, Castro-Perez J, Cohen JC, Hobbs HH. Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. J Clin Invest 2012;122:4130-44.​

Heribert Schunkert, Germany: GWAS for coronary artery disease

Heribert Schunkert.gif Heribert Schunkert is Professor of Cardiology and Director of the Cardiology Department of the German Heart Center, Munich, Germany. After completing undergraduate training at Staatsexamen, West Germany and Rheinisch-Westfälisch Technische Hochschule, Aachen, Germany, Dr Schunkert undertook a research fellowship at Brigham and Women’s Hospital, and clinical fellowships in cardiology at Beth Israel Hospital and Universitätsklinikum, Regensburg, and interventional cardiology at Massachusetts General Hospital. He was appointed Director of the Cardiology Department of the German Heart Center Munich and full Professor of the Technische Universität München in 2012. His research focuses on the molecular biology and genetics of multifactorial cardiovascular disease, with involvement in the EU-sponsored project Cardiogenics, and the European-American Leducq network CADgenomics to identify the genetic roots of myocardial infarction. Professor Schunkert is a member of the Deutsche Gesellschaft für Innere Medizin, Deutsche Gesellschaft für Kardiologie - Herz- und Kreislaufforschung and the International Society of Hypertension, and is the recipient of awards from the German Society of Cardiology, the German Society of Hypertension, and the German Society of Preventive and Rehabilitative Medicine. 

Genome-wide association studies (GWAS) have been extensively used to study common complex diseases such as coronary artery disease (CAD). To date, GWAS have identified 153 suggestive CAD loci; however, these variants only explain about 10% of genetic variability in susceptibility to CAD, leaving ∼90% of CAD heritability unexplained. In part this unexplained heritability may be due to possible context-dependent risk variants, which tend to operate only under certain environmental influences, typically over a shorter period and involving later stages of disease development. Such context-dependent risk variants are unlikely to be detected in traditional GWAS analyses.

Systems genetics may offer a complementary approach to uncovering a substantial part of this missing CAD heritability. Such an approach involves the integration of genetic and genomic datasets to build network models of relevant molecular processes, thus offering the possibility of identifying key "drivers" of disease, and ultimately novel diagnostic and therapeutic opportunities. Clinical studies that include intermediate phenotypes, and screening patients over a range of disease phenotypes, are key challenges for this approach. Ultimately, systems genetics may offer the key to resolving the puzzle of unexplained CAD heritability, and the possibility of individually tailored preventive and individual patient care.

References

Jansen H, Samani NJ, Schunkert H. Mendelian randomization studies in coronary artery disease. Eur Heart J 2014;35:1917-24.

Brænne I, Civelek M, Vilne B, Di Narzo A, Johnson AD, Zhao Y, Reiz B, Codoni V, Webb TR, Foroughi Asl H, Hamby SE, Zeng L, Trégouët DA, Hao K, Topol EJ, Schadt EE, Yang X, Samani NJ, Björkegren JL, Erdmann J, Schunkert H, Lusis AJ; Leducq Consortium CAD Genomics. Prediction of causal candidate genes in coronary artery disease loci. Arterioscler Thromb Vasc Biol 2015;35:2207-17.

Ghosh S, Vivar J, Nelson CP, Willenborg C, Segrè AV, Mäkinen VP, Nikpay M, Erdmann J, Blankenberg S, O'Donnell C, März W, Laaksonen R, Stewart AF, Epstein SE, Shah SH, Granger CB, Hazen SL, Kathiresan S, Reilly MP, Yang X, Quertermous T, Samani NJ, Schunkert H, Assimes TL, McPherson R. Systems Genetics Analysis of Genome-Wide Association Study reveals novel associations between key biological processes and coronary artery disease. Arterioscler Thromb Vasc Biol 2015;35:1712-22.​

Teri A. Manolio, USA: Leading the way to genetics and pharmacogenomics in the clinic

Teri A. Manolio.jpg Teri A. Manolio is Director of the Division of Genomic Medicine, National Human Genome Research Institute, Rockville, Maryland, Professor of Medicine at the Uniformed Services University of the Health Sciences, and is a practicing clinician at the Walter Reed National Military Medical Center, Bethesda. She completed undergraduate training at the University of Maryland, and her PhD in human genetics and genetic epidemiology at the Johns Hopkins School of Hygiene and Public Health. Dr Manolio was previously at the National Institute of Health National Heart, Lung, and Blood Institute where she was involved in large-scale cohort studies such as the Cardiovascular Health Study and the Framingham Heart Study. Her research interests focus on genome-wide association studies of complex diseases, ethnic differences in disease risk, integrating genomic research into electronic medical records, and incorporating genomic findings into clinical care.

