Integration of Metabolism, Energetics, and Signal Transduction

1. Front Matter

   Pages i-xvii

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2. Prologue

   1. Front Matter

      Pages 1-1

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   2. Disparate Themes: Origins and Integration

      Pages 3-9

3. Fatty Acids, Mitochondria, and Signal Transduction: Integrated Control of Cell Proliferation, Injury, and Death

   1. Front Matter

      Pages 11-11

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   2. Introduction to Part II

      Pages 13-18

   3. Nutrient and Energy Metabolism in Cell Proliferation

      Pages 19-45

   4. Fatty Acids and Growth Regulation

      Pages 47-75

   5. Mitochondrial Function in Cell Growth and Death

      Pages 77-119

   6. Metabolic Effects of Antiproliferative Agents

      Pages 121-142

   7. Fatty Acids and Mitochondria, Cell Growth and Injury: Broader Implications

      Pages 143-175

   8. Metabolism and Gene Expression in Liver Regeneration

      Pages 177-200

   9. Part II Conclusions

      Pages 201-204

4. Fatty Acids, Ketone Bodies, and Brain Metabolism: Implications for Neuronal Function and Alzheimer Disease

   1. Front Matter

      Pages 205-205

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   2. Introduction to Part III

      Pages 207-208

   3. Energetics of Neuronal Activation

      Pages 209-215

   4. Utilization of Oxidizable Substrates in Brain

      Pages 217-254

   5. Astrocyte Metabolism and Astrocyte-Neuron Interaction

      Pages 255-276

   6. Neuronal Energy Metabolism in Brain: Astrocyte as both Metabolic “Buffer” and Mediator of Neuronal Injury

      Pages 277-302

   7. Pathogenesis of Alzheimer Disease: Metabolic Factors

      Pages 303-353

   8. Part III Conclusions

      Pages 355-358

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 1 tumorigenesis. 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 we- 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.

• Alzheimer
• gene expression
• metabolism
• neurology
• proteins

• University of California, San Francisco, San Francisco

  Robert K. Ockner

Robert K. Ockner, M.D., Professor of Medicine at the University of California, San Francisco, graduated from Pomona College and Harvard Medical School, and completed clinical and research training at Boston City Hospital, National Institutes of Health, and Massachusetts General Hospital. He is former Director of the UCSF Division of Gastroenterology and the UCSF Liver Center, and served as Editor of Gastroenterology, Co-Editor of Progress in Liver Diseases, and Associate Editor of the Journal of Lipid Research. He and colleagues initially identified and characterized the cytosolic fatty acid binding proteins.

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