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Peroxisome
Proliferator
Activated
Receptor
s:

From Basic Science to Clinical Applications

Medical Science Symposia Series

Volume 18

The titles published in this series are listed at the end of this volume.
Peroxisome
Proliferator
Activated
Receptor
s:
From Basic Science to Clinical Applications
Edited by

J.-C. Fruchart
Institut Pasteur de Lille, Universite de Lille II, Faculte des SciencesPharmaceutiques et
Biologiques, Inserm U 545, Dept. Atherosclerose, Lille, France

A . M . Gotto, Jr.

Weill Medical College of Cornell University, New York, New York, USA

R. Paoletti
Department of Pharmacological Sciences,University of Milan, Milan, Italy
B. Staels
University of Lille II, Department of Atherosclerosis, Pasteur Institute,
Inserm U 545, Lille, France

and

A.L . Catapano

*
Department of Pharmacological Sciences,University of Milan, Milan, Italy

SPRINGER SCIENCE+BUSINESS MEDIA , B.V.

Library of Congress Cataloging-in-Publication Data

International Symposium on PPARs: From Basic Science to Clinical Applications (1st:

2001 : Florence, Italy)
Peroxisome proliferator activated receptors :frombasic science to clinical applications
/ edited by J.-C. Fruchart... [et al.].
p.; cm. — (Medical science symposia series ; v. 18)
Includes bibliographical references and index.
ISBN 978-1-4613-5427-7 ISBN 978-1-4615-1171-7 (eBook)
DOI 10.1007/978-1-4615-1171-7
1. Transcription factors-Congresses. 2. Nuclear receptors (Biochemistry)-Congresses.
3. Peroxisomes-Congresses. I. Fruchart, J. C. (Jean-Charles), 1945- II. Title. III. Series.
[DNLM: 1. Receptors, Cytoplasmic and Nuclear-Congresses. 2. Transcription
Factors-Congresses. QU 55 16476p 2002]
QP552.T68 155 2001

616'.042-dc21 2002074104

I S B N 978-1-4613-5427-7

Printed on acid-free paper

All Rights Reserved

© 2002 Springer Science+Business Media Dordrecht
Originally published by Kluwer Academic Publishers in 2002
Softcover reprint of the hardcover 1st edition 2002
No part of the material protected by this copyright notice may be reproduced or utilized in any
form or by any means, electronic or mechanical, including photocopying, recording or by any
information storage and retrieval system, without written permission from the copyright owner.
 CONTENTS

Preface

List of Contributors

STRUCTURE, FUNCTION, AND MOLECULAR MECHANISMS OF PPAR ACTION

1. Peroxisome Proliferator Activated Receptor Alpha Coordinates Intermediary

Metabolism During Fasting
S. Kersten, B. Desvergne, and W Wahli

2. Design, Structure, and Function of Novel PPAR Ligands

T.M Willson, MH Lambert, and HE. Xu

3. Functions of PPAR Gamma in Macrophages and Atherosclerosis

A. Chawla, C.-H. Lee, Y. Barak, D. Liao, and R.M. Evans

INFLAMMATION AND ATHEROSCLEROSIS

4. PPARs and Atherogenesis: Mediators or Modulators of the Inflammatory Response

in the Vessel Wall?
NMarx

5. Role ofPPARs in Inflammation, Atherosclerosis, and Thrombosis

A. Pilon, H Duez, J.-c. Fruchart, and B. Staels

6. Effects ofThiazolidinediones on Vascular Reactivity and Endothelial Dysfunction

E.s. Horton, A.E. Caballero, R. Saouaf, and A. Veves

PPARy AND a AS THERAPEUTIC TARGETS IN DIABETES

7. Activation of Human PP AR Subtypes by Pioglitazone

H Kimura, J. Sakamoto. S. Moriyama, H Odaka, Y Momose, Y Sugiyama, H
Ikeda, and H Sawada

