Sustained oxidative stress (H2O2) increases hepatic iron accumulation via translational stimulation of transferrin receptor 1 synthesis independent of the IRE/IRP network
Bibliographic record
Abstract
Aims: Various inflammatory conditions of the liver are associated with intracellular iron accumulation, e.g. in chronic hepatitis C and alcoholic steatohepatitis which are independent risk factors for disease progression and fibrosis. Previous work showed that the cellular iron master switch iron regulatory protein 1 (IRP1) is rapidly activated when cultured hepatocytes or the whole liver are exposed to H 2 O 2 . However, it is poorly understood how hepatic iron metabolism responds to sustained exposure of H 2 O 2 which more likely represents pathophysiological oxidative stress conditions. METHODS AND Results: We employed a novel enzymatic system of glucose oxidase (GOX) from Aspergillus niger and catalase for a sustained release of H 2 O 2 at steady state levels that mimic various cellular H 2 O 2 sources. We demonstrate that the prolonged exposure (24 to 48 hours) of cultured hepatoma cells (HepG2, HCT116, Huh7) to non-toxic H 2 O 2 concentrations of less than 5 micromol/liter elicits a delayed induction of transferrin receptor 1 (TfR1) protein expression in vitro – the major iron uptake protein of the liver. TfR1 induction is associated with increased uptake of 59Fe-labeled transferrin and the intracellular accumulation of iron as assessed by the calcein technique. Interestingly, IRP1 is only transiently activated and TfR1 mRNA was not increased suggesting an IRP1-independent pathway of TfR1 indcution. Pulse chase experiments with [S35] labeled methionine and immunoprecipitated TfR1 indicate that chronic H 2 O 2 exposure directly increases TfR1 synthesis at the translational level while not effecting its stability. We finally show that exposure of rat liver to non-toxic H 2 O 2 by GOX-loaded Kupffer cells for 24h confirms TfR1 upreguation in an in vivo setting without concomitant TfR1 mRNA stabilization, IRP1 induction and IL6/hepcidin involvement. Conclusions: Our results suggest a novel mechanism of hepatic iron accumulation by sustained non-toxic H 2 O 2 that is based on the translational activation of major iron uptake protein TfR1. We suggest that this mechanism contributes to pathological iron accumulation in chronic liver disease such as HCV and ASH. Literatur: Mueller S, Afdhal NH, Schuppan D. Iron, HCV, and liver cancer: hard metal setting the pace? Gastroenterology. 2006 Jun;130(7):2229-34. Mueller S. Iron regulatory protein 1 as a sensor of reactive oxygen species. Biofactors. 2005;24(1-4):171-81. Sureda A, Hebling U, Pons A, Mueller S. Extracellular H2O2 and not superoxide determines the compartment-specific activation of transferrin receptor by iron regulatory protein 1. Free Radic Res. 2005 Aug;39(8):817-24 Mutze S, Hebling U, Stremmel W, Wang J, Arnhold J, Pantopoulos K, Mueller S. Myeloperoxidase-derived hypochlorous acid antagonizes the oxidative stress-mediated activation of iron regulatory protein 1. J Biol Chem. 2003 Oct 17;278(42):40542-9. HCV - alcoholic hepatitis - hydrogen peroxide - iron - oxidative stress - transferrin receptor
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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) | 0.000 | 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) | 0.002 | 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".