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Monday, April 3, 2000
8:00 Registration, Poster
Set-Up, Coffee and Danish
Epidemiology and Drug
Development
9:00 Chairperson’s Opening
Remarks
Gerd Schmitz, M.D., Professor, Director, Institute for Clinical and
Laboratory Medicine, University Clinic of Regensburg, Germany
9:05 HDL in Health and
Disease
Ernst J. Schaefer, M.D., Professor, Chief, Lipid Metabolism Laboratory,
Director of Lipid and Heart Disease Prevention Center, New England Medical
Center
Decreased HDL cholesterol (<35mg/dl or 0.9 mmol/L) is an independent
CHD risk factor. Major determinants of HDL include BMI, gender, and
triglyceride levels, a well as alcohol intake and physical activity.
Common gene polymorphisms affecting HDL cholesterol are found at the
CETP and lipoprotein lipase gene loci. Genetic HDL deficiency states
will be discussed. Drugs which raise HDL include niacin and the fibric
acid derivatives, which both have been shown to decrease CHD risk. Based
on the HIT study we can now recommend using drug therapy to raise HDL
to >35 mg/dl in CHD patients.
9:40 Pharmaceutical Approaches
to HDL Elevation
Uday Saxena, Ph.D., Vice President of Research, AtheroGenics, Inc.
Coronary heart disease (CHD) remains the leading cause of death and
disease in North America. Epidemiological studies link low levels of
high density lipoproteins (HDL) cholesterol to increased risk of CHD.
There is renewed interest in the pharmaceutical industry to design new
drugs that can elevate HDL levels. Several new discoveries in HDL metabolism
offer potential opportunities for drug discovery and will be discussed.
10:15 Refreshment Break
& Poster Viewing
10:40 The Effects of HMG
CoA Reductase Inhibitors on HDL
Presenter: To be determined, Merck Research Laboratories
The introduction of the HMG-Co-A reductase inhibitors class (statins)
in 1987 has revolutionized the treatment of hyperlipidemia. These agents
are very effective in lowering LDL-C, apo B and triglycerides, and extremely
well tolerated. Large primary and secondary prevention studies have
shown that simvastatin, lovastatin and pravastatin reduce the risk of
CHD. Statins also raise HDL-C and apo A-I, and large epidemiologic studies
have clearly demonstrated an inverse relationship between the two lipid
variables and the risk of CHD. Although the mechanism for their increase
with statins remains unknown, recent data suggest that agents in the
class might increase HDL and apo A-I differently.
11:15 Effects of a Unique
Once-Daily Extended-Release Niacin Formulation on HDL Cholesterol and
HDL Subfractions
Mark E. McGovern, M.D., Vice-President, Medical Affairs, Kos Pharmaceuticals,
Inc.
The ability of niacin to increase HDL-C exceeds that of all other drugs.
Niacin is thought to act by blocking an HDL holoparticle receptor, thus
prolonging its half-life. Niacin also reduces LDL-C, especially small
dense LDL, triglycerides, and lipoprotein (a). In secondary prevention
studies, niacin, alone or in combination, was shown to prevent coronary
events and improve survival. Niaspan is a once-daily, extended-release
niacin designed to 1.) maintain the traditional efficacy of crystalline
niacin, particularly on HDL-C; 2.) reduce the incidence of flushing;
and 3.) avoid the hepatotoxicity associated with other long-acting formulations.
These goals were achieved through specific engineering of the release
rate and dosing regimen.
