Coordinated alteration of hepatic gene expression in fatty acid and triglyceride synthesis in LCAT-null mice is associated with altered PUFA metabolism
Bibliographic record
Abstract
Complete lecithin:cholesterol acyltransferase (LCAT) deficiency is associated with fasting hypertriglyceridemia (HTG). We recently reported that, in ldlr(-/-)xlcat(-/-) mice, fasting HTG is associated with hepatic triglyceride overproduction in association with an upregulation of the hepatic srebp1 gene and altered expression of its target genes in lipogenesis and gluconeogenesis. We further investigated the role of hepatic polyunsaturated fatty acid (PUFA) metabolism in the modulation of the lipid phenotypes. In the ldlr(-/-)xlcat(-/-) mice, using the ldlr(-/-)xlcat(+/+) littermate as controls, the hepatic level of cholesterol esters (CE) were reduced by 61.0% whereas the 20:4-CE and 22:6-CE contents were each reduced by >80%. In contrast, the hepatic levels of 20:4- and 22:6-containing phospholipid (PL) species were either unchanged or mildly elevated. Similar alterations of the hepatic PUFA in CE and in PL were also observed in the lcat(-/-) mice compared with their wild-type controls. In ldlr(-/-)xlcat(-/-) mice, hepatic mRNA level was markedly reduced for Delta-6 desaturase (fads2) (70.2%) and acyl-CoA:cholesterol acyltransferase-2 (soat2) (57.0%). A similar pattern of gene expression change was also observed in the lcat(-/-) single-knockout mice. In contrast, the acyl-CoA:diacylglycerol acyltransferase-2 (dgat2) mRNA level was 1.7-fold upregulated in the double-knockout mice. In summary, we observed coordinated alterations in hepatic expression of the gene for fads2, soat2, and dgat2, resulting in a reduction in total hepatic PUFA pool and differentially in the PUFA-CE pool, in association with an increase in dgat2 gene expression for promoting triglyceride synthesis and secretion. Some of the phenotypes are not readily explained by known mechanisms and may represent novel regulatory pathways.
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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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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".