2003 HDL CHOLESTEROL - 4th Annual Metabolic Pathways and Drug Targets

Type Documentation ISBN 1-59430-035-6 Publication Date March, 2003 Number of Pages 483 List Price $89.00 Availability In Stock

RELATED TITLES 2000 HDL CHOLESTEROL: 1st Annual Metabolic Pathways & Drug Developments 2001 HDL CHOLESTEROL - 2nd Annual International Conference on Metabolic Pathways and Drug Development 2002 HDL CHOLESTEROL - 3rd Annual International Conference on Metabolic Pathways and Drug Development

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Overview

Raising the low level of HDL cholesterol is a powerful strategy for reducing the risk of cardiovascular diseases. The complex nature of the metabolism of HDL presents a variety of targets for therapeutic intervention.

In it's fourth year, this conference will provide you the latest in the
research of HDL cholesterol metabolic pathways. Hepatic Lipase, Scavenger
Receptor B, ABCA1, Apo A1, PPAR and LXR are all major areas of interest in
the search for new therapeutics. Leading academic and industry experts will
present in-depth analysis on exciting new discoveries such as:

- Biopharmaceutical product candidates for
cardiovascular diseases
- Effect of HDL apo A-I mutations on cholesterol homeostasis
- Antioxidant properties of apo-A-I
- The influence of SR-BI on HDL cholesteryl ester and
free cholesterol
- Hepatic lipase and HDL/LDL heterogeneity
- LXR - and LXR agonists
- Regulation of PPAR g mediated gene expression
- Apo-A-I, ABCA1 and cholesterol efflux
NEW!
for the first time in this conference series!

Pre-Conference Workshop "Strategies for Lowering Cholesterol"
Sunday, March 2, 2003
This workshop will present the opportunity to discuss the importance of not only raising HDL but also lowering LDL cholesterol and to analyze the strategy of combination therapies in order to treat hypercholesterolemia.

Take advantage of this unique opportunity to hear the state of the art on
strategies to lower the risk of cardiovascular diseases.

Register early - space is limited.

RELATED LINKS

iHumans, Inc. Resources Development

Visit the Journal of Lipid Research

Table of Contents

Pre-Conference Workshop: Strategies for Lowering Cholesterol

Sunday, March 2, 2003

12:30 Registration, Coffee and Refreshments

1:00 Chairperson's Opening Remarks
Ernst J. Schaefer, M.D., Professor, Chief, Lipid Metabolism Laboratory, Director of Lipid and Heart Disease Prevention Center, New England Medical Center

1:10 Should Raising HDL Be The Primary Target of Therapy for Patients With "Isolated" Low HDL?
James D. Otvos, Chief Scientific Officer,
LipoScience, Inc.

Variation of NMR-measured lipoprotein subclass profiles as a function of HDL cholesterol in the Framingham Offspring Study provides evidence that excess LDL particle number and small LDL size are important contributors to the risk
of many individuals with low levels of HDL. Such patients would benefit from LDL lowering therapy in addition to treatments designed to raise HDL.

1:50 The Chemical, Metabolic and Pathophysiologic Properties of ApoB-containing Lipoprotein Subclasses
Petar Alaupovic, Ph.D., Cardiovascular Section, Oklahoma Medical Research Foundation, and Departments of Biochemistry and Medicine, University of Oklahoma, School of Medicine,

Apolipoprotein (apo) B-containing lipoproteins consist of five major subclasses identified and named according to their apolipoprotein composition Lp-B, Lp-B:E, Lp-B:C, Lp-B:C:E and Lp-A-II:B:C:D:E. Each subclass is characterized by its unique apolipoprotein composition, specific metabolic properties and different atherogenic capacities. The presentation will include the quantitative determination of apoB-containing lipoprotein subclasses, their profiles of dyslipoproteinemias and response to pharmacologic intervention.

2:30 New Strategies for LDL Cholesterol Reduction-Superstatins, More Effective Resins, Better Niacin, Inhibitors of Cholesterol Absorption, and Combination Therapy
Ernst J. Schaefer, M.D., Professor, Chief, Lipid Metabolism Laboratory, Director of Lipid and Heart Disease Prevention Center, New England Medical Center

Current and future strategies for LDL lowering will be reviewed.

3:10 Refreshment Break

3:40 Discovery of a Potent, Orally Active and Clinically Efficacious MTP Inhibitor via a Parallel Synthesis Paradigm

George Chang, Senior Research Investigator, Pfizer Global Research and Development

Microsomal triglyceride transfer protein (MTP) plays an obligatory role in the assembly and secretion of triglyceride-rich apoB-containing lipoproteins.
Inhibition of this protein has the potential to interfere with secretion of these lipoproteins from the liver and intestine and thus favorably affect both hypercholesterolemia and hypertriglyceridemia. Using a novel parallel synthesis paradigm, a potent, orally active inhibitor of MTP, which showed robust lipid lowering in clinical trials, was discovered.