Genome-wide association studies, DNA sequencing studies and other genomic studies are identifying an increasing number of genetic variants associated with clinical phenotypes that have application in diagnosis, and preventive and treatment strategies. The implications of this shift in clinical medicine are enormous, not only for physicians but also for healthcare systems and policy makers, who have to deal with the cost, logistics, new technologies and ethics of transitioning to an era of personalised care.

To date, translation of such knowledge to routine clinical practice has been limited. A key reason has been the lack of an accessible comprehensive evidence base for clinicians. The advent of integration of genome-scale analysis into clinical care necessitates new thinking on approaches to collecting and characterising data on the clinical implications of genetic variants, developing consensus for their application, and improving the accessibility of such information to clinicians. 

To address these multiple challenges, the National Human Genome Research Institute has initiated research programmes involving next-generation sequencing in the management of polygenic conditions, workup of undiagnosed conditions, and identification of variants associated with clinical phenotypes. Additionally, the development of educational materials for healthcare personnel working to implement the use of genomic findings in clinical care is also a priority. Collaboration between genetics researchers, data analysts, clinicians and medical institutions, professional societies and regulatory agencies will be critical to addressing the challenges posed by the pharmacogenomics era. Ultimately these complementary actions will ensure the transition of genomics from the bench to the bedside.

References

Manolio TA, Abramowicz M, Al-Mulla F, Anderson W, Balling R, Berger AC, Bleyl S, Chakravarti A, Chantratita W, Chisholm RL, Dissanayake VH, Dunn M, Dzau VJ, Han BG, Hubbard T, Kolbe A, Korf B, Kubo M, Lasko P, Leego E, Mahasirimongkol S, Majumdar PP, Matthijs G, McLeod HL, Metspalu A, Meulien P, Miyano S, Naparstek Y, O'Rourke PP, Patrinos GP, Rehm HL, Relling MV, Rennert G, Rodriguez LL, Roden DM, Shuldiner AR, Sinha S, Tan P, Ulfendahl M, Ward R, Williams MS, Wong JE, Green ED, Ginsburg GS. Global implementation of genomic medicine: We are not alone. Sci Transl Med 2015;7:290ps13.

Feero WG, Manolio TA, Khoury MJ. Translational research is a key to nongeneticist physicians' genomics education. Genet Med 2014;16:871-3.

Manolio TA, Murray MF; Inter-Society Coordinating Committee for Practitioner Education in Genomics. The growing role of professional societies in educating clinicians in genomics. Genet Med 2014;16:571-2.​

Assam El-Osta, Australia: Epigenetics in atherosclerosis

Assam El-Osta.jpg Dr Assam (Sam) El-Osta is an NHMRC Senior Research Fellow, Head of the Epigenetics in Human Health and Disease Laboratory (incorporating the Epigenomics Profiling Facility) at Baker IDI, Heart and Diabetes Institute, and Professor of Medicine, Monash University, Melbourne, Australia. His research has contributed to understanding the molecular mechanisms whereby epigenetic changes exert positive and negative transcriptional functions in specific model systems, in particular understanding the roles of specific components of regulatory complexes in the regulation of metabolic memory and cardiac hypertrophy. Dr El-Osta is the recipient of numerous awards, including the Australian Society for Medical Research AMGEN 'Australian Medical Researcher of the Year' and Juvenile Diabetes Research Foundation/Macquarie ​Group Foundation 'Diabetes Research Innovation Award for an Early Career Researcher'. 

Elucidation of epigenetic mechanisms, such as those involving DNA methylation and deacetylation, and histone modification, has significantly enhanced understanding of the pathogenesis of atherosclerosis. Importantly, such epigenetic processes are flexible genomic factors that not only allow a change in genome function with external influences, but also stable propagation of gene expression.  Both cell-specific gene expression and environment-mediated changes in expression patterns can be explained by a complex network of modifications to the DNA, histone proteins and the degree of DNA packaging.

Moreover, it is increasingly appreciated that gene-environment interactions, especially in the context of human health and disease, involve epigenetic pathways, and that epigenetic patterns may change in response to environmental exposure or nutritional status. Specific epigenetic influences of dietary glucose and lipid consumption, as well as undernutrition, are observed across numerous organs and pathways associated with metabolism. Recent studies have shown that gene regulation underlying phenotypic determinants of adult metabolic health is influenced by maternal and early postnatal diet.

These emerging concepts suggest new therapeutic potential for targeting the epigenome. Both in vitro and in vivo studies using drugs targeting enzymes involved in epigenetic modifications have shown considerable promise in atherosclerosis treatment. For example, identification of histone deacetylase inhibitors in animal models may offer novel treatments for atrial fibrillation, cardiac hypertrophy and heart failure.  Importantly, cardiovascular epigenomics research may also offer opportunities to combat the escalating pandemic of cardiometabolic disease.