8. PPARy Mechanism of Action Studies

S. Kliewer
vi

ANIMAL MODELS TO STUDY PPAR FUNCTIONS

9. The Role ofPPARa in Fatty Acid Metabolism and Hepatocarcinogenesis: Studies

with PPARa-Nuli Mice
F.J Gonzalez

PP ARa: FROM BASIC SCIENCE TO CLINICAL ApPLICATIONS

10. PPARa, Lipoprotein Metabolism, Metabolic Disease, and Atherosclerosis

J -C Fruchart, B. Staels, and P. Duriez

11. PP ARa and Atherosclerosis

J Plutzky

12. Regulation ofCD36 by PPARy: Pro- or Anti-atherogenic?

M Febbraio, A.M Gotto, Jr., J Han, A.C Nicholson, K. Sharma, E.A. Podrez,
HF. Hoff, s.L. Hazen, JD. Smith, D.P. Hajjar, and R.L. Silverstein

LIPID AND LIPOPROTEIN METABOLISM AND ATHEROSCLEROSIS

13. Anti-inflammatory Properties of High Density Lipoproteins

P. Barter, P. Baker, J. Gamble, M. Vadas, and K.-A. Rye

THE IMPORTANCE OF RAISING HDL: FROM PP ARa TO CLINICAL IMPLICATIONS

14. The Low-HDL Syndrome: Epidemiology and Pathophysiology

G. Franceschini, B. Villa, M Gomaraschi, and L. Calabresi

15. Diabetes: A Growing CHD Epidemic

A. Hamsten and G. Steiner, for the Diabetes Atherosclerosis Intervention Study
Investigators

ADIPOSE TISSUE, OBESITY, AND DIABET·ES

16. Influence of PP ARs on Muscle Lipid Metabolism and Insulin Resistance

E. W. Kraegen, G.l. Cooney, J. Ye, and S.M. Furler

17. PP ARy in Adipogenesis and Insulin Resistance

S.R. Farmer, 1.K. Hamm, B.-H. Park

PPAR8: FUNCTION AND BIOLOGY

 vii

18. Phannacology of a Selective Peroxisome Proliferator-Activated Receptor <'> Agonist,

GW501516, in Obese Dyslipidemic Primates
W Oliver, Jr., D. Sternbach, B. Hansen, and T Willson

PP ARy: FROM BASIC SCIENCE TO CLINICAL ApPLICATIONS

19. PPARy: A Regulator of Growth and Differentiation

S.R. Farmer. D. Prusty, R.F. Morrison, and M Moldes

20. Peroxisome Proliferator Activator Receptor Gamma Agonists Inhibit the

Development of Atherosclerosis in Low Density Lipoprotein Receptor-
Deficient Male Mice
A.e. Li and e.K. Glass

21. Are Thiazolidinediones Superior to Standard Therapy in the Treatment of Type 2

Diabetes?
M-R. Taskinen

CLINICAL STUDIES WITH PP AR LIGANDS

22. PP ARy Ligands and Intestinal Inflammation

A. Flanigan, T.A. Judge, J.D. Lewis, R.J. Stein, G.R. Lichtenstein, J.J. Deren,
R. Ari/uddin, S. Murthy, and G.D. Wu

23. Inflammatory Mechanisms in Alzheimer's Disease: ~-Amyloid-Stimulated

Proinflammatory Responses Are Blocked by PP ARy Agonists
G. Landreth, e. Combs, J.e. Kario, and S. Sundararajan
PREFACE

Less than one decade after the cloning of the first peroxisome proliferator-activated
receptor, PPARs attract great attention in light of the wide spectrum of genes of biological
and medical relevance identified as under their control. As a consequence, our knowledge
of the role of these receptors in physiology and pathology continues to grow at a fast pace,
and PPARs have become an interesting target for the treatment of many pathological
conditions, including diabetes and atherosclerosis.
Within this framework the First International Symposium on P PARs: From Basic
Science to Clinical Applications was held in Florence on April 4-7, 200 I, promoted and
organized by the GIOVANNI LORENZINI MEDICAL FOUNDATION (Milan, Italy and Houston,
Texas, U.S.A.). The aim of the Symposium was to provide the participants with an update
on the latest aspects of basic research and of clinical applications ofPPAR ligands, as well
as to offer an authoritative review of the field.
Attention was focused on the understanding of the molecular mechanisms involved
in PPAR activation and on the interaction with other nuclear factors/cofactors. On the
clinical side, the meeting succeeded in assessing the potential of the most recently
developed drugs in the areas of pathology and therapy, such as diabetes and atherosclerosis.
A selection of lectures presented at the Symposium is included in this volume of
Proceedings and we envision the volume as a means of readily available access to current
knowledge through the publication of critical opinions from leading clinical and scientific
experts.
The Editors would like to thank the personnel of the GIOVANNI LORENZINI
MEDICAL FOUNDATION and the sponsors for having made the Symposium and this volume
possible.

