Characterization of porcine pregnane X receptor, farnesoid X receptor and their splice variants
Bibliographic record
Abstract
The pregnane X receptor (PXR; NR1I2) and the farnesoid X receptor (FXR; NR1H4) regulate the expression of many major metabolic enzymes. With the pig being used as a model for humans in metabolic and toxicological studies and also an important food animal, we characterized the transactivation profile of the porcine orthologs of these receptors, pgPXR and pgFXR. We compared the transactivation profiles of these receptors and their splice variants to their human orthologs using mostly endogenous ligands. Five alternatively spliced variants were identified for pgFXR as part of this study, while five alternatively spliced variants of pgPXR had been previously described. Insertions and deletions within these splice variants generated truncated proteins or proteins with altered tertiary structures, resulting in altered transactivation. Realtime polymerase chain reaction analyses showed that the pgPXR variants were present in liver cDNA samples from 3.33% to 7.92% of the total pgPXR, while the pgFXR variants were present from 1.92% to 9.26% of the total pgFXR. pgFXR was fairly evenly expressed in seven different tissues. In a luciferase reporter assay, wild-type pgPXR (pgPXR-WT) and human PXR (hPXR) responded to 12 common ligands, with similar levels of activation occurring for six of these. Wild-type pgFXR (pgFXR-WT) significantly responded to three ligands, two of which also activated hFXR. 3-Methylindole (skatole) was identified as a novel inverse agonist for pgPXR-WT and pgFXR-WT as well as porcine constitutive androstane receptor. None of the pgPXR splice variants (SVs) were active in the luciferase reporter assay on their own; pgFXR-SV1 was activated by chenodeoxycholic acid to a similar degree as pgFXR-WT. When co-transfected with their corresponding wild-type proteins, pgPXR-SV1 and pgFXR-SV1 significantly increased receptor transactivation. In conclusion, pgPXR-WT and pgFXR-WT both responded to ligands that activated their human orthologs, and some of the alternatively spliced variants significantly altered pgPXR and pgFXR transactivation at in vivo expression levels.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
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 | 0.000 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".