References

Keating ST, El-Osta A. Epigenetics and metabolism. Circ Res 2015;116:715-36

Mathiyalagan P, Keating ST, Du XJ, El-Osta A. Interplay of chromatin modifications and non-coding RNAs in the heart. Epigenetics 2014;9:101-12.

Mathiyalagan P, Keating ST, Du XJ, El-Osta A. Chromatin modifications remodel cardiac gene expression. Cardiovasc Res 2014;103:7-16.​

Session II: Lipid biolo​​gy, new insights

Rudolf Zechner, Austria: Pathophysiology of intracellular and intravascular lipolysis

Rudolf Zechner.jpg Rudolf Zechner is Professor of Biochemistry, the Institute of Molecular Biosciences at the University of Graz, Austria. Professor Zechner obtained his Ph.D. in chemistry from the University of Graz, followed by postdoctoral studies at the Medical School of this university, before working as a Research Associate at the Laboratory of Biochemical Genetics and Metabolism, Rockefeller University, New York, USA. His contributions to the field of lipid metabolism include investigation of the physiological role of lipoprotein lipase and the function of hormone-sensitive lipase during fat cell lipolysis, and the discovery of adipose-triglyceride lipase (ATGL) and its coactivator protein CGI-58. ATGL/CGI-58-mediated triglyceride hydrolysis represents the rate-limiting step in fat catabolism in adipose and non-adipose tissues. Ongoing research in his laboratory is focused on understanding the mechanisms underlying the lipolytic process, defining the role of lipolysis in lipid-mediated signal transduction, and investigating the role of lipolysis in cancer and cancer-associated cachexia. Professor Zechner was awarded the 2015 Louis-Jeantet Prize for Medicine for his work in the field of lipid and energy metabolism.

All organisms use fatty acids (FAs) for energy substrates and as precursors for membrane and signalling lipids; however, triglycerides (TGs), the form in which FAs are transported and stored, are not able to cross the cell membrane. Lipolysis is key to this process. Recent discoveries, including that of glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1), the molecule that moves lipoprotein lipase (LPL) from the interstitial spaces to the capillary lumen, and adipose triglyceride lipase (ATGL) and comparative gene identification-58 (CGI-58), key to the hydrolysis of TGs within cells, have extended understanding of the underlying mechanisms. Despite this, a number of questions remain, including the molecular basis for LPL–GPIHBP1 interactions, as well as the possibility that this molecule may play a role in the margination of triglyceride-rich lipoproteins along the surface of capillaries.

Two other enzymes of the same family, hepatic lipase (HL) and endothelial lipase (EL), participate in the remodelling of plasma lipoproteins. The physiologic roles of these lipases are less well defined. Evidence to date implies that HL and EL fine-tune a complex system of lipoprotein processing, thus affecting the delivery of lipid nutrients to specific cell types.

Considering the central role of lipases in lipid and energy metabolism, it is not surprising that they have proven to be relevant to human disease. Indeed, a potential role of lipolysis in the development of obesity and insulin resistance has been suggested. Lipases have also been shown to affect tumour proliferation. These insights stimulate ongoing research into their therapeutic potential for a range of conditions, including the treatment of insulin resistance and type 2 diabetes.

References

Schweiger M, Zechner R. Breaking the barrier--Chaperone-mediated autophagy of perilipins regulates the lipolytic degradation of fat. Cell Metab 2015;22:60-1.

Schreiber R, Hofer P, Taschler U, Voshol PJ, Rechberger GN, Kotzbeck P, Jaeger D, Preiss-Landl K, Lord CC, Brown JM, Haemmerle G, Zimmermann R, Vidal-Puig A, Zechner R. Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity. Proc Natl Acad Sci U S A 2015 Oct 27. pii: 201516004. [Epub ahead of print]

Heier C, Radner FP, Moustafa T, Schreiber R, Grond S, Eichmann TO, Schweiger M, Schmidt A, Cerk IK, Oberer M, Theussl HC, Wojciechowski J, Penninger JM, Zimmermann R, Zechner R. G0/G1 Switch Gene 2 regulates cardiac lipolysis. J Biol Chem 2015;290:26141-50.​

Jörg Heeren, Germany: Adipose tissue browning and metabolic health

 Jorg Heeren.jpgJörg Heeren is Professor at the Institute for Biochemistry and Molecular Cell Biology, University Medical Center Hamburg‐Eppendorf, Germany. His research interests focus on the molecular mechanisms underlying abnormalities in lipid and lipoprotein metabolism, which are associated with the development of chronic inflammatory disorders such as atherosclerosis and type 2 diabetes. Professor Heeren elucidated the intracellular sorting of lipoprotein components, which provided a new intracellular link between the metabolism of triglyceride‐rich lipoproteins and high-density lipoprotein cholesterol. More recently, he has used state of the art nanoparticle‐based metabolic imaging to establish a key role for the brown adipose tissue in the regulation of plasma triglyceride levels​.