11:50 Lunch, sponsored
by The Knowledge Foundation
ABC1 Transporter Protein
1:15 The ATP-Binding Cassette
Transporter ABC1 Regulates HDL-Cholesterol Plasma Levels and is Involved
in Monocyte Targeting
Gerd Schmitz, M.D., Professor, Director, Institute for Clinical and
Laboratory Medicine, University Clinic of Regensburg, Germany
We have recently identified the association of mutations in the ABC1
gene and Tangier disease (TD), a disorder of lipid metabolism marked
by low HDL-cholesterol levels. In addition to rare mutations in TD patients
we have found a number of polymorphisms in control subjects. We tested
the frequencies of the four most common polymorphisms in selected groups
of individuals with specific biochemical and clinical features. The
results of our study suggest that certain ABC1 polymorphisms occur more
frequently in patients with selective reduction of HDL levels and those
affected with premature CAD. Detailed data from this study will be presented.
Genotype/phenotype analysis showed that depending on the location of
the mutation/polymorphism in the ABC1 gene a dysfunctional differentiation
of monocytes and monocyte targeting is observed, so that these cells
are directed either toward the vessel wall or the reticulo-endothelial
system, leading consequently to coronary artery disease or splenomegaly,
respectively. Studies are under way to improve our understanding of
the underlying mechanisms of the regulation of ABC1, which might provide
suitable strategies for therapeutic intervention and/or prevention of
CAD.
1:55 Removal of Excess
Cholesterol from Cells by HDL Apolipoproteins
John F. Oram, Ph.D., Research Professor of Medicine, University of
Washington
HDL apolipoproteins remove excess cholesterol from cells by an active
transport pathway controlled by a membrane protein called ABC1. Mutations
in ABC1 cause severe HDL deficiencies and cardiovascular disease, indicating
that this pathway plays a major role in HDL production and protection
against atherogenesis. This makes ABC1 and other components of this
cholesterol secretary pathway attractive targets for developing anti-atherogenic
drugs.
2:35 ABC1, Genetics and
Low HDL
Michael R. Hayden, Ph.D., F.R.C.P.(c), Professor, Dept. of Medical
Genetics, University of British Columbia, Director and Senior Scientist,
Centre for Molecular Medicine and Therapeutics, Canada
Abstract unavailable at time of print.
3:15 Refreshment Break
& Poster Viewing
Cholesterol Efflux
3:40 Macrophage Cholesterol
Efflux to Apolipoproteins
Jonathan D. Smith, Ph.D., Associate Professor, Laboratory of Biochemical
Genetics and Metabolism, The Rockefeller University
ApoAI and apoE can remove cholesterol and phospholipid from cholesterol
loaded RAW264 mouse macrophages via a pathway that is cAMP inducible.
Lipid efflux is correlated with increased cell binding and uptake of
apolipoproteins. We observed this binding occurring in coated pits,
and found that inhibitors of endocytosis block this pathway. cAMP leads
to the induction of ABC1 mRNA in RAW cells, suggesting that this is
the same pathway that is defective in Tangier disease.
4:15 Contributions of
ABC1, Caveolar and Passive Mechanisms to Cellular Cholesterol Efflux
C hristopher J. Fielding, Neider Professor of Cardiovascular Physiology,
University of California San Francisco
Multiple mechanisms contribute to the transfer of cellular cholesterol
to high density lipoprotein (HDL) acceptors. These include activity
of the ABC1 transporter, catalyzed transfer from cholesterol-rich cell
surface caveolae, and passive (nonspecific) transfers from the cell
membrane via intermediates including serum albumin. We have developed
small molecule activators which augment the efflux of cellular cholesterol.
Their specificities and mechanisms will be discussed.
4:50 Role of Phospholipid
Transfer Protein (PLTP) in High Density Lipoprotein (HDL) Metabolism
Christian Ehnholm, M.D., Ph.D., Professor, Head, Department of Biochemistry,
National Public Health Institute, Finland
High density lipoproteins (HDL) have powerful antiatherogenic properties.
The mechanism of the protection may be due to the involvement of HDL
in the process of reverse cholesterol transport. HDL are heterogeneous,
comprising a number of subpopulations some of which are better in protecting
against atherosclerosis. HDL are continuously remodeled through the
action of enzymes and lipid transfer proteins. The human plasma phospholipid
transfer protein (PLTP) governs the distribution of HDL subpopulations
and plays an important role in the regulation of plasma HDL levels and.
