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Ceramide Synthase 6 in Metabolic Response to Dietary Fat and Folic Acid

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CERAMIDE SYNTHASE 6 IN METABOLIC RESPONSE TO DIETARY FAT AND FOLIC ACID Keri Anne Barron A dissertation submitted to the faculty at the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Nutrition in the Gillings School of Global Public Health. Chapel Hill 2020 Approved by: Natalia Krupenko Sergey Krupenko Folami Ideraabdullah Susan Smith Stephen Hursting © 2020 Keri Anne Barron ALL RIGHTS RESERVED ii ABSTRACT Keri Anne Barron: Ceramide Synthase 6 in Metabolic Response to Dietary Fat and Folic Acid (Under the direction of Natalia Krupenko) Ceramides, a class of bioactive lipids, are important regulators of cellular metabolism mediating response to nutrient stress. Recent work from our laboratory demonstrated that, in cultured cells, folate stress response is mediated by ceramide synthase 6 (CerS6), a sphingolipid enzyme producing C16-ceramide. To test the hypothesis that alterations in dietary FA will induce a CerS6-dependent response in mice, we evaluated the sphingolipid and metabolomic responses in WT and CerS6 KO mice. We also investigated the role of dietary fat in the response to folate stress in WT and KO mice. This dissertation sought to characterize the sphingolipid and metabolomic responses in wild type (WT) and CerS6 knockout (KO) mice to both short-term alterations in dietary FA as well as to long-term changes in dietary FA combined with high fat diet. As expected, CerS6 KO mice compared to WT mice exhibited significant differences in liver sphingolipids, free fatty acids and phosphatidylethanolamines, among other lipids. Inducing folate stress resulted in changes to sphingolipid pools in the liver with significantly different responses between sexes. Because folate has been shown to influence lipid metabolism, we further challenged CerS6 KO and WT mice by altering folate levels in a high fat diet. We found that the low FA, high fat diet led to increased weight gain, hepatic lipid droplet accumulation, and elevated plasma sphingolipid species in male WT mice only. CerS6 KO mice were mostly iii protected from diet-induced weight gain and lipid droplet accumulation. Additionally, they exhibited significantly lower levels of many plasma sphingolipid species indicating that CerS6 plays a critical role in shaping the plasma sphingolipid profile. Interestingly, the presence of too little or too much FA was similarly detrimental in male WT mice whereas female mice demonstrated a protection on the FD diet. In summary, our studies demonstrate that dietary FA affects hepatic and plasma sphingolipid profiles after short- and long-term consumption and that CerS6 is involved in the whole-body response to folate stress. These results underscore the role of ceramides in mediating nutrient challenges as well as the need to investigate the effects of FA supplementation on tissue metabolomes. iv To my parents, Jim, Stephanie, Kaity, Andy, and Kalie for supporting me in every way, believing in me when I was unable to see the end, and encouraging me daily. I wouldn’t have gotten here without all of you. v ACKNOWLEDGEMENTS To my advisor, Natalia Krupenko, for her mentoring, support, encouragement and taking me in as a student when I needed a lab. Thank you for listening to my input on the studies we planned, always hearing me out, and telling me to calm down when I needed it most. To the original Bennett lab members- the people who first welcomed me into the NRI family and taught me the basics of science I would need for the future. Specifically, thank you to Jody and Melissa for becoming friends and family down here. You never gave up on me and were always willing to listen to me stress and vent. Melissa- thank you for only ever giving me 50% of a protocol but helping me figure it out when everything didn’t work. Jody- thank you for always being a friend even through the hard times. And for cleaning up your side of our bench from time to time. Brian- thank you for always pushing me to be better and learn more, except for learning R. That was dumb and I hated every minute of it. And thank you for buying me a brownie when mine was wrongfully consumed. To Kristen and Madeline- thanks for being supportive and optimistic even when I was miserable, for helping me out with lab work especially all of the terrible westerns, and for always being down to get coffee, shamrock shakes, and anything else that sounded delicious. Additionally, to both Krupenko labs for the laughs in lab meetings, encouragement, and constructive criticism that helped me become a better scientist. Finally, I want to thank my Refuge Church family- my Vertical girls and co-leaders over the years that have watched me stress and always remained supportive and unwaveringly vi optimistic even when you had no idea what I was talking about. To my small group and specifically the Pells for being my family in North Carolina, always providing a loving home when I needed to escape the stress in my life and encouraging me through every step of this process. And to everyone that makes up my community here in Kannapolis-Charlotte that has asked about my research, what I would do when I graduated (and kindly smiled when I said I had no idea), encouraged me when I was clearly drained, and reminded me what truly matters in life. And last but not least, to my faithful crazy companion Biscuit for reminding me there is much more to life than school and dissertations. vii PREFACE In addition to the work conducted and included in this dissertation I have co-authored 2 papers related to CerS6. The first is a comparative study of CerS6 using bioinformatic approaches and the second is a review of the literature on possible CerS6-related mechanisms in the link between alcohol and development of cancers: Holmes RS, Barron KA, Krupenko NI. Ceramide Synthase 6: Comparative Analysis, Phylogeny and Evolution. Biomolecules. 2018 Oct; 8(4). PMID: 30297675 Barron K*, Jeffries KA*, Krupenko NI. Sphingolipids and the link between alcohol and cancer. Chem. Biol. Interact., In press. Additionally, I contributed to a collaborative study with members of the nutrition department which is not related to the work presented in this dissertation. Xu X, Drobna Z, Voruganti VS, Barron K, Gonzalez-Horta C, Sanchez-Ramirez B, Ballinas- Casarrubias L, Ceron RH, Moralles DV, Terrazas FAB, Ishida MC, Gutierrez-Torres DS, Saunders RJ, Crandell J, Fry RC, Loomis D, Garcia-Vargas GG, Del Razo LM, Styblo M, Mendez MA. Association between variants in arsenic (+3 oxidation state) methyltransferase (AS3MT) and urinary metabolites of inorganic arsenic: Role of exposure level. Toxicol Sci. 2016 Sept; 153(1):112-123. PMID: 27370415 * co-first authors. viii TABLE OF CONTENTS LIST OF TABLES ....................................................................................................................... xiv LIST OF FIGURES ...................................................................................................................... xv LIST OF ABBREVIATIONS ...................................................................................................... xix CHAPTER 1: INTRODUCTION ................................................................................................... 1 CHAPTER 2: BACKGROUND ..................................................................................................... 4 Background ......................................................................................................................... 4 Folate function and its link to multiple metabolic pathways ....................................... 4 Folate deficiency affects many cellular processes ....................................................... 6 Adverse effects of excessive folate intake ................................................................... 8 Folic acid affects lipid metabolism .............................................................................. 9 Mechanisms connecting folate and lipids .................................................................. 11 Sphingolipid metabolism ........................................................................................... 13 Ceramide synthesis and isoforms of ceramide synthases .......................................... 14 Regulation of ceramide synthesis .............................................................................. 17 Dimerization is an important regulatory mechanism of CerS proteins ..................... 19 Ceramides in cellular signaling ................................................................................. 21 CerS6 and C16-ceramide metabolism......................................................................... 22 Ceramides in obesity and insulin resistance .............................................................. 24 The specific role of CerS6 in high fat diet feeding .................................................... 25 Lipotoxic actions of ceramides .................................................................................. 25 Ceramides and nutrient stress .................................................................................... 28 ix Ceramides respond to folate withdrawal ................................................................... 28 Rationale ........................................................................................................................... 29 Public Health Relevance ..................................................................................................
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