Brown adipose tissue (BAT) is a metabolically highly active organ, which lowers plasma levels of atherogenic triglyceride-rich lipoproteins and thereby protects against the development of atherosclerosis. The development of the inducible brown adipocytes, or 'beige/bright cells', is termed 'browning'. In infants, BAT accounts for about 5% of total body mass, and even in adults it appears that there are residual reserves in the shoulders and neck, although the total number of brown adipocytes in the body varies extensively.

Studies have shown that BAT activity is increased when mice are overfed, thus protecting them from obesity. Furthermore, in humans, an increase in BAT was associated with a lower body weight. Additional studies in mice have shown that short-term exposure to cold increases BAT activity, accelerating plasma clearance of triglycerides, a process dependent on local lipoprotein lipase activity. In pathophysiological settings, cold exposure corrected hyperlipidaemia and improved the effects of insulin resistance. Thus, while an unhealthy diet and sedentary lifestyle are the two chief drivers of the obesity epidemic, lack of exposure to temperature variation could be a subtle contributor. Taken together, these findings imply that BAT activity controls vascular lipoprotein homeostasis by increasing the turnover of triglyceride-rich lipoproteins and uptake into BAT, suggesting therapeutic potential for the management of elevated triglycerides, as well as in obesity. Determining which genes control the development of white and brown adipose tissue represents the first step in this novel therapeutic approach. 

References

Berbée JF, Boon MR, Khedoe PP, Bartelt A, Schlein C, Worthmann A, Kooijman S, Hoeke G, Mol IM, John C, Jung C, Vazirpanah N, Brouwers LP, Gordts PL, Esko JD, Hiemstra PS, Havekes LM, Scheja L, Heeren J, Rensen PC. Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development. Nat Commun 2015;6:6356.

Dijk W, Heine M, Vergnes L, Boon MR, Schaart G, Hesselink MK, Reue K, van Marken Lichtenbelt WD, Olivecrona G, Rensen PC, Heeren J, Kersten S. ANGPTL4 mediates shuttling of lipid fuel to brown adipose tissue during sustained cold exposure. Elife 2015 Oct 17;4. [Epub ahead of print]

Hoffmann LS, Etzrodt J, Willkomm L, Sanyal A, Scheja L, Fischer AW, Stasch JP, Bloch W, Friebe A, Heeren J, Pfeifer A. Stimulation of soluble guanylyl cyclase protects against obesity by recruiting brown adipose tissue. Nat Commun 2015;6:7235.​

David J. Mangelsdorf, USA: Nuclear receptors in lipid metabolism

 David J. Mangelsdorf.jpgDavid J. Mangelsdorf holds the Alfred G. Gilman Distinguished Chair in Pharmacology; and the Raymond and Ellen Willie Distinguished Chair in Molecular Neuropharmacology in Honor of Harold B. Crasilneck, at the University of Texas Southwestern, and is an Investigator of the Howard Hughes Medical Institute. After obtaining his PhD in Biochemistry from the University of Arizona, he completed postdoctoral studies at The Salk Institute for Biological Studies. Professor Mangelsdorf is a member of the US National Academy of Sciences. His research interests focus on the molecular biology and role of orphan nuclear receptors in lipid metabolism, most recently nuclear receptor-initiated endocrine signalling pathways that control feeding and fasting responses and are mediated by the fibroblast growth factors FGF19 and FGF21.

Nuclear receptors are ligand-dependent transcription factors involved in many pathways, including lipid metabolism. Discovery of retinoid X receptor (RXR) provided a proof of principle; subsequent research elucidated the peroxisome proliferator-activated receptors (PPARs) and liver X receptor (LXRs). These lipid-activated transcription factors have emerged as key regulators of lipid metabolism and inflammation, exerting both positive and negative control, and thus represent attractive targets for intervention in human metabolic disease.