The Editors
LIST OF CONTRIBUTORS

Razi Arifuddin, Division of Gastroenterology, Hahnemann University School of Medicine,

Philadelphia, Pennsylvania, U.S.A.

Paul Baker, University of Adelaide and Hanson Centre for Cancer Research, Adelaide,
Australia

Yaacov Barak, The Jackson Laboratory, 600 Main Street, Bar Harbor, Maine 04609, U.S.A.

Philip Barter, University of Adelaide and Hanson Centre for Cancer Research, Adelaide,
Australia

A. Enrique Caballero, Joslin Diabetes Center, Harvard Medical School, Boston,

Massachusetts, U.S.A.

Laura Calabresi, Center E. Grossi Paoletti, Department ofPharmacological Sciences, University

of Milan, via Balzaretti 9, 20133 Milan, Italy

Ajay Chawla, The Salk Institutefor Biological Studies, Howard Hughes Medical Institute, La
Jolla, California 90237, U.S.A.

Colin Combs, Departments ofNeurosciences and Neurology, Alzheimer Research Laboratory,

Case Western Reserve University, Cleveland, Ohio 44106, U.S.A.

Gregory J. Cooney, Garvan Institute of Medical Research, 384 Vistoria Street, Darlinghurst,
Sydney, NSW 2010 Australia

Julius J. Deren, Division of Gastroenterology, University of Pennsylvania School ofMedicine,

Philadelphia, Pennsylvania, U.S.A.

Beatice Desvergne, Institute of Animal Biology, University of Lausanne, CH-IOI5 Lausanne,

Switzerland

Helene Duez, U 545 INSERM, Departement d?Atherosclerose, Institul Pasteur de Lille, F-

59019 Lille, France and Faculte de Pharmacie, Universite de Lille 2, F-59006 Lille, France

Patrick Duriez, Unite de Recherche sur les Lipoproteines et I'Athirosclerose, Inserm U545,
Institut Pasteur and Universite de Lille 2 - Faculte de Pharmacie, Lille, France

Ronald M. Evans, The Salk Institute for Biological Studies, Howard Hughes Medical Institute,
Xll

La Jolla, California 90237, U.S.A.

Stephen R. Farmer, Department ofBiochemistry, Boston University School ofMedicine, 715

Albany Street, Boston, Massachusetts 02118, U.S.A.

Anne Flanigan, Division of Gastroenterology, Hahnemann University School of Medicine,

Philadelphia, Pennsylvania, U.S.A.

Maria Febbraio, Weill Medical College ofCornell University, 1300 York Avenue, New York, New
York 10021, U.S.A.

Guido Franceschini, Center E. Grossi Paoletti, Department of Pharmacological Sciences,

University of Milan, via Balzaretti 9, 20133 Milan, Italy

Jean-Charles Fruchart, Unite de Recherche surles Lipoproteines et l'AtheroscJerose, Inserm

U545, Institut Pasteur and Univers;te de Lille 2 - Faculte de Pharmacie, Lille, France

Stuart M. Furler, Garvan Institute of Medical Research, 384 Vistoria Streel, Darlinghurst,
Sydney, NSW 2010 Australia

Jennifer Gamble, University ofAdelaide and Hanson Centre for Cancer Research, Adelaide,
Australia

Christopher K. Glass, Department of Medicine, Department of Cellular and Molecular

Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-
0651, U.S.A.

Monica Gomaraschi, Center E. Grossi Paoletti, Department of Pharmacological Sciences,

University of Milan, via Balzaretti 9, 20133 Milan, Italy

Frank J. Gonzalez, Building 37, Room 3E-24, National Institutes ofHealth, Bethesda, Maryland
20892, U.S.A.

Antonio M. Gotto, Jr., Weill Medical College of Cornell University, 1300 York Avenue, New
York. New York 10021, U.S.A.

