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Bioactive Lipids in Metabolic Syndrome

WEBINAR

Only

Bioactive Lipids in Metabolic Syndrome

Tuesday, June 8, 2021, 10:30 AM - 5:10 PM EDT

Presented By

Biochemical Pharmacology Discussion Group

The New York Academy of Sciences

 

Cardiometabolic disease and metabolic syndrome refers to a cluster of related diseases of metabolism, which include cardiovascular disease, Type-2 diabetes, and nonalcoholic fatty liver disease (NAFLD/NASH).  The prevalence of these diseases is increasing and represents a critical threat to public health. In recent years, bioactive lipids have emerged as key mediators of cardiometabolic disease and inflammatory sequelae. Greater appreciation of the importance of bioactive lipids is due both to the development of “omics” technologies that have revealed new details of their functions, and to numerous genetic association studies that have linked lipid modifying enzymes to cardiovascular disease, Type-2 diabetes and NASH. As bioactive lipids are critical regulators of essential cellular processes, targeting them in disease contexts will require detailed knowledge of their behavior and regulatory mechanisms.

To address this challenge, this meeting will integrate recent data detailing the roles of bioactive lipids and inflammatory mediators across multiple cardiometabolic diseases, with the aim of identifying key lipid species and pathways that might be viable therapeutic targets for multiple disease indications.

Registration

Member
$30
Nonmember Academia, Faculty, etc.
$65
Nonmember Corporate, Other
$85
Nonmember Not for Profit
$65
Nonmember Student, Undergrad, Grad, Fellow
$45
Member Student, Post-Doc, Fellow
$15

Keynote Speaker

Edward Dennis, PhD
Edward Dennis, PhD

University of California, San Diego

Speakers

Gabrielle Fredman, PhD
Gabrielle Fredman, PhD

Albany Medical College

Barbara Kahn
Barbara Kahn, MD

Harvard Medical School

Gerald Shulman
Gerald Shulman, MD, PhD

Yale School of Medicine

Susan Smyth
Susan Smyth, MD, PhD

University of Kentucky

Sarah Spiegel, PhD
Sarah Spiegel, PhD

Virginia Commonwealth University

Matthew Spite, PhD
Matthew Spite, PhD

Harvard Medical School

Joseph Witztum, MD
Joseph Witztum, MD

University of California, San Diego

Scientific Organizing Committee

Edward Dennis, PhD
Edward Dennis, PhD

University of California, San Diego

Gregory Tesz, PhD
Gregory Tesz, PhD

Pfizer

Michelle Clasquin
Michelle Clasquin, PhD

Pfizer

Min Wan
Min Wan, PhD

Pfizer

Sara Donnelly
Sara Donnelly, PhD

The New York Academy of Sciences

Sonya Dougal
Sonya Dougal, PhD

The New York Academy of Sciences

Tuesday

June 08, 2021

10:30 AM

Introduction and Welcome Remarks

Speakers

Alison Carley, PhD
New York Academy of Sciences
Gregory Tesz, PhD
Pfizer
10:45 AM

Keynote Lecture: Specificity and Mechanism of Phospholipase A2 in Initiating Inflammatory Mediator Production

Speaker

Edward Dennis, PhD
University of California San Diego

Lipids play critical roles in Metabolic Syndrome and Inflammation, which encompass the major diseases of our times, and over 45,000 distinct molecular species of lipids have been identified by the LIPID MAPS Consortium (www.lipidmaps.org). Our laboratory1 discovered and demonstrated that membranes interact allosterically with enzymes to regulate cell signaling and metabolic pathways leading to inflammation2. We have recently employed substrate lipidomics coupled with molecular dynamics to reveal enzyme specificity linked to highly specific hydrophobic binding sites for the sn-2 fatty acyl chains in membrane phospholipid substrates3. We discovered unexpected headgroup and acyl chain specificity for each of the major human phospholipase A2 (PLA2) enzymes that explains the observed specificity at a new atomic level. A unique hydrophobic binding site — and not each enzyme’s catalytic residues or polar headgroup binding site — dominates each enzyme’s specificity. Each PLA2 shows unique specificity for its required fatty acid ranging from pro-inflammatory omega-6 arachidonic acid or anti-inflammatory fish oil omega-3 EPA and DHA; others favor membrane remodeling linolenic acid, or antibacterial saturated fatty acids, or oxidized fatty acids in LDL. Each PLA2 releases a specific fatty acid after the enzyme associates allosterically with membranes and extracts a single phospholipid substrate into its catalytic site. Stereospecific inhibitors4 have been designed for the specific sites. After decades of advances in lipid research, we can now correlate PLA2 specificity and inhibition potency with molecular structure and physiological function using a novel lipidomics platform that provides a paradigm for protein-membrane lipid interactions in general.

