Day 2 :
Keynote Forum
M. Raj Lakshman
The George Washington University, USA
Keynote: Brown fat and metabolic syndrome
Time : 10:00-10:30
Biography:
Professor Lakshman is currently the Director of Research Laboratories and the Chief of Lipid Research at the VA Medical Center, Washington, D.C. He also has joint appointments as a Professor in the Departments of Biochemistry & Molecular Medicine as well as in the Department of Medicine at the George Washington University, Washington, D.C. He directs studies in the areas of Alcoholism, Alcoholic Liver Disease, Oxidative Stress, Coronary Artery Disease, Lipids & Lipoproteins, Metabolic & Genetic Obesity, Hepatotoxins, Gene Regulation & Expression. He joined the National Institute of Health, to work on Alcoholic Hyperlipidemia under the able guidance of Professors Richard Veech and Nobel Laureate, Hans Krebs. In 1979, he received the prestigious VA Research Career Scientist Award working in the field of Alcohol and Alcoholism at the VA Medical Center, Washington, D.C. He was honored the “Washington Heart Ball” Research Award in 1990 in the field of Hyperlipidemia. Professor Lakshman has chaired as well as has been an invited speaker in several Symposia in International and National Meetings all over the world. He is a member of several professional societies such as American Society of Biochemistry & Molecular Biology, American Institute of Nutrition, etc.
Abstract:
Currently, there is world-wide epidemic of Obesity, Metabolic Syndrome, and particularly, Childhood obesity. The primary cause for this alarming malady is defective energy expenditure Linked to metabolic disease. Metabolic syndrome is a complex disease of the industrialized societies that encompasses obesity, type 2 diabetes, hypertension and hyperlipidemia. Poor dietary habits and sedentary life style lead to impaired adipose tissue fuel handling, and ectopic lipid deposition in vital organs such as liver, pancreas, muscle and heart. Obesity and its metabolic consequences represent a significant clinical problem. Thermodynamically speaking, obesity is due to a gross imbalance in energy intake and expenditure. However, lifestyle interventions by reducing energy intake and/or increasing energy expenditure have proved to be ineffective in the prevention and/or treatment of obesity, primarily because of poor longterm adherence to such interventions. Mitochondria, the power house of mammalian cells, play a major role in energy expenditure. Significantly, roughly 80% of mitochondrial membrane potential generated by fuel oxidation is responsible for ATP production, whereas the remaining 20% is dissipated as heat energy due to mitochondrial uncoupling reactions. The uncoupling of mitochondrial phosphorylation with the assistance of the uncoupling protein 1 (UCP1) represents a viable mechanism for the dissipation of fuel energy essentially as heat, and could potentially lead to weight control.
Our body has both UCP1-poor White Adipose Tissue and (WAT) and UCP1-rich Brown/Beige Adipose Tissue (BAT). While BAT was considered to be present only in the neonates, the recent rediscovery of BAT depots in adult humans has revived tremendous promise in the manipulation of mitochondrial uncoupling reactions as a means to transform fuel energy into heat, thereby counteracting obesity and Metabolic Syndrome. A number of tissues and cell types have been found to secrete factors that regulate brown and beige adipose activity through systemic, autocrine and paracrine mechanisms. Dr. Lakshman will discuss the current status of the relative roles of WAT versus BAT in the maintenance of lipid homeostasis in humans with special emphasis on potential mechanisms by which the relative proportions of WAT and BAT can be controlled by tissue-specific strategies that could lead to a therapeutic role of UCP1 in the treatment of Obesity and Metabolic Syndrome.
Keynote Forum
Charles H. Hennekens
Florida Atlantic University, USA
Keynote: Statins in the Treatment and Prevention of Cardiovascular Diseases: Current and emerging clinical and public health challenges
Time : 10:30-11:00
Biography:
Professor Hennekens is the first Sir Richard Doll Professor and Senior Academic Advisor to the Dean. He was first John Snow and first Eugene Braunwald Professor of Medicine at Harvard Medical School and first Chief of Preventive Medicine at Brigham and Women’s Hospital. His 173 H-index ranks him #14 Top Scientist in World. He was 3rd most widely cited medical researcher in world and 5 of top 20 were former trainees. He is #81 in world history for saving 1.1 million lives. He is a Fellow of the American College of Preventive Medicine (FACPM) and the American College of Cardiology (FACC).