David P. Hajjar, Weill Medical College of Cornell University, 1300 York Avenue, New York, New
York 10021. U.S.A.

Jonathan K. Hamm, Department ofBiochemistry, Boston University School ofMedicine, 715

Albany Street, Boston, Massachusetts 02118, U.S.A.
 xiii

Anders Hamsten, King GustafV Research Institute, Karolinska Hospital, S-l71 76 Stockholm,
Sweden

Jihong Han, Weill Medical College ofCornell University, 1300 York Avenue, New York, New York
10021, US.A.

Barbara Hansen, Obesity and Diabetes Research Center, University of Maryland School of
Medicine, Baltimore, Maryland 21201, U.S.A.

Stanley L. Hazen, Cleveland Clinic Foundation, Cleveland, Ohio, US.A.

Henry F. Hoff, Cleveland Clinic Foundation, Cleveland, Ohio, US.A.

Edward S. Horton, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts,
U.S.A.

Hitoshi Ikeda, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka,
Japan

Thomas A. Judge, Division of Gastroenterology, University of Pennsylvania School of

Medicine, Philadelphia, Pennsylvania, U.S.A.

J. Colleen Karlo, Departments of Neurosciences and Neurology, Alzheimer Research

Laboratory, Case Western Reserve University, Cleveland, Ohio 44106, U.S.A.

Sander Kersten, Nutrition, Metabolism and Genomics Group, Wageningen University, PO Box
8129, 6700 EV Wageningen, The Netherlands

Hiroyuki Kimura, Discovery Research Laboratories IV, Pharmaceutical Discovery Research

Division, Takeda Chemical Industries, Ltd., 17-85, Jusohonmachi 2-chome, Yodogawa-ku,
Osaka 532-8686, Japan

Steven Kliewer, GlaxoSmithKline Research and Development, Five Moore Dr., Research
Triangle Park, North Carolina 27709, U.S.A.

Edward W. Kraegen, Garvan Institute ofMedical Research, 384 Vistoria Street, Darlinghurst,
Sydney, NSW 2010 Australia

Millard H. Lambert, Nuclear Receptor Discovery Research, GlaxoSmithKline, Five Moore Drive,
Research Triangle Park, North Carolina 27709-3398, US.A.

Gary Landreth, Departments of Neurosciences and Neurology, Alzheimer Research

XIV

Laboratory, Case Western Reserve University, Cleveland, Ohio 44106, U.S.A.

Chih-Hao Lee, The Salk Institute for Biological Studies, Howard Hughes Medical Institute,
La Jolla, California 90237, U.S.A.

James D. Lewis, Division of Gastroenterology, University ofPennsylvania School ofMedicine,

Philadelphia, Pennsylvania, U.S.A.

Andrew C. Li, Department of Medicine, Department of Cellular and Molecular Medicine,

University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651 U.S.A.

Debbie Liao, The Salk Institute for Biological Studies, Howard Hughes Medical Institute, La
Jolla, California 90237, U.S.A.

Gary R. Lichtenstein, Division of Gastroenterology, University of Pennsylvania School of

Medicine, Philadelphia, Pennsylvania, U.S.A.

Nikolaus Marx, Department ofInternal Medicine II- Cardiology, University of Ulm, Robert-Koch-
Str. 8, D-89081 Ulm, Germany

Marthe Moldes, Department of Biochemistry, Boston University School of Medicine, 715 Albany
Street, Boston, Massachusetts, U.SA.

Yu Momose, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan
Shinji Moriyama, Pharmaceutical Discovery Research Division, Takeda Chemical Industries,
Ltd., Osaka, Japan

Ron F. Morrison, Department ofBiochemistry, Boston University School ofMedicine, 715 Albany
Street, Boston, Massachusetts, U.SA.

Sreekant Murthy, Division of Gastroenterology, Hahnemann University School of Medicine,

Philadelphia, Pennsylvania, U.S.A.

Andrew C. Nicholson, Weill Medical College of Cornell University, i300 York Avenue, New
York, New York 10021, U.SA.

Hiroyuki Odaka, Pharmaceutical Research Division, Takeda Chemical industries, Ltd., Osaka,
Japan

William Oliver, Jr., GlaxoSmithKline Research Triangle Park, North Carolina 27709, U.S.A.

