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Regulation of Ketone Body and Coenzyme a Metabolism in Liver

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Regulation of Ketone Body and Coenzyme a Metabolism in Liver REGULATION OF KETONE BODY AND COENZYME A METABOLISM IN LIVER by SHUANG DENG Submitted in partial fulfillment of the requirements For the Degree of Doctor of Philosophy Dissertation Adviser: Henri Brunengraber, M.D., Ph.D. Department of Nutrition CASE WESTERN RESERVE UNIVERSITY August, 2011 SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of __________________ Shuang Deng ____________ _ _ candidate for the ________________________________degree Doctor of Philosophy *. (signed) ________________________________________________ Edith Lerner, PhD (chair of the committee) ________________________________________________ Henri Brunengraber, MD, PhD ________________________________________________ Colleen Croniger, PhD ________________________________________________ Paul Ernsberger, PhD ________________________________________________ Janos Kerner, PhD ________________________________________________ Michelle Puchowicz, PhD (date) _______________________June 23, 2011 *We also certify that written approval has been obtained for any proprietary material contained therein. I dedicate this work to my parents, my son and my husband TABLE OF CONTENTS Table of Contents…………………………………………………………………. iv List of Tables………………………………………………………………………. viii List of Figures……………………………………………………………………… ix Acknowledgements………………………………………………………………. xii List of Abbreviations………………………………………………………………. xiv Abstract…………………………………………………………………………….. xvii CHAPTER 1: KETONE BODY METABOLISM 1.1 Overview……………………………………………………………………….. 1 1.1.1 General introduction of ketone bodies……………………………….. 1 1.1.2 Ketogenesis is stimulated by fasting, stress and diabetes………… 1 1.1.3 Ketone body utilization in peripheral tissues………………………. 2 1.2 Adipose tissue lipolysis and regulation…………………………………….. 3 1.2.1 General introduction of lipolysis………………………………………. 3 1.2.2 Lipolysis is regulated by dietary, hormonal and neurological factors…………………………………………………………………... 3 1.2.3 Enzymes involved in lipolysis…………………………………………. 4 1.2.4 Mechanism of lipolysis…………………………………………………. 5 1.2.5 Measurement of lipolysis………………………………………………. 7 1.2.6 Adipocyte lipolysis provides substrates for ketogenesis…………… 8 1.3 Fatty acid β-oxidation and its regulation……………………………………. 9 1.3.1 Formation of acyl-CoA and its regulation……………………………. 9 1.3.2 CPT system and its regulation by malonyl- CoA, dietary and iv hormonal factors………………………………………………………... 10 1.3.3 The mitochondrial β-oxidation cycle and its regulation…………….. 12 1.3.4 Generation and utilization of acetyl-CoA…………………………….. 13 1.4 The β-hydroxy-β-methylglutaryl-CoA (HMG-CoA) cycle and its regulation.……………………………………………………………….. 1 4 1.4.1 Overview of the HMG-CoA cycle……………………………………... 14 1.4.2 Function of the mitochondria HMG-CoA…………………………….. 14 1.4.3 Regulation of the HMG-CoA cycle……………………………………. 14 1.5 C5-ketogenesis and its regulation…………………………………………… 15 1.5.1 Overview………………………………………………………………… 15 1.5.2 Sources of odd-chain fatty acids in animals…………………………. 17 1.5.3 C5-ketone body formation and its regulation………………………… 17 1.6 The ketone body utilization…………………………………………………... 18 1.6.1 The ketone body utilization pathway…………………………………. 18 1.6.2 The ketone body utilization in fetal liver…………………………….. 20 1.6.3 The ketone body utilization in peripheral tissues…………………… 21 1.7 The role of ketone bodies in mammalian metabolism…………………….. 24 1.8 The measurement of ketone body turnover………………………………... 25 1.8.1 The measurement of ketone body turnover with isotopic methods.. 25 1.8.2 Pseudoketogenesis…………………………………………………….. 27 CHAPTER 2: ANAPLEROSIS 2.1 Overview……………………………………………………………………….. 29 2.2 The cataplerosis……………………………………………………………… 29 v 2.3 The anaplerosis……………………………………………………………….. 31 2.3.1 The significance of anaplerosis……………………………………….. 31 2.3.2 Anaplerotic substrates…………………………………………………. 32 2.3.3 The measurement of anaplerosis…………………………………….. 35 2.3.4 The anaplerotic diet therapy…………………………………………... 36 CHAPTER 3: THE SYNTHESES OF ADENINE NUCLEOTIDES, COENZYME A (CoA) AND DEOXYRIBONUCLEIC ACID (DNA) IN RAT LIVER 3.1 Overview of the biosynthesis pathways of adenine nucleotides, CoA and DNA………………………………………………………………………... 38 3.1.1 Overview………………………………………………………………… 38 3.1.2 The biosynthesis pathway of adenine nucleotides………………… 38 3.1.3 The CoA biosynthesis pathway……………………………………….. 42 3.1.4 The DNA biosynthesis pathway………………………………………. 45 3.2 The techniques used for tracing the biosynthesis pathways…………….. 46 3.2.1 The techniques used for tracing ATP synthesis from ADP………… 47 3.2.2 The echniques used for tracing CoA synthesis……………………... 48 3.2.3 The techniques used for tracing DNA synthesis……………………. 48 3.3 Tracing the syntheses of biopolymers with [2H]water…………………….. 