CTP: Phosphoethanolamine Cytidylyltransferase (Pcyt2) Deficiency in The Development of Non-Alcoholic Fatty Liver Disease
Why this work is in the frame
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Bibliographic record
Abstract
Phosphatidylethanolamine (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.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from it