Abstract:
CVD is and will remain the leading avoidable cause of premature deaths in the US and is rapidly becoming so worldwide. The totality of available evidence on statins in the treatment and prevention of CVD is robust and includes over 200,000 randomized subjects from dozens of large scale trials designed a priori to test the hypothesis and their meta-analyses. In secondary and high-risk primary prevention, clinicians should more widely prescribe evidence based doses of statins as first line drugs. In low-risk primary prevention subjects previously considered ineligible, statins also have a favorable benefit to risk ratio. Statins should be adjuncts, not alternatives to TLCs of proven benefit including weight loss, physical activity, avoidance or cessation of cigarettes and diet. In addition, any decision to prescribe statins should be based on individual clinical judgments that include all the risk factors of an individual and not simply those in any risk algorithm. Further, for individuals optimally treated with a statin and the responsible clinician wishes to prescribe additional therapy, the data are far less persuasive die nicotinic acid, omega-3 fatty acids, fibrates and ezetimibe. Finally, new and novel therapies, even if eventually proven to have a favorable benefit to risk ratio, will generally be adjuncts not alternatives to statins The utilization of guidelines as guidance for clinicians should lead to more widespread and judicious prescription of evidence based doses of statins which, in turn, will lead to even greater net clinical and public health benefits in the treatment and prevention of CVD.
Keynote Forum
Edward A. Dennis
University of California at San Diego, USA
Keynote: Phospholipase A2 Substrate and Inhibitor Specificity Revealed at the Molecular Level
Time : 12:10-12:40
Biography:
Dennis is Distinguished Professor of Chemistry and Biochemistry and of Pharmacology in the School of Medicine at the University of California at San Diego (UCSD). He received his BA from Yale and a Ph.D. from Harvard and was a postdoctoral fellow at Harvard Medical School. He has served as Chair of the Department of Chemistry and Biochemistry. His research focus has been on the mechanism of the enzyme phospholipase A2, signal transduction, inflammation, lipid metabolism, eicosanoid action, and lipidomics. He authored over 380 publications, is Editor-in-Chief of the Journal of Lipid Research and Director of the LIPID MAPS Consortium.
Abstract:
The phospholipase A2 (PLA2) superfamily exhibits a large array of functions, but of special interest is the inflammatory cascade which is initiated by the release of free arachidonic acid by some types of phospholipase A2, all of which interact with membrane phospholipids [Chem Rev, 111, 6130-85 (2011)]. However, different PLA2 types have unique three-dimensional structures and unique catalytic residues as well as specific tissue localization, distinct biological functions, and with which membrane phospholipids have unique allosteric interactions. Understanding how the different PLA2s associate with phospholipid membranes, specific phospholipid substrate molecules, and inhibitors on a structural and molecular basis has advanced in recent years due to the introduction of hydrogen/deuterium exchange mass spectrometry approaches [Annu Rev Biochem, 80, 301-25 (2011)]. We will emphasize recent results utilyzing hydrogen/deuterium exchange approaches and molecular dynamics [J Biol Chem, 288, 1806-13 (2013)] on the major types of PLA2, including secretory s-PLA2, cytosolic c-PLA2, lipoprotein-associated LpPLA2, and calcium-independent iPLA2 with inhibitors [J Am Chem Soc, 135, 1330-37 2013)] and substrates. We will also discuss new results on the precise nature and molecular dynamics of the interaction of these enzymes with specific substrate phospholipids pulled into the catalytic site from membranes [Proc Natl Acad Sci U S A, 112, E516-25 (2015)] and how new potent specific inhibitors block substrate phospholipid binding. Phospholipase A2 is the initiator of eicosanoid formation in inflammatory processes, so it is a critical enzyme and inhibitors could provide new approaches to disease treatment. [Nature Immunology Reviews, 15, 511-523 (2015)] [NIH GM 20,508-40]
- Lipids in Signaling and Intracellular Trafficking | Lipids: Nutrition and Health| Lipids in Molecular Medicine