Hae-Hang Park, Department of Biochemistry, Boston University School of Medicine. 715

Albany Street, Boston, Massachusetts 02118, U.S.A.
 xv

Antoine Pilon, U 545 INSERM, Departement d?Athirosc/erose, Institut Pasteur de Lille, F-

59019 Lille, France and Faculte de Pharmacie, Universite de Lille 2, F-59006 Lille, France

Jorge Plutzky, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical
School, 211 LongwoodAve., Boston, Massachusetts 20115, U.SA.
Eugene A. Podrez, Cleveland Clinic Foundation, Cleveland, Ohio, U.SA.

Deepanwita Prusty, Department of Biochemistry, Boston University School of Medicine, 715

Albany Street, Boston, Massachusetts, U.SA.

Kerry-Anne Rye, University ofAdelaide and Hanson Centre for Cancer Research, Adelaide,
Australia

Junichi Sakamoto, Pharmaceutical Discovery Research Division, Takeda Chemical Industries,

Ltd., Osaka, Japan

Rola Saouaf, Department of Radiology, Columbia Presbyterian Medical Center, Col/ege of

Physicians and Surgeons, Columbia University Medical School, New York, New York, U.S.A.

Hidekazu Sawada, Pharmaceutical Discovery Research Division, Takeda Chemical Industries,

Ltd., Osaka, Japan

Kavita Shanna, Weill Medical College of Cornell University, 1300 York Avenue, New York, New
York 10021, U.SA.

Roy L. Silverstein, Weill Medical College of Cornell University, 1300 York Avenue, New York,
New York 10021, U.SA.

Jonathan D. Smith, The Rockefeller University, New York, New York, U.SA.

Bart Staels, UR.545INSERM, Departement d'Atherosc/erose, Institut Pasteur de Lil/e, 1 rue

Calmette, BP 245, 59019 Lil/e, France

Robert J. Stein, Division of Gastroenterology, University ofPennsylvania School ofMedicine,

Philadelphia, Pennsylvania, U.S.A.

George Steiner, Department of Endocrinology and Metabolism, The Toronto Hospital/General

Division, NUW 9-112, 200 Elizabeth Street, Toronto, Ontario, M5G 2C4 Canada

Dan Sternbach, GlaxoSmithKline Research Triangle Park 27709, North Carolina, U.S.A.

Yasuo Sugiyama, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka,
xvi

Japan

Sophia Sundararajan, Departments of Neurosciences and Neurology, Alzheimer Research

Laboratory, Case Western Reserve University, Cleveland, Ohio 44106, U.S.A.

Marja-Riitta Taskinen, Department of Medicine, University of Helsinki, Helsinki, Finland

Aristidis Veves, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard
Medical School, Boston, Massachusetts, U.S.A.

Barbara Villa, Center E. Grossi Paoletti, Department of Pharmacological Sciences, University

of Milan, via Balzaretti 9, 20133 Milan, Italy

Mathew Vadas, University ofAdelaide and Hanson Centre for Cancer Research, Adelaide,
Australia

Walter Wahli, Institute of Animal Biology, University of Lausanne, CH-lO 15 Lausanne,

Switzerland

Timothy M. Willson, Nuclear Receptor Discovery Research, GlaxoSmithKline, Five Moore

Drive, Research Triangle Park, North Carolina 27709-3398, U.S.A

Gary D. Wu, 600 Clinical Research Building, 415 Curie Boulevard, Philadelphia,
Pennsylvania 19104-6144, U.S.A.

H. Eric Xu, Nuclear Receptor Discovery Research, GlaxoSmithKline, Five Moore Drive, Research
Triangle Park, North Carolina 27709-3398, U.S.A.