It facilitates the transfer of phospholipids between lipoproteins and
it can also induce HDL conversion, a process which remodels HDL into
populations of large HDL and small particles similar to preß-HDL, the
initial acceptors of membrane cholesterol. The role of PLTP in HDL metabolism
will be discussed.
5:25 End of Day One
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Tuesday, April 4, 2000
8:30 Poster Viewing &
Coffee and Danish
Lipases
9:00 Chairperson’s Opening
Remarks
Jonathan D. Smith, Ph.D., Associate Professor, Laboratory of Biochemical
Genetics and Metabolism, The Rockefeller University
9:05 Role of Secreted
Phospholipases in Regulation of HDL Metabolism and Function
Daniel J. Rader, M.D., Assistant Professor of Medicine, University
of Pennsylvania Medical Center
HDL is rich in phospholipids, which are an important determinant of
HDL metabolism and function. Secreted phospholipases such as secretory
PLA2 and endothelial lipase have the ability to hydrolyze HDL phospholipids,
thereby influencing HDL metabolism and function. Modulation of secreted
phospholipases could be a novel target for raising HDL and reducing
atherosclerosis.
9:40 A New Member of the
Triglyceride Lipase Gene Family which Modulates HDL Metabolism
Michael C. Jaye, Research Advisor, Cardiovascular Biology Dept.,
R&D, Rhone-Poulenc Rorer Pharmaceuticals, Inc.
Endothelial lipase (EL) is a 500-residue protein, unlike other members
of the triglyceride lipase family, is expressed by vascular endothelial
cells. In collaboration with D. Rader, we found that intravenous injection
of a recombinant adenovirus expressing human EL in wild-type and apoA-I
transgenic mice profoundly reduced HDL. The endothelial expression,
enzymatic attributes, and effects on lipoproteins in vivo suggest that
EL may have a distinctive role in lipoprotein metabolism and vascular
biology.
10:15 Refreshment Break
& Poster Viewing
Cholesteryl Ester Transfer
ProteIn (CETP)
10:40 An Immunotherapeutic
Approach for the Treatment of Low Plasma HDL - Cholesterol
Charles W. Rittershaus, Director of Discovery Research, AVANT Immunotherapeutics,
Inc.
One determinant of plasma HDL-cholesterol (HDL-C) concentration is cholesteryl
ester transfer protein (CETP) activity. Inhibition of CETP activity
increases plasma HDL-C, thus providing a potential therapeutic approach
to atherosclerosis. CETi-1 is a vaccine-like immunotherapeutic designed
to elicit transient antibodies that reduce endogenous CETP activity.
In a preclinical model, CETi-1 reduced CETP activity, raised HDL-C,
and reduced atherosclerotic lesions. Currently, CETi-1 is undergoing
Phase 1 clinical trials.
11:15 Low Molecular Weight
CETP Inhibitors: A New Approach for the Treatment of Hypoalphalipoproteinemia?
Hilmar Bischoff, Ph.D., Senior Research Scientist, Bayer AG, PH-R
Cardiovascular III, Germany
Low HDL-C is well accepted as an independent risk factor for CAD. It
is believed that plasma cholesteryl ester transfer protein (CETP) plays
a central role in reverse cholesterol transport. CETP exchanges cholesteryl
ester and triglycerides between HDL and apoB - containing lipoproteins,
leading to a decrease in HDL-C. Inhibition of CETP activity by low molecular
weight inhibitors substantially increased HDL-C in animal models. The
‘artificial disease’ of low HDL-C in hCETP transgenic mice was completely
reversed and their lipoprotein pattern was normalized.