Session Introduction
M. Raj Lakshman
The George Washington University, USA
Title: Synergy between ASH and NASH
Time : 11:20-11:45
Biography:
Professor Lakshman is currently the Director of Research Laboratories and the Chief of Lipid Research at the VA Medical Center, Washington, D.C. He also has joint appointments as a Professor in the Departments of Biochemistry & Molecular Medicine as well as in the Department of Medicine at the George Washington University, Washington, D.C. He directs studies in the areas of Alcoholism, Alcoholic Liver Disease, Oxidative Stress, Coronary Artery Disease, Lipids & Lipoproteins, Metabolic & Genetic Obesity, Hepatotoxins, Gene Regulation & Expression. He joined the National Institute of Health, to work on Alcoholic Hyperlipidemia under the able guidance of Professors Richard Veech and Nobel Laureate, Hans Krebs. In 1979, he received the prestigious VA Research Career Scientist Award working in the field of Alcohol and Alcoholism at the VA Medical Center, Washington, D.C. He was honored the “Washington Heart Ball” Research Award in 1990 in the field of Hyperlipidemia. Professor Lakshman has chaired as well as has been an invited speaker in several Symposia in International and National Meetings all over the world. He is a member of several professional societies such as American Society of Biochemistry & Molecular Biology, American Institute of Nutrition, etc.
Abstract:
Fatty Liver (hepatosteatosis) is the earliest abnormality in the pathogenesis of Alcoholic Steatohepatitis (ASH) and Non-Alcoholic Steatohepatitis (NASH) and due either to metabolic risk factors associated with chronic alcohol abuse or with insulin resistance and/or metabolic syndrome in the absence of alcohol consumption. When unchecked, both ASH and NASH lead to liver fibrosis, cirrhosis, hepatocellular carcinoma (HCC) and eventual death. A number of common mechanisms contribute to the above various stages of hepatocyte injury including lipotoxicity, endotoxin release, oxidative and ER stress leading to increased pro-inflammatory cytokines that stimulate hepatic fibrogenesis and cirrhosis by activating the quiescent hepatic stellate cells (HSC) into myofibroblasts. Significantly, patients with either ASH or NASH respond favorably to early treatment modalities to reduce hepatic fat accumulation and consequent increased inflammatory signaling and activation of hepatic stellate cells. Although the pathogenic pathways associated with ASH and NASH are seemingly similar, differentiation of the molecular mechanism/s of the pathogenesis of these liver diseases is critical in identifying the unique molecular signatures especially in the early diagnosis of ASH and NASH. Current clinical practice requires the invasive biopsy procedure for the conclusive diagnosis of ASH and NASH. Micro RNAs (miRNAs) are ~22 nucleotide non-coding sequences that bind to the 3'-untranslated region of target transcripts and regulate gene expression by degradation of target mRNAs or inhibition of translation. Emerging studies may prove to establish miRNAs as excellent non-invasive tools for the early diagnosis of various stages of liver diseases.
Raman Puri
Lipid Association of India, India
Title: Implementation of lipid association of India (LAI) expert consensus statement on management of dyslipidaemia will be an investment for prevention of CVD in India Raman Puri1, 2
Time : 11:45-12:10
Biography:
Raman Puri is working as Senior Interventional Cardiologist at IP Apollo Hospital since October 1996 and was Head of Cardiology Unit in Ram Manohar Lohia Hospital. He is the Founder and Chairman of Lipid Association of India established since 2012. He established the Department of Cardiology in Safdarjung Hospital in 1992. He has also contributed to advances in intervention. He had worked as fellow in Interventional Cardiology in Hospital Charles Nicolle, France and National Cardiovascular Center, Osaka-Japan. His work involves interventions including coronary angiographies, coronary angioplasty and stenting, valvuloplasty, device closure of the heart defects such as ASD, PDA, left atrial appendage closure for prevention of stroke in patients with atrial fibrillation and pacemaker implantation besides clinical cardiology practice. He has special interest in preventive cardiology especially dyslipidaemia and hypertension.