Jiming Ye, Garvan Institute of Medical Research, 384 Vistoria Street, Darlinghurst, Sydney,
NSW 2010 Australia
PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA COORDINATES
INTERMEDIARY METABOLISM DURING FASTING

Sander Kersten, Beatrice Desvergne, and Walter Wahli

Introduction

In response to repeated and long-lasting food shortages during evolution, humans have
evolved with an intricate metabolic control system that allows them to survive prolonged
period of food deprivation. One hallmark of this adaptive system is the ability to store large
amounts of energy in the form of fat in times of plenty and mobilize this energy under
conditions of food shortage such as fasting.
The liver plays a central role in the coordination of energy metabolism during
fasting. For instance, fatty acids are oxidized to form ketone bodies, which are used by
peripheral tissues for energy. In addition, to maintain plasma glucose levels during fasting,
the liver breaks down glycogen and synthesizes glucose from gluconeogenic precursors
such as lactate and glycerol. The metabolic function of the liver is controlled by numerous
transcription factors that regulate the expression of enzymes, binding proteins, transporters,
and many other genes. Indeed, micro-array experiments have revealed the dramatic impact
offasting on hepatic gene expression (Kersten and Wahli, unpublished data). One of these
transcription factors that mediate the hepatic response to fasting is the peroxisome
proliferator activated receptor alpha (PPARa).
PP ARa is one of three different PP AR isotypes that are known to date [1]. The
PPARs are members of the nuclear hormone receptor superfamily. They can be activated
by certain ligands and influence DNA transcription by binding to specific nucleotide
sequences in the promoter region of target genes. The PPARa isotype is mostly expressed
in liver and is the cellular target of fibrate drugs. Fibrates, which include gemfibrozil,
bezafibrate, and fenofibrate, are potent hypolipidemic drugs widely used in the treatment
of cardiovascular disease. It is now evident that one ofthe main functions ofPPARa is to
stimulate the expression of genes involved in fatty acid metabolism in liver, which includes
fatty acid uptake through membranes, fatty acid binding in cells, fatty acid oxidation
(mitochondrial, peroxisomal, and microsomal), and lipoprotein assembly and transport [1].
Clues that PP ARa may be implicated in the hepatic response to fasting were
twofold: first, the expression ofPP ARa follows a circadian rhythm with lowest expression
levels achieved during the nocturnal part, when mice tend to eat [2]. Second, PP ARa
increases the expression of numerous genes involved in hepatic fatty acid oxidation, a
2

process which is known to be activated during fasting [3]. To study the role ofPPARa in
the hepatic response to fasting, we used mice in which the PP ARa gene had been
inactivated. Careful analysis of these mice revealed that they had defects at the level of
lipid, carbohydrate, as well as amino acid metabolism. These effects are elaborated on
below.

Lipid Metabolism

Fasting is normally associated with a dramatic rise in plasma ketone body concentration,
reflecting the accelerated rate of hepatic fatty acid oxidation. However, in mice in which
the PPARa gene has been inactivated, plasma ketone body levels hardly rise, indicating a
marked impairment in fatty acid oxidation and ketogenesis [4,5]. Micro-array and Northern
blot analysis revealed that this was due to reduced mRNA expression of numerous genes
involved in fatty acid oxidation, including acyl-CoA dehydrogenases and HMG-CoA
synthase [4-6]. In contrast to ketone bodies, plasma free fatty acid levels were increased in
fasted PPARa null mice [4]. This probably reflects the diminished capacity for fatty acid
binding and uptake in PP ARa null mice, due to lowered expression of fatty acid
transporters and binding proteins. Fasting ofPP ARa null mice was also associated with the
development of a mild steatosis (fatty liver) phenotype, which indicates the impaired ability
of the liver to properly dispose offatty acids [4].

Carbohydrate Metabolism

During fasting, the plasma glucose level declines, reaching a stable level that is supported
by gluconeogenesis. Interestingly, in PPARa null mice, the drop in plasma glucose is much
more dramatic, causing severe hypoglycemia after a 24-hour fast. Two possible
mechanisms may explain this phenotype. First, the impaired oxidation offatty acids may
compromise gluconeogenesis via interference in allosteric regulation and by causing a
hepatic energy shortage [4]. Second, gluconeogenesis may be reduced because ofdecreased
expression levels of gluconeogenic enzymes in PPARa null mice (Escher and Kersten,
unpublished data). This does not include phosphoenolpyruvate carboxykinase (PEPCK)
whose expression is unaltered in fasted PP ARa null mice compared to wild-type mice [4].

