GLUCURONIDATION: THE LAST DEFENSIVE LINE AGAINST BILE ACID TOXICITY DURING CHOLESTASIS.
Bibliographic record
Abstract
Glucuronidation is a detoxification reaction for bile acids (BA). The present study evaluates its efficiency to protect liver cells during acute (biliary obstruction, BO) and chronic (primary biliary cholangitis, PBC and primary sclerosing cholangitis, PSC) cholestatic situations. BA-glucuronides (G) were first profiled in sera from control, PBC, PSC and BO donors. An impressive accumulation of BA-Gs, formed from toxic BAs, is observed in sera from BO patients. Liver samples from control, PBC, or PSC donors and human hepatic cells were exposed to BAs, BA-G, agonists of the BA sensors Pregnane X-Receptor (PXR) or Farnesoid X-Receptor (FXR) and were analyzed for the expression of BA-conjugating UDP-glucuronosyltransferase (UGT) enzymes using quantitative RT-PCR and/or immnunoblot. Expression of the BA-conjugating UGT1A3, 1A4, and 2B4 enzymes was increased in hepatocytes exposed to BA levels mimicking BO. PXR activation also induced expression of the 3 UGTs, while FXR agonists only activated the UGT1A4 and 2B4 genes. Gelshift and luciferase transfection assays identified PXR response elements within UGT1A3 and 1A4 gene promoters. Finally, Inflammation markers have been reduced in hepatocytes treated with BA-G instead of BA. Conclusion: The present study identifies glucuronidation as a self-defense mechanism against BA toxicity during cholestasis. While of limited efficiency by itself, this endogenous mechanism is proposed as a novel pharmacological target in the treatment of chronic cholestatic diseases.
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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 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 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".