4:20 Poststatin Drug Discovery for Hypercholesterolemia/Atherosclerosis
Charles Q. Meng, Distinguished Scientist, AtheroGenics, Inc.

Although the statins reduce mortality due to coronary artery disease (CAD) remarkably, many patients with CAD do not respond to this therapy. Drugs working through different mechanisms than the statins are still in need. On the other hand, non-lipid aspects of atherosclerosis have been overlooked.
This presentation will focus on cholesterol lowering through other mechanisms and non-lipid aspects of atherosclerosis.

5:00 Discussion

5:15 End of Workshop

Main Conference

Monday, March 3, 2003

8:30 Registration, Poster / Exhibit Set - Up, Coffee and Pastries

9:30 Chairperson's Opening Remarks
Christopher J. Fielding Ph.D., Neider Professor of Cardiovascular Physiology, Cardiovascular Research Institute and Department of Physiology, University of California San Francisco

Drug Developments

9:35 HDL Raising -The Next Frontier in Heart Disease Prevention
Ernst J. Schaefer, M.D., Professor, Chief, Lipid Metabolism Laboratory, Director of Lipid and Heart Disease Prevention Center, New England Medical Center

Discussion of the mechanisms affecting HDL cholesterol levels and the treatment strategies for increasing it.

10:10 Regulation of Cholesterol Efflux from
Vascular Cells
Christopher J. Fielding Ph.D., Neider Professor of Cardiovascular Physiology, Cardiovascular Research Institute and Department of Physiology, University of California San Francisco

Vascular cells, like most peripheral cells, control their sterol content primarily at the level of efflux. Multiple mechanisms are now recognized to regulate cholesterol efflux. These include change in plasma membrane domain
structure, expression of different transporters, and classical signaling pathways that modify cell division, attachment and migration. Multiple new targets are now available to promote cholesterol unloading.

10:45 A Novel Mechanism for the Beneficial Vascular Effects of HDL Cholesterol
Richard Karas, Dept. of Medicine, New England Medical Center Hospitals, Inc., Tufts University School of Medicine

A number of mechanisms have already been identified for the apparent atheroprotective effects of HDL. We recently observed that raising HDL with niacin improved vascular endothelial function in patients with coronary artery disease and already well-controlled LDL levels. To investigate the mechanism by which HDL enhances endothelial function, a series of in vitro studies were conducted which demonstrated that HDL and apolipoprotein AI increase the abundance of endothelial cell nitric oxide synthase (eNOS).
Further molecular studies demonstrate that HDL increases eNOS protein abundance by activating both the MAP kinase and Akt kinase pathways. Taken together, these studies identify a previously unrecognized mechanism by which
HDL can exert beneficial vascular effects.

11:20 Refreshment Break

11:50 Effect of Niacin on Cardiovascular Events and Mortality in Patients With Impaired Fasting Glucose, Impaired Glucose Tolerance, or Diabetes
Mark E. McGovern, M.D., FACC, FACP, Senior Vice President, Chief Medical Officer, Kos Pharmaceuticals, Inc.

Niacin is the most potent drug currently available to raise HDL-C. It belongs to the class of HDL holoparticle catabolism receptor antagonists (or apoA-I catabolism receptor blockers). Niacin is also a potent inhibitor of
lipolysis and triglyceride synthesis. Recent studies show that once-daily extended-release niacin is a therapeutic option for some patients with diabetes. In addition, a new analysis from a long term, placebo-controlled secondary prevention trial has evaluated the effect of niacin on cardiac outcome and mortality in patients with elevated fasting or 1-hour glucose, diabetes, or metabolic syndrome.

12:25 Biopharmaceutical Product Candidates for Cardiovascular Disease.
Charles L. Bisgaier, Ph.D., Vice President, Pharmacology, Esperion Therapeutics, Inc.

Biopharmaceutical functional HDL product candidates may have acute therapeutic benefits for cardiovascular diseases. Preclinical models provide an opportunity to explore unique applications for these agents. In this regard, ETC-216, a product candidate designed to mimic nascent HDL and comprised of apoA-Imilano and phospholipid, was tested for its ability to prevent ischemia reperfusion injury. Our experiments suggest acute ETC-216 treatment can significantly reduce tissue damage in ex vivo models of global cardiac ischemia and in vivo models of regional cardiac ischemia.

1:00 Luncheon, sponsored by The Knowledge Foundation, Inc.