Amino Acid Metabolism

Amino acids are an important energy source for the liver. Indeed, in the fed state, they
probably contribute the major share of energy for liver function. Except for the branched
chain amino acids, most of the amino acids are metabolized in the liver, yielding urea,
which harbors the nitrogen portion of the amino acid molecule, and a diverse array of
carbon-based end products. During fasting, hepatic amino acid metabolism slows down,
resulting in decreased urea production by the liver. Our results suggest that PP ARa
probably plays a role in this process by causing a decrease in the expression of genes
involved. Using subtractive hybridization, micro-array, and Northern blot we find that the
 3

expression of numerous genes involved in transamination, deamination, and the urea cycle
is increased in PP ARu null mice. In contrast, the expression of these genes is reduced by
the synthetic PPARu activator WY14643, suggesting that PPARu is directly involved in
the regulation of amino acid metabolism. This is clearly shown by arginino succinate lyase,
an enzyme of the urea cycle whose expression is increased in fasted PPARu null mice and
decreased by WY14643 (Figure 1).
+/+ -/-
fasted
+/+ -/- WY WY

arginino succinate
lyase

Figure 1. PPARu down-regulates expression of arginino succinate lyase. Expression was

determined by Northern blot using RNA from mouse liver ofPPARu +/+ or -/- mice, fasted
or treated with the synthetic PPARu activator WY14643

Conclusion

Together, these results demonstrate that PPARu plays a central role in intermediary
metabolism during fasting. The overall picture indicates that, during fasting, PPARu
coordinately regulates lipid, carbohydrate, and amino acid metabolism in order to maintain
liver and whole body homeostasis (see Figure 2). As fatty acids serve as ligands for
PPARu, these results also raise the interesting possibility that the fatty acids that are
liberated from the adipose tissue during fasting serve as some kind of hormonal signal that
regulates the activity of a whole repertoire of metabolic reactions via PP ARu.

fat tissue

liver
fatty aci ds •

!I
PPARa + fatty acid oxidation!
:.----~ ketogenesis
+

Figure 2. Schematic representation of the role of PP ARu in hepatic energy metabolism

4

References

1. Kersten S, Desvergne B, Wahli W. Roles ofPPARs in health and disease. Nature 2000;
405 :421-24.
2. Lemberger T, Saladin R, Vazquez M, et al. Expression of the peroxisome proliferator-
activated receptor alpha gene is stimulated by stress and follows a diurnal rhythm. J BioI
Chern 1996;271:1764-69.
3. Aoyama T, Peters JM, Iritani N, et al. Altered constitutive expression "Of fatty acid-
metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha
(PPARalpha). J BioI Chern 1998;273:5678-84.
4. Kersten S, Seydoux J, Peters 1M, Gonzalez FJ, Desvergne B, Wahli W. Peroxisome
proliferator-activated receptor alpha mediates the adaptive response to fasting. J Clin
Invest 1999; 103: 1489-98.
5. Leone TC, Weinheimer CJ, Kelly DP A critical role for the peroxisome proliferator-
activated receptor alpha (PP ARalpha) in the cellular fasting response: The PPARalpha-null
mouse as a model of fatty acid oxidation disorders. Proc Nat! Acad Sci USA 1999;96:
7473-78.
6. Le May C, Pineau T, Bigot K, Kohl C, Girard J, Pegorier J-P. Reduced hepatic fatty acid
oxidation in fasting PP ARa null mice is due to impaired mitochondrial
hydroxymethylglutaryl-CoA synthase gene expression. FEBS Letters 2000;475: 163-66.
 Another Random Document on
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most people that Biorn and those with him went down in the sea of
worms, for they were never heard of again.
It is but little more than this which is known about the fate of the
Huntsman and his followers. One time, traders came back to
Greenland with the tale that Thorhall had been shipwrecked in
Ireland, and that his men had been made thralls of and grievously
misused, and that he had met his death there. No one ever got
other tidings than these.
Better luck went with Thorfinn Karlsefne and Gudrid and those in
their following, for the summer after they had landed in Greenland
they went home to Iceland, and lived there in great splendor and
happiness; and many famous men and high-minded women have
descended from them.
Best luck of all, the foretelling of Karlsefne has come true; and
despite delays and hindrances, his countrymen have found a peace-
land and a never-emptied treasure-house not only in Vinland the
Good but in the whole of the new-world country which those who
are alive to-day call America the Free.

