Phosphoethanolamine reverses aberrant DNA methylation in non-alcoholic steatohepatitis caused by Pcyt2 deficiency
Bibliographic record
Abstract
Abstract Background Accumulating evidence links disruptions in phospholipid homeostasis to obesity, type 2 diabetes, and fatty liver diseases. Mice with a heterozygous ablation of the phosphatidylethanolamine (PE) synthesizing enzymePcyt2+/−show reduced PE synthesis and turnover and develop an age-dependent metabolic syndrome that is characterized by impaired fatty acid and glucose metabolism, hypertriglyceridemia, insulin resistance, obesity, and all characteristics of NASH. Aberrant DNA methylation can lead to the onset of pathological phenotypes and is increasingly being implicated in age-related metabolic diseases, including NASH. The methylation of PE to phosphatidylcholine (PC) is a major consumer of liver S-adenosyl methionine (SAM) and thus, alterations in PE metabolism have the potential to influence DNA methylation by modulating SAM availability. Here, we hypothesize that abnormal DNA methylation patterns underly the development ofPcyt2+/−NASH. We conduct an epigenome-wide methylation analysis to determine differential methylation and investigate whether treatment with the Pcyt2 substrate phosphoethanolamine (PEtn) for 8 weeks can reverse aberrant DNA methylation through the stimulation PE synthesis. ResultsPcyt2+/−NASH liver experiences significant alterations in DNA hypo- and hypermethylation relative toPcyt2+/+. Differentially methylated genes belong to pathways including PI3K-Akt signalling pathway, Foxo signalling pathway, oxidative phosphorylation and insulin signalling/secretion indicating that epigenetic regulation underlies many of our previously established pathological mechanisms ofPcyt2+/−NASH. Previously unidentified pathways during Pcyt2 deficiency are highlighted such as cell cycle regulation and cellular senescence that may contribute to NASH development. Treatment with PEtn dramatically reverses aberrant total and protein-coding DNA methylation patterns by 96%. PEtn treatment restored the methylation status of key genes involved in epigenetic modifications and induced differential methylation of genes associated with obesity and T2DM such asAdyc3, Celsr2, Fam63b.Conclusion ThePcyt2+/−liver methylome and transcriptome is altered and likely underlies much of the pathology inPcyt2+/−NASH phenotype. PEtn significantly attenuates aberrant DNA methylation inPcyt2+/−liver by stimulating the CDP:Ethanolamine Kennedy pathway and corrects the epigenetic regulation of genes involved in the pathogenesis of NASH, showing its therapeutic potential. This analysis provides critical insight into the epigenetic basis of NASH pathophysiology and suggests diagnostic markers and therapeutic targets.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| 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 | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".