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dc.contributor.advisorSacks, Frank
dc.contributor.authorByles, Vanessa Ann
dc.date.accessioned2020-10-05T12:04:06Z
dash.embargo.terms2022-03-01
dc.date.created2020-03
dc.date.issued2020-01-22
dc.date.submitted2020
dc.identifier.citationByles, Vanessa Ann. 2020. ATF4 in the Control of Liver Metabolism Downstream of Anabolic and Stress Signals. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
dc.identifier.urihttps://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37365521*
dc.description.abstractThe liver is a highly biosynthetic organ that mediates systemic metabolic flexibility by altering key metabolic pathways to match the dynamic fluctuations in nutrients that occur with fasting and feeding cycles. Despite the long-standing observation that the key nutrient sensing pathway mechanistic target of rapamycin complex 1, mTORC1, is stimulated with feeding in the liver, the metabolic response orchestrated downstream of its activation remains poorly defined. Activating Transcription Factor 4 (ATF4) is a well-characterized effector of the integrated stress response that promotes adaptation through control of amino acid metabolism. Beyond this role, ATF4 moonlights downstream of mTORC1 to control anabolic metabolism through the regulation of de novo purine nucleotide synthesis in proliferative cellular systems. However, the role of ATF4 in physiological settings remains largely understudied. In this dissertation, I implicate ATF4 as a novel downstream effector of hepatic mTORC1 signaling with feeding. Using RNA-sequencing in liver-specific Atf4 knockout mice, I define the transcriptional program mediated by ATF4 with feeding, which demonstrates little overlap with its stress-regulated functions in the liver. Specifically, ATF4 regulates genes involved in amino acid synthesis and one carbon metabolism with feeding in the liver and with insulin in a hepatocyte-intrinsic manner. I further demonstrate that mTORC1 controls amino acid synthesis and de novo purine and pyrimidine nucleotide synthesis in a cell-autonomous manner in the liver through downstream regulation of ATF4. Overall, these findings define a role for the mTORC1-ATF4 axis in liver metabolic flexibility through the calibration of metabolic pathways to organismal nutrient status. In addition, using a candidate-based approach, I describe transcriptional regulation of the cholesterol esterification enzyme, Soat2, by ATF4 in hepatocyte cell lines downstream of stress signals and anabolic signals through mTORC1. I hypothesized that regulation of Soat2 downstream of stress and anabolic signals would protect hepatocytes against lipotoxicity in the endoplasmic reticulum (ER) as this is the main site of de novo cholesterol synthesis and a central hub in cellular cholesterol trafficking. Despite robust transcriptional regulation of Soat2 in an ATF4-dependent manner, I was unable to observe a functional consequence of such regulation or translate the findings in vivo. The utility of ATF4 regulation of Soat2 mRNA and the context in which such regulation is important remains largely elusive. Collectively, these studies reveal ATF4 as a novel regulator of metabolism in physiological, non-proliferative settings downstream of both anabolic and stress signals that can ultimately contribute to hepatic metabolic flexibility.
dc.description.sponsorshipBiological Sciences in Public Health
dc.format.mimetypeapplication/pdf
dc.language.isoen
dash.licenseLAA
dc.subjectATF4
dc.subjectmTORC1
dc.subjectLiver
dc.subjectFasting
dc.subjectFeeding
dc.subjectDe Novo Nucleotide Synthesis
dc.subjectAmino Acid Synthesis
dc.subjectSOAT2
dc.subjectCholesterol Metabolism
dc.titleATF4 in the Control of Liver Metabolism Downstream of Anabolic and Stress Signals
dc.typeThesis or Dissertation
dash.depositing.authorByles, Vanessa Ann
dash.embargo.until2022-03-01
dc.date.available2020-10-05T12:04:06Z
thesis.degree.date2020
thesis.degree.grantorGraduate School of Arts & Sciences
thesis.degree.grantorGraduate School of Arts & Sciences
thesis.degree.levelDoctoral
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy
thesis.degree.nameDoctor of Philosophy
dc.contributor.committeeMemberYuan, Zhi-Min
dc.contributor.committeeMemberLu, Quan
dc.contributor.committeeMemberPuigserver, Pere
dc.type.materialtext
thesis.degree.departmentBiological Sciences in Public Health
thesis.degree.departmentBiological Sciences in Public Health
dash.identifier.vireo
dash.author.emailvbyles@gmail.com


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