Abstract:
The burden of cardiovascular disease (CVD) in Indian population is high regardless of their country of residence. World Health Organisation estimates 60% of world’s cardiac patients will be Indians with 50% of CVD related deaths occurring in patients below 70 years compared to 23% in the West. Indian ethnicity is regarded as a non modifiable risk factor by CVD prevention guidelines. The mission of the LAI expert consensus statement on management of dyslipidaemia is to address early onset and higher risk for CVD in this population by simplifying the process of identification at an early age as well as to intensify treatment to aggressively mange risk factors including life style changes at a lower risk levels compared to other global guidelines. The choice of a lower target of LDL C of < 50 mg/dl and non-HDL C of < 80 mg/dl for the high risk group as well as secondary prevention will help India achieve the expected reduction in CVD. Adoption of non HDL-C as a co primary target will address atherogenic lipoprotein pattern that incorporates the low HDL and high Triglyceride level in this population. The consensus statement recommends a lower threshold for not using statin at < 5% but the use of life time risk assessment in this group. Reducing the age threshold for screening for CVD risk to 18 years (at entry to university education) is likely to have a greater impact in reducing the CVD epidemic. While considerable success is seen with the effort taken by LAI to implement the advice to Indian physicians, adoption of this expert advice by governmental bodies, other professional organisation within and outside India will provide a greater impetus to reduce premature CVD in this high risk population irrespective of their place of residence.
- Special Session on Phospholipid and sphingolipid signaling: Challenges for the development of novel medicinal agents
Chair
George Kokotos
University of Athens, Greece
Co-Chair
Sasanka Ramanadham
University of Alabama at Birmingham, USA
Session Introduction
Edward A Dennis
University of California at San Diego, USA
Title: Phospholipase A2 substrate and inhibitor specificity revealed at the molecular level
Biography:
Edward A Dennis is a distinguished Professor of Chemistry and Biochemistry and of Pharmacology in the School of Medicine at the University of California at San Diego (UCSD). He received his BA from Yale and a PhD from Harvard and was a Post-doctoral fellow at Harvard Medical School. He has served as Chair of the Department of Chemistry and Biochemistry. His research focus has been on the mechanism of the enzyme phospholipase A2, signal transduction, inflammation, lipid metabolism, eicosanoid action, and lipidomics. He authored over 380 publications, is Editor-in-Chief of the Journal of Lipid Research and Director of the LIPID MAPS Consortium.
Abstract:
The phospholipase A2 (PLA2) superfamily exhibits a large array of functions, but of special interest is the inflammatory cascade which is initiated by the release of free arachidonic acid by some types of phospholipase A2, all of which interact with membrane phospholipids. However, different PLA2 types have unique three-dimensional structures and unique catalytic residues as well as specific tissue localization, distinct biological functions, and with which membrane phospholipids have unique allosteric interactions. Understanding how the different PLA2s associate with phospholipid membranes, specific phospholipid substrate molecules, and inhibitors on a structural and molecular basis has advanced in recent years due to the introduction of hydrogen/deuterium exchange mass spectrometry approaches. We will emphasize recent results utilyzing hydrogen/deuterium exchange approaches and molecular dynamics on the major types of PLA2, including secretory s-PLA2, cytosolic c-PLA2, lipoprotein-associated LpPLA2, and calcium-independent iPLA2 with inhibitors and substrates. We will also discuss new results on the precise nature and molecular dynamics of the interaction of these enzymes with specific substrate phospholipids pulled into the catalytic site from membranes and how new potent specific inhibitors block substrate phospholipid binding. Phospholipase A2 is the initiator of eicosanoid formation in inflammatory processes, so it is a critical enzyme and inhibitors could provide new approaches to disease treatment.