Recent studies have shown that one of the mediators of PPARα action is the endocrine hormone FGF21. In mice, FGF21 promotes several of the body's adaptive responses to starvation, including the mobilisation of stored fat and its conversion into ketone bodies, suppression of growth and female reproduction, and alterations in sleep/wake cycles. Administration of FGF21 to obese animals and humans led to weight loss, as well as reduction in circulating levels of insulin, triglycerides, and cholesterol. These findings suggest potential for FGF21 in the management of the metabolic syndrome, although other effects, such as bone loss and elevated glucocorticoids, need to be minimised. Current evidence suggests that most of the actions of FGF21 are mediated via the brain, thereby indicating a novel neuroendocrine circuit regulating nutrient metabolism.

While the discovery of these nuclear receptors has provided new opportunities for therapeutic intervention, especially for the treatment of human diseases in which lipids have a central role, a number of unmet goals remain. Chief of these is understanding how nuclear receptors control the transcriptional process, and understanding the factors by which signal dependent transcription factors can activate target gene networks.

References

Patel R, Bookout AL, Magomedova L, Owen BM, Consiglio GP, Shimizu M, Zhang Y, Mangelsdorf DJ, Kliewer SA, Cummins CL. Glucocorticoids regulate the metabolic hormone FGF21 in a feed-forward loop. Mol Endocrinol 2015;29:213-23.

Mansuy-Aubert V, Gautron L, Lee S, Bookout AL, Kusminski C, Sun K, Zhang Y, Scherer PE, Mangelsdorf DJ, Elmquist JK. Loss of the liver X receptor LXRα/β in peripheral sensory neurons modifies energy expenditure. Elife 2015;4.

Evans RM, Mangelsdorf DJ. Nuclear Receptors, RXR, and the Big Bang. Cell 2014;157:255-66.​

Peter Carmeliet, Belgium: Angiogenesis and endothelial cell dysfunction in atherosclerosis: a novel target for treatment


Peter Carmeliet.jpgPeter Carmeliet is a physician and professor at the Katholieke Universiteit Leuven (Leuven, Belgium). He is former director (2008-2015) of the Vesalius Research Center, VIB - KU Leuven  and is heading the Laboratory of Angiogenesis and Vascular Metabolism at the VRC​. His research interests are vasculogenesis, angiogenesis, and vascular endothelial growth factors.  His research group has sought to elucidate the molecular basis of angiogenesis with the aim of translating their findings to therapeutic concepts and ultimately novel treatments. Latest findings indicate that the efficacy of current anti-angiogenic therapy in cancer is limited by intrinsic refractoriness and acquired drug resistance. To overcome this problem, his research team pioneered the study of endothelial cell metabolism during vessel sprouting.  Professor Carmeliet is the recipient of numerous awards, including InBev-Baillet Latour health prize (2010), Ernst Jung-Priz für Medizin (2010), the Blaise Pascal Medal in Medicine and Life Sciences by the European Academy of Sciences (2011), the Münster Heart Center Award (2015), and award of the Noble title of Baron, granted by King Filip of Belgium (2015).

The endothelium plays a key role in regulating blood vessels, influencing angiogenesis as well as physiological function. Changes in both are defining features of various diseases. While angiogenic growth factors such as vascular endothelial growth factor have been a focus, accumulating evidence also implicates metabolism as a co-determinant of endothelial cell (EC) responses. It is thought that maladaptation of EC metabolism results in pathological angiogenesis (as in cancer) or dysfunction (as in diabetes). Furthermore, many of EC metabolic alterations that lead to EC dysfunction are likely induced by cardiovascular risk factors such as such as hypercholesterolaemia, diabetes and obesity.

As a consequence of these findings, targeting EC metabolism is emerging as a novel therapeutic strategy. Two approaches have been used: reverse and forward profiling. While the former is hypothesis-driven, the "forward" strategy is hypothesis-generating, enabling the possibility of identifying novel therapeutic targets in metabolic pathways that are generally not considered to be important in vascular disease. For example, increased EC glucose metabolism is emerging as a key feature of angiogenic and hyper-proliferative ECs, with initial studies showing that targeting EC glucose metabolism attenuates pathological angiogenesis.  Ultimately, profiling of EC metabolism may offer insights as to which pathways are affected in cardiovascular disease, with the ultimate aim of identifying new targets for pharmacological intervention.​

References

Schoors S, Bruning U, Missiaen R, Queiroz KC, Borgers G, Elia I, Zecchin A, Cantelmo AR, Christen S, Goveia J, Heggermont W, Goddé L, Vinckier S, Van Veldhoven PP, Eelen G, Schoonjans L, Gerhardt H, Dewerchin M, Baes M, De Bock K, Ghesquière B, Lunt SY, Fendt SM, Carmeliet P. Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature 2015;520:192-7.

Eelen G, de Zeeuw P, Simons M, Carmeliet P. Endothelial cell metabolism in normal and diseased vasculature. Circ Res 2015;116:1231-44.

