Integration of Metabolism, Energetics, and Signal Transduction: Unifying Foundations in Cell Growth and Death, Cancer, Atherosclerosis, and Alzheimer Disease

392 Pages·2004·8.41 MB·English

by  Robert K. Ockner M.D. (auth.)

Integration of Metabolism,
Energetics, and
Signal Transduction
Integration of Metabolism,
Energetics, and
Signal Transduction
Unifying Foundations in Cell Growth
and Death, Cancer, Atherosclerosis,
and Alzheimer Disease
Robert K. Ockner, M.D.
University of California, San Francisco
San Francisco, California
KLUWER ACADEMIC PUBLISHERS
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DEDICATION
This book is dedicated to my wife Elaine; my sons Jim, Matt, and Peter;
my brother Steve; and to my parents, the late Lee and Sara Ockner.
v
PREFACE
Complex and unexplained phenomena tend to foster unorthodox
perspectives. This publication is an example, as is a prior publication that
emphasized the concept that intermediary metabolism might play a
significant and determining role in hepatocyte proliferation and
tumorigenesis1. Formulation of this hypothesis was based on an attempt to
clarify several poorly understood phenomena; including the observations: 1)
that xenobiotic peroxisome proliferators such as the fibrate hypolipidemic
agents induce hepatocyte proliferation and carcinogenesis in rodents; 2) that
benign and malignant liver tumors complicate the human syndrome of
glycogen storage disease type I (glucose-6-phosphatase deficiency); and 3)
that in this same syndrome, administration of glucose exerts an anti-tumor
effect. Fatty acid and glucose metabolism are tightly linked in a well-
established and profoundly inportant interplay. This connection, together
with the fact that peroxisome proliferator-induced hepatocyte proliferation
and carcinogenesis reflects inhibition of mitochondrial carnitine
palmitoyltransferase-I and fatty acid oxidation, suggested the possibility that
regulation of fatty acid metabolism could prove to be a pivotal determinant
in the control of cell growth.
In 1993, the year in which the paper cited above was published, insight
into the importance of growth factors and signal transduction pathways in
cell cycle regulation was increasing rapidly, but metabolic and energetic
aspects of cell proliferation had attracted relatively little attention. Despite
this, the concept seemed inescapable that the two seemingly distinct and
unrelated determinants — signal transduction and metabolism — were
integrally linked. Moreover, it is known that growth regulation in the
earliest eukaryotes was governed largely or exclusively by nutritional,
metabolic, and energetic factors hundreds of millions of years before the
appearance of intercellular signaling in higher organisms. It seemed
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viii Preface
plausible, therefore, that these factors had retained a dominant regulatory
role, at least under certain conditions, throughout the evolution of today’s
more advanced and complex species. What has emerged through the
development of this treatise is evidence strongly suggesting that metabolism
and energetics, while at times referred to as “housekeeping” functions, are
intimately and directly linked to those signal transduction pathways that are
essential to survival of the cell, the organism, and the species.
Initial work on the project (later to become Part II of the present volume)
involved review of published contributions of many insightful and
productive scientists. These addressed a broad range of relevant issues,
including intermediary metabolism, signal transduction, and cell cycle
regulation, and the effects of alternative substrates on mitochondrial
energetics. Our preliminary2 and unpublished experiments addressed the
effects of endogenous and xenobiotic growth modulators on fatty acid
metabolism and mitochondrial function, and provided critically important
early insight and stimulus.
Unexpectedly, it also became appreciated during this time that, despite
suppression of glucose utilization in brain regions affected by Alzheimer
disease, neurons in those regions remained viable. Viewed in the context of
the current project, this otherwise seemingly unrelated observation suggested
the possibility that utilization of alternative substrates might also prove to be
a critical determinant in the energetics, function, and injury of the neuron.
Pursuit of published research related to this hypothesis led to the recognition
of what appeared to be important parallels in intermediary metabolism and
signal transduction between neuronal activation (Part III of this volume) and
cell proliferation (Part II). Initially, Parts II and III were developed as
separate analytical reviews. With the passage of time, however, their
sustained growth in size, scope, and relatedness made separate publication
less feasible and less desireable. As a result, they are included in the present
combined format, along with short introductory and concluding sections
(Parts I and IV, respectively) that provide overall perspective.
As work on the project progressed, it required ongoing review of
increasing numbers of new publications in diverse fields; those findings
most relevant to the integrated approach were selected for incorporation.
Encouragingly, few published reports offered serious challenge to the
present interpretations and hypotheses; of those, the more important are cited
and discussed. Moreover, with continuing development of the project, its
