Ldlr <sup>−/−</sup> Mice Lacking PEMT Have Elevated Plasma Trimethylamine‐oxide Levels But Are Protected From High Fat Diet‐Induced Atherosclerosis.
Bibliographic record
Abstract
Background Phosphatidylethanolamine N‐methyltransferase (PEMT) is a hepatic enzyme that converts phosphatidylethanolamine into phosphatidylcholine (PC) via three methylation reactions. The PEMT pathway makes 30% of the PC required in the liver and is the only de novo source of choline. PEMT deficient mice are protected against atherosclerosis when bred with either the Ldlr −/− and Apoe −/− mice. PEMT deficiency causes decreased VLDL secretion, plasma LDL levels and homocysteine, which are risk factors for atherosclerosis. Recently, choline supplementation was shown to enhance atherosclerosis in ApoE −/− mice and was dependent on the conversion of choline to trimethylamine (TMA) by the microbial flora in the gut, which was oxidized to trimethylamine N ‐oxide (TMAO) by hepatic enzymes. In addition, plasma choline and TMAO have been associated with increased risk of CVD in multiple cohort studies. The purpose of this study was to examine the effects of dietary choline supplementation on plasma TMAO levels, and investigate whether choline supplementation eliminates the atheroprotective effect of PEMT deficiency in LDLR −/− mice Methods We performed two sets of experiments: In first experiment, 10–12 week old Pemt +/+ /Ldlr −/− and Pemt −/− /Ldlr −/− mice were fed a chow diet for 12 weeks. In the second experiment, Pemt +/+ /Ldlr −/− and Pemt −/− /Ldlr −/− mice were fed a 40% high‐fat/0.5% cholesterol diet (HFD) supplemented with either 3 or 10 g/kg choline for 12 weeks. Results PEMT +/+ /Ldlr −/− and PEMT −/− /Ldlr −/− mice do not develop atherosclerosis on chow diet and there was no difference in plasma cholesterol between genotypes. When fed a HFD, PEMT −/− /Ldlr −/− mice are protected against atherosclerosis as compared to PEMT +/+ /Ldlr −/− mice. Interestingly, choline supplementation did not increase atherosclerosis in the PEMT −/− /Ldlr −/− mice. Plasma cholesterol levels were reduced in PEMT −/− /Ldlr −/− , which did not increase on choline supplementation. Surprisingly, PEMT −/− /Ldlr −/− mice have elevated TMAO levels, which was reduced to control levels by choline supplementation. Furthermore, liver histology showed that PEMT −/− /Ldlr −/− mice developed fatty liver that was improved by choline supplementation. Conclusion Choline supplementation does not reverse the protection of PEMT −/− /Ldlr −/− mice against atherosclerosis. PEMT −/− /Ldlr −/− mice have high TMAO levels and fatty liver on HFD. Surprisingly, choline supplementation normalized TMAO levels and reduced the fatty liver. Therefore, plasma TMAO levels are not associated with atherosclerosis but may be associated with fatty liver disease. Support or Funding Information Funding: ALMA, NSERC and CIHR
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.002 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.009 | 0.005 |
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".