Cantelmo AR, Brajic A, Carmeliet P. Endothelial metabolism driving angiogenesis: emerging concepts and principles. Cancer J 2015;21:244-9.​

Session III: Future therapeutic challanges

Karsten Suhre, Qatar: An integrative omics approach in human disease research

Karsten Suhre.jpg Karsten Suhre is Professor of Physiology and Biophysics and Director of the Bioinformatics Core, Weill Cornell Medical College in Qatar. Prior to this appointment, he was Professor of Bioinformatics at the Ludwig-Maximilians-University (Faculty of Biology) in association with the Institute for Bioinformatics and Systems Biology (MIPS) at Helmholtz Zentrum München, Munich, Germany. His research interests focus on metabolomics, specifically human metabolic individuality that may influence susceptibility to complex diseases such as diabetes​.

Evidence from genome-wide association studies indicates that common genetic variants influence the metabolic composition of the individual, and hence their susceptibility to complex diseases such as cardiovascular disease and type 2 diabetes. However, information on the underlying biological processes is often lacking. To unravel the complex mechanisms underlying these molecular processes and to understand how the different functional levels interact with each other, new approaches are required to allow for interrogation of molecular alterations in human disease, hence the development of an integrative 'omics' approach.

Analysis of ​genotype-dependent metabolic phenotype is one example of an 'omics' approach which can provide information on the susceptibility to metabolic traits, thereby allowing clinicians the possibility of tailoring treatment to the individual. Studies to date have identified over 150 genetic loci associated with blood metabolite concentrations, which have provided functional insights relevant for cardiovascular disease. Indeed, most individuals carry one or more risk alleles that may influence susceptibility to disease, response to a specific pharmacotherapy, or dietary or environmental factors.

The 'omics' approach to human disease research is increasingly important in the context of personalized medicine, where treatment decisions are based on patients' omics, demographic, clinical and environmental data, and also offers opportunities for targeted pharmacotherapeutic development.

References

Shin SY, Fauman EB, Petersen AK, Krumsiek J, Santos R, Huang J, Arnold M, Erte I, Forgetta V, Yang TP, Walter K, Menni C, Chen L, Vasquez L, Valdes AM, Hyde CL, Wang V, Ziemek D, Roberts P, Xi L, Grundberg E, The MuTHER Consortium, Waldenberger M, Richards JB, Mohney RP, Milburn MV, John SL, Trimmer J, Theis FJ, Overington JP, Suhre K, Brosnan MJ, Gieger C, Kastenmüller G, Spector TD, Soranzo N. An atlas of genetic influences on human blood metabolites. Nature Genetics 2014;46:543-50.

Petersen AK, Zeilinger S, Kastenmüller G, Römisch-Margl W, Brugger M, Peters A, Meisinger C, Strauch K, Hengstenberg C, Pagel P, Huber F, Mohney RP, Grallert H, Illig T, Adamski J, Waldenberger M, Gieger C, Suhre K. Epigenetics meets metabolomics: An epigenome-wide association study with blood serum metabolic traits. Hum Mol Genet 2014;23:534-45.

Altmaier E, Fobo G, Heier M, Thorand B, Meisinger C, Römisch-Margl W, Waldenberger M, Gieger C, Illig T, Adamski J, Suhre K, Kastenmüller G. Metabolomics approach reveals effects of antihypertensives and lipid-lowering drugs on the human metabolism. Eur J Epidemiol 2014;29:325-36.​

Matthias H. Tschöp, Germany: Drugs for metabolic disorders and obesity

 Matthias H. Tschöp.jpgMatthias Tschöp is Research Director of the Helmholtz Diabetes Center and Director of the Institute for Diabetes and Obesity, Helmholtz Zentrum München, Germany. He also holds the Chair of the Division of Metabolic Diseases at Technische Universität München, and is Adjunct Professor at Yale University, New Haven, Connecticut, USA. Professor Tschöp received his M.D. from Ludwig-Maximilians-Universität in Munich, and completed a postdoctoral fellowship at the Eli Lilly Research Laboratories, USA.  After establishing his independent research laboratory at the German Institute of Human Nutrition Potsdam-Rehbrücke in Germany in 2002 and 2003, he returned to Cincinnati where he led a research institute as a tenured Professor of Endocrinology and Diabetes at the University of Cincinnati Metabolic Diseases Institute.  Until 2009, Professor Tschöp was the Arthur Russell Morgan Endowed Chair of Medicine and Research Director of the University of Cincinnati’s Metabolism Center of Excellence for Diabetes and Obesity. His research focuses on molecular investigation of diabetes and obesity. A key area of interest is the role of gut-brain communication in the regulation of adiposity, glucose homeostasis and energy metabolism. Professor Tschöp is the recipient of numerous awards including the Alexander von Humboldt Professorship, the highest-endowed German research award, in 2012.