Session 1: Diabetes, Cardiovascular, and NASH Triad

11:15 AM

De novo lipogenesis in Adipose Tissue and the Production of Signaling Lipids with Beneficial Metabolic and Anti-inflammatory Effects

Speaker

Barbara Kahn, MD
Harvard Medical School
11:45 AM

Plasma Membrane sn-1,2-Diacylglycerols Mediate Lipid-Induced Liver, Muscle and White Adipocyte Insulin Resistance

Speaker

Gerald Shulman, MD, PhD
Yale School of Medicine

Non-alcoholic fatty liver disease is strongly associated with hepatic insulin resistance; however, the key lipid species and molecular mechanisms linking these conditions are widely debated. We developed a subcellular fractionation method combined with liquid chromatography-tandem mass spectrometry to quantify diacylglycerol (DAG) stereoisomers and ceramides in the endoplasmic reticulum, mitochondria, lipid droplets, cytosol and plasma membrane. Acute knockdown (KD) of diacylglycerol acyltransferase-2 in liver induced hepatic insulin resistance in rats. This could be attributed to plasma membrane sn-1,2-DAG accumulation, which promoted Protein Kinase C-epsilon activation, and insulin receptor kinase (IRK)-T1160 phosphorylation resulting in decreased IRK-T1162 phosphorylation. Plasma membrane sn-1,2-DAG content and IRK-T1160 phosphorylation in the liver were also higher in humans with hepatic insulin resistance. In rats, liver-specific PKC-epsilon KD ameliorated high-fat diet-induced hepatic insulin resistance by lowering IRK-T1160 phosphorylation, while liver-specific overexpression of constitutively active PKC-epsilon-induced HIR by promoting IRK-T1160 phosphorylation. In contrast there was no consistent association between hepatic ceramide content and hepatic insulin resistance. These studies identify sn-1,2-DAGs in the plasma membrane as the key bioactive lipid and intracellular compartment that are responsible for mediating lipid-induced hepatic insulin resistance and that hepatic PKC-epsilon is both necessary and sufficient in mediating HIR [1]. We also show that increases in plasma membrane sn-1,2-DAGs leading to activation of novel PKCs are also responsible for lipid-induced insulin resistance in skeletal muscle [2] and white adipose tissue [3] and that this hypothesis explains the dissociation between increases in ectopic lipid content in liver and skeletal muscle and insulin resistance in these organs under certain conditions.

12:15 PM

Break

12:25 PM

Central Role of Oxidized Phospholipid in Inflammatory Diseases

Speaker

Joseph Witztum, MD
University of California, San Diego
12:55 PM

Session 1 Discussion and Audience Q&A

1:10 PM

Break

Session 2: Short talks

2:10 PM

Short talks to be selected from submitted abstracts

Session 3: Bioactive Lipid Mediators of Inflammation

2:40 PM

Pro-resolving Lipid Mediators

Speaker

Matthew Spite, PhD
Harvard Medical School
3:10 PM

Lysophospholipids in Cardiovascular Disease

Speaker

Susan Smyth, MD, PhD
University of Kentucky
3:40 PM

Break

3:50 PM

Sphingosine-1-Phosphate: Functions and Regulation

Speaker

Sarah Spiegel, PhD
Virginia Commonwealth Universit
4:20 PM

Session 2 Discussion and Audience Q&A

4:35 PM

To be announced

5:05 PM

Closing Remarks

5:10 PM

Adjourn