fundamental concepts became applicable to a growing number of
surprisingly diverse additional areas, ranging from an early focus on liver
regeneration to include programmed cell death3, cancer cachexia,
atherosclerosis, ischemia-reperfusion injury, regulation of feeding behavior,
aspects of synaptic function, and the pathogenesis of Alzheimer disease.
Preface ix
While their broad relevance has provided additional support to many of the
concepts, it has also required considerable stringency in the selection of
publications for citation. As the regrettable but inevitable result, it was not
possible to include reference to numerous other excellent publications that
seemed less related to the present focus or less essential to its development.
In any case, the project’s very nature dictates that it will remain a work in
progress.
REFERENCES
1.R. Ockner, R. Kaikaus, and N. Bass, Fatty acid metabolism and the pathogenesis of
hepatocellular carcinoma: review and hypothesis, Hepatology 18:669-676 (1993).
2.R. Ockner, N. Lysenko, N. Wu, and N. Bass, Hepatocyte growth inhibitors modulate
mitochondrial and extramitochondrial fatty acid oxidation, Hepatology 24:253A
(Abstract) (1996).
3.R. Ockner, Apoptosis and liver diseases: Recent concepts of mechanisms and significance,
J Gastroenterol Hepatol 16:248-260 (2001).
ACKNOWLEDGEMENTS
I thank my bright, creative, and collegial former associates in fatty acid
and fatty acid binding protein research at the University of California, San
Francisco (UCSF), among them Nathan M. Bass, Ruth Brandes, David A.
Burnett, Alfred Gangl, John L. Gollan, Albert L. Jones, Raja M. Kaikaus,
Richard A. Weisiger, Nina Lysenko, Joan A. Manning, and, in collaborative
projects, David H. Alpers, Jeffrey I. Gordon, and E. Raghupathy. I also
wish to express appreciation for encouragement in the present project by
other colleagues at UCSF: Rudi Schmid, D. Montgomery Bissell, Stephen
DeArmond, Richard J. Havel, the late Ira Herskowitz, John Kane, Young S.
Kim, Robert Mahley, Frank McCormick, Bruce Miller, R. Curtis Morris, and
Marvin H. Sleisenger. Members of the UCSF Liver Center, Division of
Gastroenterology, and Comprehensive Cancer Center have represented an
ongoing and congenial source of information and stimulation. Sadie
McFarlane provided expert assistance in preparation and formatting of the
manuscript; she also accomplished the digital transformation of my original
drawings to clear and informative illustrations. The project was supported in
part at its inception by research grant R01 AM13328, and throughout its
development by Liver Center Grant P30 DK26743, both from the National
Institutes of Health. Figures 1 and 2 from Journal of Gastroenterology and
Hepatology, 2001;16:248-260, are used with the permission of Blackwell
Publishing. Finally, to the extent that my time and energies became
increasingly devoted to this project, others in the Division of
Gastroenterology and Liver Center have carried a correspondingly increased
workload; their efforts are truly appreciated.
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CONTENTS
PART I:
PROLOGUE 1
1.DISPARATE THEMES: ORIGINS AND INTEGRATION 3
PART II:
FATTY ACIDS, MITOCHONDRIA, AND SIGNAL
TRANSDUCTION: INTEGRATED CONTROL OF CELL
PROLIFERATION, INJURY, AND DEATH 11
2. INTRODUCTION TO PART II 13
3. NUTRIENT AND ENERGY METABOLISM IN CELL
PROLIFERATION 19
3.1. INTRODUCTION 19
3.2. INTERMEDIARY METABOLISM: GENERAL
CONSIDERATIONS 19
3.3. ATP GENERATION, CARBOHYDRATE METABOLISM,
AND CELL GROWTH 22
3.3.1.AerobicGlycolysis, Mitochondrial Respiration, and
OxidativePhosphorylation 23
3.3.2. Wingless/Wnt-Like Signaling: Convergence of
Antecedents and the Unpredictable 27
3.3.2.1. Broader Significance of wg/Wnt-Like
Signaling 31
3.3.2.2. Lithium 33
3.3.2.3. Reactive Oxygen Species 33
3.4. REFERENCES 35
4. FATTY ACIDS AND GROWTH REGULATION 47
4.1. INTRODUCTION 47
4.2. OMEGA-6 FATTY ACIDS 48
4.3. OMEGA-3 FATTY ACIDS 51
4.3.1. Metabolic Effects 51
4.3.2. Growth Effects 52
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xiv Contents
4.4. FATTY ACIDS, MODULATION OF CELL GROWTH,
AND THE AMP-ACTIVATED PROTEIN KINASE 53
4.4.1. AMP-Activated Protein Kinase 57
4.4.2. Stoichiometric Considerations 58
4.5. METABOLIC INTERACTION BETWEEN TUMOR AND
HOST: CANCER CACHEXIA 61
4.6. REFERENCES 64
5. MITOCHONDRIALFUNCTION IN CELL GROWTH AND
DEATH 77
5.1. INTRODUCTION 77
5.2. PEROXISOME PROLIFERATOR-ACTIVATED
RECEPTORS (PPAR) AND LIGANDS:
MITOCHONDRIAL REDOX,MACROPHAGES, AND
MITOSIS 78
5.2.1. 78
5.2.2. 84
5.2.3. 85
5.3. MITOCHONDRIAL FUNCTION IN APOPTOSIS 85
5.3.1.The Bcl-2 Protein Family 88
5.3.2. wg/Wnt-Like Signaling: Convergence of
Mitochondria, p53, and Telomerase 90
5.3.3.Mitochondria and FasL-Independent Activation of
Fas 93
5.3.4. Apoptosis and the Cell Cycle: Chronic Viral
Hepatitis and Cancer 95
5.4. REFERENCES 98
6. METABOLIC EFFECTS OF ANTIPROLIFERATIVE
AGENTS 121
6.1. INTRODUCTION 121
6.2. BUTYRATE 121
6.3. TRANSFORMING GROWTH 125
6.4. SALICYLATES AND OTHER NONSTEROIDAL
ANTI-INFLAMMATORY DRUGS (NSAIDS) 127
6.5. REFERENCES 132
7. FATTY ACIDS AND MITOCHONDRIA, CELL GROWTH
AND INJURY: BROADER IMPLICATIONS 143
7.1. INTRODUCTION 143
7.2. ADVERSE EFFECTS OF FATTY ACIDS ON
MITOCHONDRIAL FUNCTION AND CELL REDOX
BALANCE 143
7.3. ORIGINS OF INTRAMITOCHONDRIAL OXIDATIVE
STRESS 145
7.4. CONSEQUENCES OF INTRAMITOCHONDRIAL
OXIDATIVE STRESS: ATHEROSCLEROSIS
AND BEYOND 148
7.4.1. Atherosclerosis and Arterial Hypertension 149