The escalating pandemics of diabetes and obesity substantially impact morbidity, mortality and healthcare costs. Beyond lifestyle, the cornerstone of management, and bariatric surgery for management of obesity, pharmacotherapeutics options are so far limited.

The ideal anti-obesity drug would produce sustained weight loss with minimal side effects. However, given that the mechanisms that regulate energy balance overlap with other physiological functions, and are also influenced by a range of factors that compromise the efficacy of pharmacological interventions, it is not surprising that anti-obesity drug discovery research and development is littered with failure. Additionally, side effects have proved to be an issue with a number of new agents.

New treatments for obesity that are both better tolerated and more efficacious are therefore urgently needed. In this context, advances in understanding of the basic neurobiology of hunger and satiety, especially in the case of ghrelin, cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), and of homeostatic mechanisms related to leptin and its upstream pathways in the hypothalamus, suggest new potential. Of note, GLP-1 receptor agonists are promising, not only because these agents are now available as diabetes treatments but also because of potential body-weight-lowering effects in humans. It is likely that the development of efficacious and safe anti-obesity treatments will require multiple strategies to allow for the tailoring of therapy to the individual to ensure the sustainability of weight loss.  

References

Schwenk RW, Baumeier C, Finan B, Kluth O, Brauer C, Joost HG, DiMarchi RD, Tschöp MH, Schürmann A. GLP-1-oestrogen attenuates hyperphagia and protects from beta cell failure in diabetes-prone New Zealand obese (NZO) mice. Diabetologia 2015;58:604-14

Finan B, Yang B, Ottaway N, Smiley DL, Ma T, Clemmensen C, Chabenne J, Zhang L, Habegger KM, Fischer K, Campbell JE, Sandoval D, Seeley RJ, Bleicher K, Uhles S, Riboulet W, Funk J, Hertel C, Belli S, Sebokova E, Conde-Knape K, Konkar A, Drucker DJ, Gelfanov V, Pfluger PT, Müller TD, Perez-Tilve D, DiMarchi RD, Tschöp MH. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med 2015;21:27-36.

Pfluger PT, Kabra DG, Aichler M, Schriever SC, Pfuhlmann K, García VC, Lehti M, Weber J, Kutschke M, Rozman J, Elrod JW, Hevener AL, Feuchtinger A, Hrabě de Angelis M, Walch A, Rollmann SM, Aronow BJ, Müller TD, Perez-Tilve D, Jastroch M, De Luca M, Molkentin JD, Tschöp MH. Calcineurin links mitochondrial elongation with energy metabolism.  Cell Metab 2015 Sep 23. [Epub ahead of print]​

Erik S.G. Stroes, The Netherlands: The use of novel therapies in atherosclerosis: from antibodies to nanotechnology

​ Erik S.G. Stroes.jpgErik Stroes is Chairman, Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands. Over the last two decades, the role of the vessel wall in atherogenesis development has been his major research interest. His current focus of investigation is lipid disorders in relation to atherogenesis. Professor Stroes has participated in numerous lipid lowering trials using surrogate markers such as intima media thickness (ENHANCE study) and flow mediated dilation. More recently, 3T-MRI has been added as a surrogate marker for vascular disease progression. In addition, novel gene defects contributing to lipid disorders have been pursued by collecting families with autosomal dominant forms of these disorders. In parallel, Professor Stroes has been involved in the development of novel therapeutic agents for the management of dyslipidaemia, including lipoprotein lipase gene therapy, apolipoprotein B antisense treatment and reconstituted high-density lipoprotein infusion.

Much of the emphasis on novel treatments in atherosclerosis has been on apolipoprotein (apo)B-containing lipoproteins, especially in view of extensive information establishing the causality of the predominant apoB-containing lipoprotein, low-density lipoprotein (LDL). In 2015, the first of the monoclonal antibody therapies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) were licensed in Europe and the USA. These treatments have been shown to provide reductions in LDL cholesterol of 50-60% against a background of statin therapy, with consistency in response demonstrated across the spectrum of high cardiovascular risk patients. No significant safety signal has been observed to date, even at very low LDL cholesterol levels. Exploratory analyses suggest potential for reduction in cardiovascular outcomes, although definitive evidence for both efficacy and long-term safety is still needed from ongoing studies with hard clinical endpoints.