1:55 Chairperson's Remarks
Jonathan D. Smith, Dept. of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation

Scavenger Receptor B

NEW Speaker: 2:00 Monty Krieger, MIT

2:30 Concentration of Scavenger Receptor BI (SR-BI) in Microvillar Extensions Suggests a Role for this Plasma Membrane Domain as a Way Station for Cholesterol Trafficking Between HDL and Cells
David L. Williams, Ph.D., Professor and Interim Chair, Pharmacological Sciences, University Medical Center, SUNY at Stony Brook

Scavenger receptor BI (SR-BI) is an HDL receptor that mediates the selective uptake of cholesteryl ester into the liver and steroidogenic cells. SR-BI is also expressed at lower levels in macrophages in atherosclerotic lesions and
in endothelial cells of the vasculature. In addition to mediating the selective uptake of cholesteryl ester, SR-BI stimulates free cholesterol flux between cells and HDL and alters the distribution of cholesterol in plasma membrane domains. Plasma membrane morphology is altered in cells over expressing SR-BI in culture and in adrenal cells from the SR-BI knockout mouse. SR-BI is highly concentrated in plasma membrane microvillar extensions. Microvillar extensions may serve as a plasma membrane way station in the movement of cholesterol between cells and HDL. Thus, SR-BI influences the uptake and distribution of both HDL cholesteryl ester and free cholesterol and may play a key role in reverse cholesterol transport.

Apo A1 / HL

Human hepatic lipase hydrolyses phospholipids and triglycerides in LDL and HDL particles in the liver leading to smaller and denser lipoproteins. The interaction with CETP depends on characteristics of the triglyceride
containing lipoproteins. A potential non-catalytic function of hepatic lipase is to contribute to the hepatic recognition of chylomicron and VLDL remnant lipoproteins. Some of the effects of hepatic lipase would appear to be
proatherogenic, while some would be antiatherogenic.

3:40 Refreshment Break and Poster / Exhibit Viewing

4:10 Antioxidant Properties of ApoA-IMilano: Development of a New Class of Peptide Mimetics to Combat Inflammatory Diseases.
John K. Bielicki, Scientist, Lawrence Berkeley National Laboratory

The monomeric form of apoA-IMilano possesses antioxidant activity attributed to the presence of a free thiol at the polar/nonpolar interface of an amphipathic a-helix. ApoE3 and apoAV share similar structural features suggesting the presence of an antioxidative "motif" in apolipoproteins. We
are investigating this possibility and have embarked on a systematic evaluation of the types of amphipathic a helices that can support thiol-dependent antioxidant activity.

4:45 HDL ApoA-I Mutations and Their Effects on Cholesterol Homeostasis
Mary Sorci-Thomas, Ph.D., Professor of Pathology, Wake Forest University Health Sciences

This talk will describe primarily the structure and function of high density lipoprotein (HDL) apolipoprotein A-I (apo A-I) in the activation of lecithin:cholesterol acyltransferase (LCAT) and its role in promoting the maturation of HDL particles and the removal of excess cholesterol from peripheral tissues. I will present studies in which we have created transgenic animals expressing mutant forms of apo A-I in order to elucidate the mechanisms responsible for activation of LCAT by apo A-I and the metabolic importance of repeat 6 mutants on HDL metabolism and the development of atherosclerosis. It is our hope that this information may eventually lead to new therapies for the prevention and treatment of
atherosclerosis and coronary artery disease.

NEW: 5:20 Genes associated with HDL-C levels identified through a whole genome association study
Andreas Braun, CMO, SEQUENOM, Inc.

6:00 End of Day One

Tuesday, March 4, 2003

9:10 Chairperson's Opening Remarks
Richard Karas, Dept. of Medicine, New England Medical Center Hospitals, Inc., Tufts University School of Medicine

ABCA1

9:15 An Extracellular Matrix Binding Site for ApoA-I Participates in ABCA-1 Dependent Cholesterol Efflux
Jim W. Burgess, Ph.D., Scientist, Liponex, Inc., Canada

This presentation will describe a trypsin-sensitive and lipid-containing binding site for apoA-I on the extracellular matrix of macrophages. The studies will provide evidence that the matrix binding site is required for ABCA-1 mediated cholesterol efflux and nascent HDL particle formation.

9:50 Recent Studies on the Mechanism of ABCA1-Mediated Lipid Efflux
Jonathan D. Smith, Dept. of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation

Lipid efflux from RAW264 cells to apoAI is dependent upon extracellular calcium ions. We present new data to demonstrate that a specific calcium binding protein plays a role in ABCA1-mediated lipid efflux. In addition, it
has been proposed that ABCA1 may function by a two-step pathway in which it first mediates the efflux of phospholipid to apoAI, and that cholesterol can
then follow in an ABCA1-independent fashion. We present evidence that this two-step model is largely an artifact of cyclodextran pretreatment, and is independent of the apoAI acceptor.

