Coordinate Induction of ATP‐Binding Cassette (ABC) Proteins by Bile Acids via Nrf2 is Mediated by Mitogen Activated Protein Kinases (MAPK)
Bibliographic record
Abstract
Many liver ATP‐binding cassette (ABC) proteins can be induced by bile acids. Because these efflux transporters are capable of extruding bile salts, their induction constitutes a cytoprotective role to limit bile acid accumulation and toxicity. Nrf2 silencing via siRNA in human liver HepG2 revealed that ABC transporters such as ABCC2 (MRP2), ABCC3 (MRP3) and ABCG2 (BCRP) induced by bile acids are dependent on Nrf2. The mechanisms, particularly the involvement of signaling kinases, by which this adaptive response occurs were sought. Using a quantitative multiplex kinase activation assay, we found that lithocholic acid (LCA)‐treated HepG2 had higher phosphoproteins representing activation of mitogen‐activated protein kinase (MAPK), c‐Jun N‐terminal kinase, and phosphatidylinositol 3‐kinase pathways. Inhibition of MAPK, but not the other kinases, significantly mitigated LCA‐induced ABC transporter genes and Nrf2 target genes. Activation of Nrf2 transcription machinery by LCA was prevented by blocking of MAPK as shown by reduced nuclear accumulation of Nrf2 and antioxidant‐response element (ARE) reporter activities. Moreover, exposure to LCA in the presence of inhibitors of MAPK or ABC transporters sensitized HepG2 cells to LCA‐induced cell death. In summary, our findings suggest that MAPK signaling mediates Nrf2 activation and induction of ABC transporter genes by bile acids. (Supported by 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 | 0.000 | 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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.007 | 0.002 |
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".