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Cmt Thesis Before Fat in hearts: Uptake, storage, and turnover Chad M Trent Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy under the Executive Committee of the Graduate School of Arts and Sciences COLUMBIA UNIVERSITY 2014 © 2014 Chad M Trent All rights reserved Fat in hearts: Uptake, storage, and turnover Chad M Trent Abstract The heart is one of the most energy demanding organs and is metabolically flexible to meet those demands. A major fraction of the hearts energy is derived from the uptake of circulating lipids; this dissertation reviews general pathways of lipid metabolism and then discusses how the heart obtains lipids and how these lipids are processed once inside the heart. Furthermore, derangements in lipid uptake and processing that are associated or causative of cardiac dysfunction are discussed. A new finding describes how the mouse heart requires lipoprotein lipase derived fatty acids for intracellular lipid droplets formation. Finally, the implications of these findings and future studies are described. Table of Contents List of Figures ................................................................................................................................ iv List of Tables ............................................................................................................................... viii List of Abbreviations ..................................................................................................................... ix Chapter 1: Introduction to lipid metabolism ................................................................................... 1 Overview of lipids ....................................................................................................................... 1 Activation of lipids ...................................................................................................................... 2 Esterification of lipids ................................................................................................................. 3 Fatty acid oxidation ..................................................................................................................... 4 Fatty acid synthesis ..................................................................................................................... 6 Dietary lipid absorption and circulation ...................................................................................... 6 In vivo models of lipoprotein lipase function .............................................................................. 9 Characterization of the fatty acid transporter cluster of differentiation 36 ............................... 11 Additional proteins involved in FFA transport ......................................................................... 13 Lipid droplets and associated proteins ...................................................................................... 19 Lipid droplet synthesis and degradation .................................................................................... 25 i Intracellular lipolysis ................................................................................................................. 26 Transcriptional regulation of lipid metabolism ......................................................................... 27 Chapter 2: Lipid metabolism and toxicity in the heart ................................................................. 31 Introduction ............................................................................................................................... 31 Lipid uptake and turnover in the heart ...................................................................................... 33 Creation of cardiac lipotoxicity in mice .................................................................................... 37 Lipid stores and the causes of toxicity ...................................................................................... 38 Correction of lipotoxic heart disease ......................................................................................... 40 Conclusions ............................................................................................................................... 44 Chapter 3: Lipoprotein lipase activity is required for cardiac lipid droplet production ............... 45 Abstract ..................................................................................................................................... 45 Introduction ............................................................................................................................... 45 Materials and Methods .............................................................................................................. 47 Results ....................................................................................................................................... 56 Fasted Ppara-/- mice do not store lipids in the heart .............................................................. 56 Fasted Cd36-/- mice do not store lipids in the heart ................................................................ 66 ii Fasted hLpL0 mice do not store lipids in the heart ................................................................ 75 Plin2 and Plin5 protein expression is not affected by cardiac lipid stores ............................ 85 Blocking circulating TG degradation prevents cardiac lipid accumulation ........................... 90 Cardiac TG accumulation during fasting does not impair heart function ............................ 104 Discussion ............................................................................................................................... 109 Chapter 4: Conclusions and future directions ............................................................................. 121 References ................................................................................................................................... 125 iii List of Figures Figure 1 - Uptake, storage, and oxidation of fatty acids ................................................................. 5 Figure 2 - Adrenergic regulation of intracellular lipolysis ........................................................... 23 Figure 3 - PPARs: transcriptional control of lipid metabolism .................................................... 28 Figure 4 - Cartoon of cardiac lipid metabolism ............................................................................ 36 Figure 5 - Correcting cardiac lipotoxicity ..................................................................................... 43 Figure 6 - Plasma biochemistry of fed and fasted Ppara+/+ and Ppara-/- mice ............................. 56 Figure 7 - Lipid measurements from hearts of fed and fasted Ppara+/+ and Ppara-/- mice .......... 57 Figure 8 - ORO staining of hearts from fed and fasted Ppara+/+ and Ppara-/- mice ..................... 58 Figure 9 - PAS staining of hearts from fed and fasted Ppara+/+ and Ppara-/- mice ................... 59 Figure 10 - Glycogen content of hearts from fed and fasted Ppara+/+ and Ppara-/- mice ............ 60 Figure 11 - Gene expression in hearts from fed and fasted Ppara+/+ and Ppara-/- mice .............. 62 Figure 12 - Supplemental gene expression in hearts from fed and fasted Ppara+/+ and Ppara-/- mice ............................................................................................................................................... 64 Figure 13 - TG lipase activity in hearts from fed and fasted Ppara+/+ and Ppara-/- mice ............ 65 Figure 14 - Plasma biochemistry of fed and fasted Cd36+/+ and Cd36-/- mice ............................. 67 iv Figure 15 - Lipid measurements from hearts of fed and fasted Cd36+/+ and Cd36-/- mice ........... 68 Figure 16 - ORO staining of hearts from fed and fasted Cd36+/+ and Cd36-/- mice ..................... 69 Figure 17 - PAS staining of hearts from fed and fasted Cd36+/+ and Cd36-/- mice ...................... 70 Figure 18 - Glycogen content of hearts from fed and fasted Cd36+/+ and Cd36-/- mice ............... 71 Figure 19 - Gene expression in hearts from fed and fasted Cd36+/+ and Cd36-/- mice ................. 72 Figure 20 - Supplemental gene expression in hearts from fed and fasted Cd36+/+ and Cd36-/- mice ....................................................................................................................................................... 73 Figure 21 - TG lipase activity in hearts from fed and fasted Cd36+/+ and Cd36-/- mice ............... 74 Figure 22 - Plasma biochemistry of fed and fasted LpLflox/flox and hLpL0 mice .......................... 76 Figure 23 - Lipid measurements from hearts of fed and fasted LpLflox/flox and hLpL0 mice ....... 77 Figure 24 - ORO staining of hearts from fed and fasted LpLflox/flox and hLpL0 mice .................. 78 Figure 25 - PAS staining of hearts from fed and fasted LpLflox/flox and hLpL0 mice ................... 79 Figure 26 - Glycogen content of hearts from fed and fasted LpLflox/flox and hLpL0 mice ............ 80 Figure 27 - Gene expression in hearts from fed and fasted LpLflox/flox and hLpL0 mice .............. 82 Figure 28 - Supplemental gene expression in hearts from fed and fasted LpLflox/flox and hLpL0 mice ............................................................................................................................................... 83 v Figure 29 - TG lipase activity in hearts from fed
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