10:25 ABCA1 Protein-Protein Interactions and Cholesterol Efflux
Michael L. Fitzgerald, Ph.D., Division of Endocrinology, Massachusetts General Hospital, Harvard University

ABCA1 has a conserved COOH terminus that is critical for efflux activity and cell surface expression of the transporter in polarized and non-polarized cells. How protein-protein interactions with the COOH terminus of ABCA1 may mediate this functional role will be further discussed.

11:00 Refreshment Break and Poster / Exhibit Viewing
11:30 Functional Interactions of ApoA-I With ABCA1 and SR-BI. Implications for the Biogenesis and the Functions of HDL.
Vassilis I. Zannis, Professor of Medicine/Biochemistry, Director, Section of Molecular Genetics, Boston University School of Medicine

Using numerous apoA-I mutants, we have shown that the cAMP-dependent (ABCA1-mediated) cholesterol efflux by WT apoA-I requires residues 220-231. Efflux was restored by deletion of both the amino- and carboxy-terminal domains of apoA-I. Adenovirus-mediated gene transfer in apoA-I-deficient mice showed that mutants defective in cholesterol efflux fail to form HDL in vivo, whereas the double-deletion mutant formed discoidal HDL. The findings establish that although the central helices of apoA-I can promote ABCA1-mediated lipid efflux, residues 220-231 are required for lipid efflux in vitro and HDL formation in vivo by the full-length apoA-I. The ability of only specific forms of apoA-I to promote both efflux and HDL formation suggest a specificity of ABCA1 for the apoA-I ligand.
Other studies examined cholesterol efflux by reconstituted HDL particles containing WT or mutant forms of apoA-I in cells expressing wt or mutant forms of SR-BI. This analysis showed that specific mutations in helix 4 or helix 6 of apoA-I reduced cholesterol efflux from cells expressing the WT SR-BI without affecting receptor binding. On the other hand, the mutation in helix 6 of apoA-I restored cholesterol efflux and receptor binding in cells expressing a specific SR-BI mutant. The findings suggest that efficient cholesterol efflux requires not only binding, but also the formation of a productive (functional) complex between apoA-I and SR-BI.

Nuclear Receptors

LXRs are master transcription factors regulating a myriad of target genes involved in cholesterol and fatty acid metabolism. The talk will discuss new LXR target genes identified that are involved in lipid metabolism as well as
a new metabolic pathway that may point to its potential application to diseases in addition to dislipidemia and atherosclerosis.

12:40 Lunch on Your Own

2:00 Synthetic and Natural LXR Agonists: Effects In Vivo and in Cell Culture
Erik G. Lund, Ph.D., Merck Research Laboratories

LXRb and LXRa are nuclear receptors that upon cellular cholesterol excess initiate programs of cholesterol removal. Agonists of LXR have recently emerged as potential HDL-raising, artery wall-acting anti-atherosclerotic
agents with great promise. We here describe effects of synthetic LXR agonists on lipid metabolism in animals and in cell culture, and compare to the effects of cholesterol overload in cells.

2:35 LXR Ligands, SREBP1c, ABCA1 and Diabetes, Are They Compatible?
Jeffrey W. Chisholm, Ph.D., Scientist, Discovery Research, CV Therapeutics Inc.

The discovery of ABCA1 as a major regulator of HDL production has resulted in an intense effort to develop drugs that increase ABCA1 activity leading to increased HDL levels and reduced risk of Cardiovascular Heart Disease.
Activation of the LXR receptor with T0901317, a selective LXR ligand, has been shown in vivo, in non-diabetic animals, to raise HDL levels through enhanced ABCA1 expression, while also inducing mild hypertriglyceridemia
through activation of the SREBP1c pathway. Surprisingly, we have found that the hypertriglyceridemic effects of this compound are greatly enhanced in a mouse diabetic model resulting in a severe hypertriglyceridemia, hepatotoxicity and a reduction in plasma HDL. Given that a large portion of the future market for ABCA1 drugs will likely be diabetic patients, these studies suggest that mild SREBP1c side effects could be greatly aggravated in diabetes.

3:10 Regulation of PPARg-Mediated Gene Expression: A New Mechanism of Action for High Density Lipoprotein
Andrew C. Nicholson, D.V.M., Ph.D., Associate Professor of Pathology, Weill Medical College of Cornell University

We tested the hypothesis that HDL could inhibit cellular lipid accumulation by modulating expression of peroxisome proliferator activator receptor-g (PPAR-g) responsive genes. To this end, we evaluated expression of two PPAR-g
responsive genes, CD36, a receptor for oxidized LDL and aP2, a fatty acid binding protein. HDL decreased expression of macrophage CD36 and ap2 in a dose-dependent manner. Our data demonstrated that HDL increased MAP kinase-mediated phosphorylation of PPAR-g inhibited expression of PPAR-g
responsive genes, and suggests mechanisms by which HDL may inhibit cellular lipid accumulation.

3:45 End of Conference
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