49 3.3.1 Overview………………………………………………………………… 49 3.3.2 Principle of the use of [2H]water to trace the biosyntheses of (pseudo)-biopolymers………………………………………………….. 50 3.3.3 General protocols of application of [2H]water……………………….. 53 vi 3.3.4 The pros and cons of using [2H]water………………………………... 54 3.3.5 Tracing the syntheses of biopolymers……………………………….. 56 CHAPTER 4: RESEARCH PROPOSAL 4.1 Project 1. C4- and C5-ketogenesis in rat liver……………………………… 62 4.2 Project 2. Tracing the syntheses of adenine nucleotides, CoA and DNA 65 in rat liver………………………………………………………….. 4.3 Publications…………………………………………………………………… 68 4.3.1 Deng S., Zhang G.F., Kasumov T., Roe C.R., and Brunengraber H. Interrelations between C4-ketogenesis, C5-ketogenesis, and anaplerosis In the perfused rat liver. J Biol Chem 284:27799- 27807,2009. …………………………………………………………………………… 68 4.3.2 Deng S., Zhang G.F., Kombu R.S. Harris S.R. DeSantis D., Vasquez E.J., Puchowicz M.A., Anderson V.E., Brunengraber H. Tracing the syntheses of adenine nucleotides, CoA and DNA in rat liver. To be submitted to J Biol Chem. …………………………………………………………………………… 105 CHAPTER 5: IMPLICATIONS AND FUTURE DIRECTIONS 5.1 C4-and C5-ketogenesis in rat liver…………………………………………... 146 5.1.1 Results and Discussion………………………………………………. 146 5.1.2 Future directions……………………………………………………….. 148 5.2 Tracing the syntheses of adenine nucleotides, CoA and DNA in rat liver …………………………………………………………………………... 1 50 5.2.1 Discussion and conclusions…………………………………………... 150 5.2.2 Future directions……………………………………………………….. 152 LITERATURE CITED…………………………………………………………….. 154 vii LIST OF TABLES Table 4.1. Apparent kinetics of the labeling of CoA and its components from 2H-enriched body water in rats over 10 and 31 days………. 129 viii LIST OF FIGURES Figure 1.1. Mechanism of adipocyte lipolysis regulation mediated by PKA… 6 Figure 1.2. Formation of ketone bodies from fatty acid partial β-oxidation…. 16 Figure 1.3. Pathway of ketone-body utilization in peripheral tissues………… 19 Figure 1.4. Pseudoketogensis in extrahepatic tissues………………………… 28 Figure 2.1. Main anaplerotic processes feeding into citric acid cycle……….. 30 Figure 3.1. Biosynthesis pathways of adenine nucleotides, CoA and DNA ………………………………………………………………………… 39 Figure 3.2. Pathway of Coenzyme A synthesis………………………………... 43 Figure 3.3. Protocol for using [2H]water to trace the rates of synthesis and degradation of biopolymers in vivo………………………………… 55 Figure 4.1. Scheme of C4-ketogenesis and C5-ketogenesis in the liver…….. 95 Figure 4.2. Comparison between the uptake of octanoate (A), heptanoate (B), or propionate (C) and the production of C4-ketone bodies and C5-ketone bodies………………………………………………… 96 Figure 4.3. Competition between octanoate and heptanoate for uptake by perfused rat livers……………………………………………………. 97 Figure 4.4. Competition between C4-ketogenesis from octanoate and C5- ketogenesis from heptanoate in perfused rat livers……………… 98 Figure 4.5. Profiles of concentrations of octanoate (●) and propionate (▲) in the effluent perfusate……………………………………………… 99 Figure 4.6. Labeling pattern of effluent β-hydroxybutyrate (BHB) and tissue acetyl-CoA from livers perfused with increasing concentrations ix 13 13 of [1- C]octanoate (A) or [8- C]octanoate (B)………………….. 100 Figure 4.7 Sharing of acetyl groups between C4- and C5-ketogenesis reflected by the mass isotopomer distribution of BHB and BHP… 101 Figure 4.8 Mass isotopomer distribution of HMG-CoA (A) and HEG-CoA (B) in livers perfused with constant 1 mM [1-13C]heptanoate and increasing concentrations of unlabeled octanoate……………….. 102 Figure 4.9 Mass isotopomer distribution of BHB-CoA and AcAc-CoA in livers perfused with increasing concentrations of [1-13C]octanoate …………………………………………………………………………. 103 Figure 4.10 Anaplerosis and glucose labeling from increasing 13 13 concentrations of [ C3]propionate (♦) or [5,6,7- C3]heptanoate (■,▲)…………………………………………………………………. 104 Figure 4.11. Sites of labeling of nucleotides, CoA and DNA from [2H]water ………………………………………………………………………... 132 Figure 4.12. In vivo labeling of liver CoA from [2H]water over 31 days……… 133 Figure 4.13. In vivo labeling of liver dR-DNA [2H] from water over 10 days… 134 Figure 4.14. Mass isotopomer distribution of liver perfusate glucose in 2 100% H2O buffer…………………………………………………... 135 Figure 4.15. Mass isotopomer distribution of glucose-6-P, ribose-5-P and PEP in livers perfused with 4 mM unlabeled glucose in 100% 2 H2O buffer………………………………………………………….. 136 Figure 4.16. M1 enrichment of AMP, ADP, ATP and CoA in livers perfused 2 with 4 mM unlabeled glucose in 100% H2O buffer……………… 137 x Figure 4.17. M1 enrichment of AMP, ADP, ATP in livers perfused with 4 mM unlabeled glucose in buffers enriched 0 to 100% with 2 H2O…………………………………………………………………... 138 Figure 4.18. M1 enrichment of CoA and its components in livers perfused with 4 mM unlabeled glucose in buffers enriched 0 to
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