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At Aunt Anna's.
Colored Frontispiece and other Illustrations by William L. Jacobs.
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Miss Lochinvar.
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While this book is written for girls, it contains much of interest

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one."
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Illustrated by B. West Clinedinst. 12mo. Cloth, $1.50.

"It is in every sense an out-and-out boys' book, simple and

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—Boston Herald.

D. APPLETON AND COMPANY, NEW YORK.

ILLUSTRATED JUVENILE STORIES.

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A Story for Girls and Boys. By Katharine N. Birdsall. Illustrated in two
colors by Walter Russell, with many text cuts. 12mo. Cloth, $1.50.

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Christine's Career.
A Story for Girls. By Pauline King. Illustrated.
8vo. Cloth, $1.50.

This book tells of an American girl who has been raised in

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Stories of American History.

By Charlotte M. Yonge (Aunt Charlotte) and H. H. Weld, D.D.
Illustrated. 12mo. Cloth, $1.50.
 A book for young people just beyond the elementary histories of
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D. APPLETON AND COMPANY, NEW YORK.

BY HEZEKIAH BUTTERWORTH.

Brother Jonathan; or, the Alarm Post in the Cedars.

A Tale of Early Connecticut. Illustrated. Colored Frontispiece. 12mo.
Cloth, $1.50.

A stirring tale of the early days of Connecticut, dominated by

the forceful personality of Jonathan Trumbull, whose name,
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A Tale of the "Protector of Birds." Illustrated by B. West Clinedinst
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A Tale of the Discovery of the Philippines. Illustrated by F. T. Merrill
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The Pilot of the Mayflower.
Illustrated by H. Winthrop Peirce and others. $1.50.
True to his Home.
A Tale of the Boyhood of Franklin. Illustrated by H. Winthrop Peirce.
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The Wampum Belt; or, The Fairest Page of History.
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A Tale of the Fortunes of Lafayette. With 6 full-page Illustrations.
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D. APPLETON AND COMPANY, NEW YORK.

YOUNG HEROES OF OUR NAVY.

NEW VOLUME.

With the Flag in the Channel.

 The Adventures of Captain Gustavus Conyngham. By James
Barnes. Illustrated. 12mo. Cloth, $1.00.

OTHER VOLUMES IN THE SERIES.

Illustrated. 12mo. Each, $1.00.
Reuben James.

A Hero of the Forecastle. By Cyrus Townsend Brady, Author of

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The Hero of Manila.

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By Molly Elliot Seawell. With 6 full-page Illustrations.

D. APPLETON AND COMPANY, NEW YORK.

BY WILLIAM O. STODDARD.

Each Illustrated. 12mo. Cloth, $1.50.

The Fight for the Valley.

Colored Frontispiece and other Illustrations.

A narrative of the brave defence of Fort Schuyler and the battle
of Oriskany.

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Illustrated. Colored Frontispiece.

A story of the Yorktown campaign and Benedict Arnold.

With the Black Prince.

A Story of Adventure in the Fourteenth Century. Illustrated by B.

West Clinedinst.
The absorbing interest of this stirring historical romance will
appeal to all young readers.

Success Against Odds; or, How an American Boy made his

Way.
 Illustrated by B. West Clinedinst.
In this spirited and interesting story Mr. Stoddard tells the
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town. It is a tide of pluck and self-reliance capitally told.

The Red Patriot.

A Story of the American Revolution. Illustrated by B. West

Clinedinst.

The Windfall; or, After the Flood.

Illustrated by B. West Clinedinst

Chris, the Model-Maker.

A Story of New York. With 6 full-page Illustrations by B. West

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On the Old Frontier.

With 10 full-page Illustrations.

The Battle of New York.

With 11 full page Illustrations and colored Frontispiece.

Little Smoke.

A Story of the Sioux Indians. With 12 full-page Illustrations by F.

S. Dellenbaugh, portraits of Sitting Bull, Red Cloud, and other
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Crowded Out o' Crofield.

The Story of a country boy who fought his way to success in the
great metropolis. With 23 Illustrations by C. T. Hill.

D. APPLETON AND COMPANY, NEW YORK.

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