11:50 Lunch on your own
Scavenger Receptor B Type
I
1:15 Regulation of Cla-1/SR-BI
and ABC-1 Mediated Pathways as Key Determinants of Apo A1/HDL Induced
Cholesterol Efflux
Wolfgang Drobnik, M.D., Institute of Clinical Chemistry and Laboratory
Medicine, University Clinic of Regensburg, Germany
Recently, we have identified ABC-1 as a key mediator in the conversion
of apo AI and lipid poor HDL-precursor to mature HDL. The underlying
mechanism involves the function of ABC-1 to promote cholesterol and
phospholipid efflux from peripheral cells. We have thoroughly investigated
the second messenger regulation of this pathway and report on the modulatory
impact of a variety of phospholipid breakdown products including 1,2-diacylglycerol,
phosphatidic acid and ceramide as well as cAMP activated kinase. Beside
ABC-1, a major role in HDL metabolism has recently been attributed to
Cla-1/SR-BI. This HDL-receptor is primarily involved in the uptake of
HDL-cholesterol in the liver and the adrenals but has also been suggested
to participate in the lipid efflux from peripheral cells. In support
for the latter mechanism we provide evidence that Cla-1 is up-regulated
during phagocytic differentiation of human monocytes and regulated by
several pro-inflammatory stimuli including TNF-alpha. In collaboration
with Buechler C. and Schmitz G., Institute of Clinical Chemistry and
Laboratory Medicine, University Clinic of Regensburg, Germany.
1:55 SR-BI-Mediated Cholesterol
Transport Between HDL and Cells
Michael C. Phillips, Research Professor, The Children’s Hospital
of Philadelphia
SR-BI is expressed in liver and adrenal cells where it mediates cellular
uptake of cholesterol from HDL. The so-called selective uptake of cholesteryl
ester (CE) from HDL involves binding of HDL to SR-BI. This allows diffusion
of CE molecules along a non-aqueous channel created by SR-BI between
the bound HDL and the plasma membrane. SR-BI is also expressed in peripheral
cells such as macrophages where it can facilitate efflux of free cholesterol
(FC) from the plasma membrane. This occurs because SR-BI alters plasma
membrane FC organization.
2:35 Effects of in vivo
SR-BI Overexpression on HDL Metabolism and Atherosclerosis
Karen F. Kozarsky, Ph.D., SmithKline Beecham Pharmaceuticals
Hepatic overexpression of the HDL receptor SR-BI in normal mice has
been shown to result in decreased plasma HDL cholesterol levels. To
determine whether SR-BI overexpression is proatherogenic or is protective
against atherosclerosis, we have overexpressed SR-BI in a strain of
mice that develops atherosclerosis, and show that overexpression significantly
decreases atherosclerotic lesions. SR-BI may provide a novel target
for therapeutic intervention in atherosclerotic cardiovascular disease.
3:15 End of Conference
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Conference Co-chairs
Gerd Schmitz, University Clinic of Regensburg, Germany
Jonathan D. Smith The Rockefeller University
Distinguished Faculty
Hilmar Bischoff, Bayer AG, Germany
Wolfgang Drobnik, University Clinic of Regensburg, Germany
Christian Ehnholm, National Public Health Institute, Finland
Christopher J. Fielding, University of California San Francisco
Michael R. Hayden, University of British Columbia, Canada
Michael C. Jaye, Rhone-Poulenc Rorer Pharmaceuticals
Karen F. Kozarsky, SmithKline Beecham Pharmaceuticals
Mark E. McGovern, Kos Pharmaceuticals, Inc. Merck Research Laboratories
John F. Oram, University of Washington
Michael C. Phillips, The Children’s Hospital of Philadelphia
Daniel J. Rader, University of Pennslyvania Medical Center
Charles W. Rittershaus, AVANT Immunotherapeutics, Inc.
Uday Saxena, AtheroGenics, Inc.
Ernst J. Schaefer, New England Medical Center
Gerd Schmitz, University Clinic of Regensburg
Jonathan D. Smith, The Rockefeller University
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