CTP: Phosphoethanolamine Cytidylyltransferase (Pcyt2) Deficiency in The Development of Non-Alcoholic Fatty Liver Disease

dc.contributor.advisorBakovic, Marica
dc.contributor.authorGrapentine, Sophie
dc.date.accessioned2023-01-06T15:00:40Z
dc.date.available2023-01-06T15:00:40Z
dc.date.copyright2023-01
dc.date.created2022-12-16
dc.degree.departmentDepartment of Human Health and Nutritional Sciencesen_US
dc.degree.grantorUniversity of Guelphen
dc.degree.nameDoctor of Philosophyen_US
dc.degree.programmeHuman Health and Nutritional Sciencesen_US
dc.description.abstractPhosphatidylethanolamine (PE) is the most abundant phospholipid on the inner leaflet of cellular membranes, and the dysregulation of PE homeostasis is increasingly associated with metabolic disease. The major pathway responsible for PE synthesis is the CDP-Ethanolamine Kennedy pathway, in which CTP: Phosphoethanolamine cytidylyltransferase (Pcyt2) is the rate limiting enzyme. Mice with the heterozygous deletion of Pcyt2 (Pcyt2+/-) show reduced flux through the CDP-Ethanolamine pathway and develop adult-onset obesity. In this thesis we probe the metabolic consequences of Pcyt2 deficiency in the liver and skeletal muscle of Pcyt2+/- mice. Young Pcyt2+/- mice exhibit hepatic gene and protein expression changes in metabolic regulators but exhibit no symptoms of disease. By 6-8 months of age, Pcyt2+/- mice show impaired systemic fatty acid (FA) mobilization and insulin resistance, and perturbations to liver and skeletal muscle FA and glucose metabolism that results in the development of non-alcoholic steatohepatitis (NASH). The Pcyt2+/- liver exhibits increased glucose production, an accumulation of TAG and glycogen, fibrosis, and inflammation. In addition, there are significant alterations in DNA hypo- and hypermethylation in the Pcyt2+/- liver. Differentially methylated and expressed genes show a significant enrichment in pathways related to FA and glucose metabolism and liver health indicating that alterations in the epigenome and transcriptome likely underly NASH pathogenesis in Pcyt2+/- mice. Pcyt2+/- skeletal muscle shows signs of disturbed muscle structure and function with an infiltration of macrophages, development of fibrosis, the accumulation DAG and TAG, and infiltration of intramuscular adipose tissue. Pcyt2+/- skeletal muscle exhibits elevated lipogenesis, reduced FA oxidation, and altered glucose metabolism with elevated glycogen content, impaired insulin signaling and reduced glucose uptake. Lastly, we demonstrate that treatment with the Pcyt2 substrate phosphoethanolamine was able to reverse aberrant DNA methylation and multiple aspects of Pcyt2+/- NASH, showing its therapeutic potential and proof of concept data on the role of methylation in the development of Pcyt2+/- NASH. Together, this thesis shows the consequences of Pcyt2 deficiency within the liver and skeletal muscle, which cause perturbed lipid and glucose metabolism, inflammation, the accumulation of DAG, TAG and glycogen, aberrant hepatic DNA methylation, and the development of non-alcoholic fatty liver disease.en_US
dc.description.sponsorshipCanadian Institutes of Health Research
dc.identifier.citationGrapentine S, Bakovic M. Significance of bilayer-forming phospholipids for skeletal muscle insulin sensitivity and mitochondrial function. Journal of Biomedical Research. 2020 Jan;34(1):1. doi: 10.7555/JBR.33.20180104
dc.identifier.citationGrapentine, S., Singh, R.K., Basu, P. et al. Pcyt2 deficiency causes age-dependant development of nonalcoholic steatohepatitis and insulin resistance that could be attenuated with phosphoethanolamine. Sci Rep 12, 1048 (2022). https://doi.org/10.1038/s41598-022-05140-y
dc.identifier.urihttps://hdl.handle.net/10214/27376
dc.language.isoenen_US
dc.publisherUniversity of Guelphen
dc.rights.licenseAll items in the Atrium are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjectphospholipidsen_US
dc.subjectPcyt2en_US
dc.subjectnonalcoholic steatohepatitisen_US
dc.subjectnonalcoholic fatty liver diseaseen_US
dc.subjectphosphatidylethanolamineen_US
dc.subjectphosphoethanolamineen_US
dc.subjectmembranesen_US
dc.titleCTP: Phosphoethanolamine Cytidylyltransferase (Pcyt2) Deficiency in The Development of Non-Alcoholic Fatty Liver Diseaseen_US
dc.typeThesisen

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