In addition, increasing knowledge of plaque biology has driven the development of nanotechnology as a strategy to facilitate management of atherosclerosis. This approach is already starting to have an impact in the detection, diagnosis and treatment of atherosclerosis. Of key interest is the development of adaptive biosensors for detection of disease-specific biomarkers, as well as the use of plaque homing cells for long-term imaging and therapy delivery. The use of multifunctional nanoscale devices capable of providing clinical feedback or releasing therapy in response to molecular cues is another possibility. Finally, given that atherosclerosis is a chronic inflammatory condition, the use of nanoparticle-based delivery of pharmacotherapy to inhibit local macrophage proliferation within the plaque may offer future potential for the attenuation of atherosclerosis.  

References

Verweij SL, van der Valk FM, Stroes ES. Novel directions in inflammation as a therapeutic target in atherosclerosis. Curr Opin Lipidol 2015 Sep 18. [Epub ahead of print]

Bernelot Moens SJ, van Capelleveen JC, Stroes ES. Inhibition of ApoCIII: the next PCSK9? Curr Opin Lipidol 2014;25:418-22.

van der Valk FM, Kroon J, Potters WV, Thurlings RM, Bennink RJ, Verberne HJ, Nederveen AJ, Nieuwdorp M, Mulder WJ, Fayad ZA, van Buul JD, Stroes ES. In vivo imaging of enhanced leukocyte accumulation in atherosclerotic lesions in humans. J Am Coll Cardiol 2014;64:1019-29.​

Daniel Gaudet, Canada: Lessons learned from emerging therapies for severe hypertriglyceridaemia

 Gaudet.PNGDaniel Gaudet is Professor of Medicine at Université de Montréal, Canada. He founded the Université de Montréal Community Genomic Medicine Center, the Lipid Research Group, as well as the ECOGENE-21 research group. Dr. Gaudet is currently the scientific director of the Genome Quebec Biobank. His research interests focus on rare genetic lipid disorders and their associated impact on risk for cardiovascular disease, type 2 diabetes, pancreatitis and metabolic consequences to obesity. Dr. Gaudet was the recipient of the Genesis Genome Quebec Biotechnology of Tomorrow Award in 2012.  

Severe hypertriglyceridaemia is associated with an increased lifelong risk of recurrent pancreatitis, usually severe and often associated with complications including pancreatic insufficiency, necrosis and abscess. Treatment options are limited, and often compromised by genetic defects and lifestyle risk factors, highlighting the need for new approaches.

Given that severe hypertriglyceridaemia often has a monogenic basis, the rarity of these conditions poses issues when investigating potential new therapies. Furthermore, the most clinically relevant endpoint, as well as the risk versus benefit of treatment, warrants consideration. For example, in clinical trials in patients with lipoprotein lipase deficiency, investigation of alipogene tiparvovec did appear to reduce triglycerides, although in most cases the effect was transient. Due to the lack of a placebo control, mandated for ethical and practical reasons, patients were followed before and after treatment for both primary (triglycerides) and secondary (incidence of pancreatitis) endpoints; the therapy was finally approved on the basis of reduced risk of pancreatitis.

Recent data indicate potential for ISIS 304801, a second-generation antisense therapy to apolipoprotein (apo) CIII, a key regulator of triglyceride-rich lipoprotein metabolism. Mendelian randomisation studies showing loss-of-function mutations in the APOC3 gene coding for apoCIII were associated with low levels of triglycerides, as well as a lower risk of cardiovascular disease, provided a rationale for this approach. In patients with familial chylomicronaemia, treatment resulted in dose-dependent reductions in triglycerides, either as monotherapy or as add-on to fibrate therapy. However, there was also a corresponding increase in plasma low-density lipoprotein cholesterol levels, although this was less pronounced when combined with fibrate therapy. While a promising therapy, evaluation of the long-term efficacy of this treatment in a larger number of patients is still needed. Insights from genome-wide association studies also suggest novel targets for transcriptional and post-transcriptional regulation of triglyceride-rich lipoprotein metabolism which may offer future potential.

References

Gaudet D, Alexander VJ, Baker BF, Brisson D, Tremblay K, Singleton W, Geary RS, Hughes SG, Viney NJ, Graham MJ, Crooke RM, Witztum JL, Brunzell JD, Kastelein JJ. Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia. N Engl J Med 2015;373:438-47.

Rosenson RS, Davidson MH, Hirsh BJ, Kathiresan S, Gaudet D. Genetics and causality of triglyceride-rich lipoproteins in atherosclerotic cardiovascular disease. J Am Coll Cardiol 2014;64:2525-40.

Gaudet D, Brisson D, Tremblay K, Alexander VJ, Singleton W, Hughes SG, Geary RS, Baker BF, Graham MJ, Crooke RM, Witztum JL. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med 2014;371:2200-6.​



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