George Kokotos
University of Athens, Greece
Title: Targeting the phospholipase A2 – Autotaxin Axis: A challenge to develop novel agents for the treatment of inflammatory and autoimmune diseases
Time : 12:40-13:05
Biography:
George Kokotos is the Chairman of the Department of Chemistry at the University of Athens, Greece. He studied chemistry at the University of Athens where he also obtained his PhD. He then conducted postdoctoral work in the Department of Pharmaceutical and Biological Chemistry at the University of London. He has spent a sabbatical leave as a visiting Professor in the Department of Chemistry and Biochemistry at the University of California, San Diego. He has authored over 140 publications in peer-reviewed journals and edited two books on Bioactive Lipids and Lipases. He is also co-inventor of more than 12 patents.
Abstract:
Phospholipases A2 (PLA2) are enzymes that hydrolyze the sn-2 ester bond of the membrane phospholipids releasing free fatty acids and lysophospholipids. Arachidonic acid may be converted into a variety of eicosanoids by various enzymes, while lysophosphatidylcholine into lysophosphatidic acid (LPA) by a secreted enzyme that exhibits lysophospholipase D activity known as autotaxin (ATX). Both enzymes are involved in the production of inflammatory mediators and thus, constitute attractive targets for the development of novel agents for the treatment of inflammatory diseases. In addition, increased ATX expression and LPA production have been detected in a variety of cancers, which renders this enzyme a target for cancer treatment. A variety of small molecule PLA2 inhibitors have been developed and some of them reached clinical trials. In the case of ATX, several inhibitors have been reported, however only limited studies using animal models are known. In our labs, we have developed several classes of novel PLA2 inhibitors, including 2-oxoamides and thiazolyl ketones targeting GIVA cPLA2, and fluoroketones targeting GVIA iPLA2. We have recently shown that administration of fluoroketone FKGK18 to non-obese diabetic mice significantly reduced diabetes incidence in association with improved glucose homeostasis, and β-cell preservation. In this presentation, we will discuss our most recent potent PLA2 and ATX inhibitors. We will present two novel classes of highly potent inhibitors: 2-oxoesters for GIVA cPLA2 and beta-lactones for GVIA iPLA2. Such inhibitors were found to suppress the release of PGE2 in renal mesangial cells. A lipidomic approach to monitor the effect of inhibitors will be discussed.
Berit Johansen
Norwegian University of Science and Technology, Norway
Title: Cytosolic Phospholipase A2, a powerful regulator of inflammation and a potent candidate for therapeutic intervention in chronic disease
Time : 14:00-14:25
Biography:
Berit Johansen is professor of Biotechnology at Norwegian University of Science and Technology (NTNU), Norway; and gründer and CSO of Avexxin AS. She has a PhD in Molecular Genetics, obtained at NTNU. She has spent several periods as visiting scientist at international universities and companies, including: UCLA, Biogen Inc., University of Groningen, University of Uppsala and UCSD. Her scientific interests encompass unraveling cellular communication processes involving lipid signalling, with special emphasis on phospholipase A2 (PLA2) enzymes, including drug development targeting cPLA2ï¡. “Proof of concept” for topical treatment of psoriasis with a small molecule cPLA2ï¡ inhibitor has been achieved with. She received “Young scientist award” from European Federation of Biotechnology in 2003.
Abstract:
Eicosanoids, the oxygenated metabolites of arachidonic acid (AA) comprise a large family of bioactive lipids that have diverse roles in regulating homeostatic processes, in modulating inflammation and immune responses. Phospholipase A2s (PLA2s) are a group of enzymes that hydrolyze the sn-2 position of membrane phospholipids to release (typically unsaturated) fatty acids, including AA, and lysophospholipids. Three major classes of PLA2s exist in the mammalian system, including low molecular weight extracellular or secretory, sPLA2; high moleular weight calcium-independen, iPLA2; and the group IVA calcium-dependent cytosolic PLA2, cPLA2α. The latter has received the most attention because it is widely expressed in nearly all mammalian cells and due to its active participation in cell metabolism. cPLA2ï¡ is identified as the the rate-limiting provider of proinflammatory mediators, including AA, and is thus an attractive target for the development of novel antiinflammatory agents. It is found that cPLA2α plays a major role in the chronic inflammation characterizing both psoriasis and rheumatoid arthritis. Novel inhibitors showing high potency and selectivity targeting cPLA2α are developed. These represent different chemistries, thus enabling various regimes for formulation, administration and tissue accumulation. Results will be presented to demonstrate mode of action for potent cPLA2α inhibitors in relevant cellular model systems for psoriasis and rheumatoid arthritis, efficacy in animal models of disease and “Proof of concept” for treatment of human disease.
Sasanka Ramanadham
University of Alabama at Birmingham, USA
Title: Importance of Ca2+-Independent Phosphoplipase A2b-Derived Lipids to Type 1 Diabetes Development
Time : 14:25-14:50
Biography:
Dr. Ramanadham was awarded his PhD from the Department of Pharmacology at Texas Tech University Health Sciences Center in 1985. He thesis project focused on cardiovascular complications associated with diabetes. He has continued work in the diabetes area and is now engaged in studies to understand the contribution of lipid singnaling to type 1 diabetes development. He has nearly 100 publications, serves on Journal Editorial Boards, and as a grant reviewer for both National and Intenational Diabetes Foundations. He is currently a Professor in the Department of Cell, Developmental, and Integrative Biology, and a Senior Scientist in the Comprehesive Diabetes Center at UAB.
Abstract:
Type 1 diabetes (T1D) is a consequence of pancreatic islet b-cell destruction, due to apoptosis. Our lab is investigating underlying mechanisms that contribute to b-cell loss and we identified a prominent role for the group VIA Ca2+-independent phosphoplipase A2b (iPLA2b) in this process. The cytosolic iPLA2b catalyzes hydrolysis of the sn-2 sbstituent from membrane phopsholipids. The islet b-cell membranes are enriched in arachidonate-containing phospholipids and activation of iPLA2b in the b-cells leads to accumulations in arachidonic acid and its various oxidized metabolites (i.e. eicosanoids). The eicosanoids manifest different activities, some of which are proinflammatory and apoptotic and some are ant-inflammatory and anti-apoptotic. Inhibition, knockdown, or knockout of iPLA2b significantly reduces b-cell apopotosis due to ER stress or proinflammatory cytokines. Further, during the development of autoimmune T1D, expression and activity of iPLA2b increases and this is associated with generation of proinflammatory and apoptotic lipid signals. Consistent with this, we find that with selective inhibition of iPLA2b in the spontaneously diabetes-prone non-obese diabetic (NOD) mouse, there is a significant reduction in islet infiltration by leukocytes, preservation of b-cell mass, and a dramatic amelioration of T1D. We further find that iPLA2b inhibition markedly reduces immune responses. These observations provide strong evidence for contribution of iPLA2b-derived lipids to T1D development. Our on-going investigations reveal that activation of iPLA2b triggers molecular mechanisms that favor generation of pro -apoptotic/pro-inflammatory signals and these work in concert to promote T1D development. Our work was supported by the American Diabetes Association, NIH/NIDDK, and the Iacocca Family Foundation.
L. Ashley Cowart
Medical University of South Carolina, USA
Title: Sphingosine-1-Phosphate signaling regulates key metabolic outcomes of obesity
Time : 14:50-15:15
Biography:
L. Ashley Cowart obtained her PhD in 2001 from Vanderbilt University and performed postdoctoral studies at the Medical University of South Carolina, where she is now associate professor in Biochemistry. Dr. Cowart has participated heavily in developing the strong research programs in lipid signaling and lipidomics at MUSC. She has published over 40 manuscripts and authored numerous reviews in sphingolipid metabolism and signaling in diabetes.
Abstract:
Sphingosine-1-phosphate is a lysophospholipid signaling molecule that works through both receptor dependent and independent mechanisms. Sphingosine-1-phosphate is generated via phosphorylation of sphingosine by Sphingosine Kinases. We discovered that Sphingosine Kinase 1 is upregulated by saturated fatty acids, a finding which placed this pathway in the context of metabolic homeostasis. Since those initial studies, our group and others have demonstrated roles for Sphingosine Kinase 1 in pathophysiological processes in numerous organs including pancreas, skeletal muscle, adipose tissue, and liver. Moreover, ablation of this pathway in mice conferred resistance to obesity-induced inflammation and insulin resistance. Together, these data have supported the general idea that Sphingosine Kinase 1 mediates obesity-induced disease. To gain more mechanistic insights, we recently generated mice with an adipocyte-specific sphingosine kinase 1 deletion. Data from these animals has revealed novel and surprising roles for this pathway in maintaining metabolic homeostasis. For example, in contrast to the whole-body deletion, which exhibits protection from obesity-induced insulin resistance, the adipocyte-specific sphingosine kinase 1 deletion mouse exhibits basal insulin resistance. These and other data have revealed that this pathway serves both protective and deleterious roles depending on cell type and disease context. Ongoing work in the laboratory is addressing the specific roles for sphingosine-1-phosphate signaling in regulating crucial adipocyte functions including lipogenesis, lipolysis, proliferation, and differentiation. These pathways might eventually be pharmacologically targeted for treatment of obesity and/or obesity-induced disease.
Charles E. Chalfant
Virginia Commonwealth University, USA
Title: Cytosolic phospholipase A2ï¡: a tale of two functions.
Time : 15:15-15:40
Biography:
Charles Chalfant received his PhD from the University of South Florida-College of Medicine and was an NRSA postdoctoral fellow at both Duke Medical Center and The Medical University of South Carolina under Dr. Yusuf hannun.. He is currently a GS15 Research Career Scientist with the Richmond VAMC. He is also a tenured Professor and Vice Chair of the Department of Biochemistry & Molecular Biology at Virginia Commonwealth University (VCU)-School of Medicine. He is currently holds the Paul M. Corman, M.D. Endowed Chair in Cancer Research for the VCU Massey Cancer Center and has published >100 papers in reputed journals.
Abstract:
New roles for sphingolipids such as ceramide, ceramide-1-phosphate (C1P), and sphingosine-1-phosphate continue to emerge. My research, for example, has implicated C1P as a major regulator of eicosanoid synthesis, and despite the importance of eicosanoids in the inflammatory process, the regulation of eicosanoid synthesis proximal to the activation of Group IVA phospholipase A2 (cPLA2a) is still an enigma. In this regard, my laboratory demonstrated that C1P is a direct and required lipid co-factor for cPLA2a activation in cellular models. In further studies, the interaction site for C1P was localized to the calcium-lipid binding domain (C2 domain) of the enzyme allowing for the genetic ablation of the site in vivo via the generation of a cPLA2a knock-in (KI) mouse. In this lecture, the characterization of this new mouse model in comparison to the full genetic ablation of the enzyme will be presented. Specifically, the loss of the C1P/cPLA2a interaction induced a “class-switch” in the production specific eicosanoids and specialized lipid mediators driving both sepsis resistance and accelerated wound repair. In further mechanistic studies, C1P was found to modulate the substrate specificity of cPLA2a explaining the “class switch” as to bioactive lipid mediators observed in the cPLA2a KI mouse. Overall, these observations led to two new findings: 1) C1P is a pro-inflammatory signaling molecule that directs cPLA2a in the utilization of primarily phospholipids with sn-2 arachidonic acid while simultaneously blocking the utilization of phospholipids with sn-2 docosahexaenoic acid; and 2) cPLA2a has previously overlooked functions in the resolution of inflammation and immune responses.
Christoforos G. Kokotos
University of Athens, Greece
Title: Synthetic methods to 2-hydroxy fatty acids and lipolytic enzyme inhibitors
Time : 16:00-16:25
Biography:
Christoforos G. Kokotos is an Assistant Professor of Organic Chemistry at the Department of Chemistry at the National and Kapodistrian University of Athens, Greece. He studied chemistry at the University of Athens and he moved to the University of Bristol, UK to obtain his Ph.D. He then conducted postdoctoral work in the Department of Chemistry of Princeton University, USA. He has authored over 45 publications in peer-reviewed journals and has been selected in prestigious rising star events of organic chemistry including EuCheMS Young Investigators Workshop 2014, 9th Young Academic Investigators Award, 248th ACS Meeting 2014 and Burgenstock Conference 2016.
Abstract:
2-Hydroxy fatty acids are important components of a subset of mammalian sphingolipids. Current evidence clearly shows that 2-hydroxy ceramides and 2-hydroxy complex sphingolipids have unique functions in membrane homeostasis and cell signaling. The biosynthesis of 2-hydroxy fatty acids is accomplished by the enzyme fatty acid 2-hydroxylase (FA2H), which stereospecifically produces the (R)-enantiomers. On the other hand, 2-hydroxy oleic acid has been identified as a potent antitumor compound (Minerval) acting against cancer by inducing cell cycle arrest, followed by apoptosis in human leukemia cells or differentiation and autophagy in the case of human glioma cells. In 2011, the European Medicines Agency designated 2-hydroxy oleic acid as an orphan medicinal product for the treatment of glioma. We have been previously involved in the asymmetric organocatalytic α-functionalization of carbonyl compounds. In this presentation, we will discuss our most recent application of these methodologies, as well as the development of novel synthetic approaches for the synthesis of enantioenriched α-substituted fatty acids. We will present the successful application of this methodology in the α-functionalization of fatty acids with hydroxyl, fluoro and sulfenyl moieties. Having in hand a methodology for the fast assembly of chiral and racemic α-functionalized fatty acids, their properties as enzyme inhibitors and signaling-molecules will be pursued. In addition, organocatalytic methodologies for the synthesis of phospholipase A2 inhibitors will be presented.
Suzanne E. Barbour
University of Georgia, USA
Title: Novel Roles of iPLA2ï¢ in Hepatic Lipid Metabolism
Time : 16:25-16:50
Biography:
Suzanne E. Barbour has a BS (Chemistry) from Rutgers University, a PhD (Molecular Biology and Genetics) from The Johns Hopkins University, and postdoctoral training from the University of California San Diego. From 1993-2015, Suzanne was on the faculty at the Virginia Commonwealth University School of Medicine. In 2013, she became a Program Director in the Molecular and Cellular Biosciences at the National Science Foundation where she ran a program in cellular dynamics and function. Suzanne moved to the University of Georgia in July 2015 where she is Dean of the Graduate School and Professor of Biochemistry & Molecular Biology.
Abstract:
The Group VIA phospholipase A2 (iPLA2b) is highly expressed in metabolically active tissues and recent studies have connected the enzyme to a variety of metabolic diseases. Our studies are focused on the role of the enzyme in fatty liver disease. Exogenous unsaturated fatty acids (UFA) suppress expression and processing of sterol regulatory element binding protein-1 (SREBP-1), a transcription factor that regulates lipogenic gene expression in the liver. We compared hepatic lipid metabolism in iPLA2b-/- and wild type mice, to test the hypothesis that the iPLA2b might be a source of endogenous UFA that regulate SREBP-1 and thereby modulate fatty liver. As expected, iPLA2b-/- livers contained more SREBP-1c and exhibited increased processing of this protein, compared to wild type livers. The changes in SREBP-1 expression/ processing correlated with increased lipogenic gene expression, synthesis of fatty acids and triacylglycerols (TAG), and TAG mass in iPLA2b-/- livers. We also observed evidence of reduced secretion of TAG, cholesterol, and cholesterol ester in iPLA2b-/- hepatocytes, suggesting that TAG accumulation in iPLA2b-/- livers is the result of both increased synthesis and reduced secretion. Our studies indicate that iPLA2b-derived lipids contribute to pathogenesis of at least two metabolic diseases. Identification of the bioactive lipids and their mechanisms of action may uncover novel ways to treat diabetes mellitus and fatty liver disease.