Abstract 15414: Ablation of Aryl Hydrocarbon Nuclear Translocator (ARNT) in the Heart Leads to Diabetic Cardiomyopathy Phenotype Through PPARα Activity
Bibliographic record
Abstract
Background: Metabolic changes decrease cardiac efficiency and energetics in diabetes. Impaired hypoxia inducible factor (HIF) signaling may contribute to cardiac metabolic abnormalities. ARNT, also known as HIF1β, is a transcription factor that regulates several cellular processes by dimerizing with certain proteins, including HIF-1α or -2α, and its function in the heart is unknown. We hypothesized that cardiac deletion of ARNT leads to metabolic derangement and cardiac dysfunction. Methods and Results: Cardiac-specific ARNT knockout (csARNT-KO) mice were generated by our lab as previously described. ARNT deletion in the heart resulted in dilated cardiomyopathy and significant lipid accumulation, which was determined by electron microscopy, oil-red staining and triglyceride level quantification. We found that loss of ARNT in the heart increased PPARα activity, as confirmed by 2-fold increase in fatty acid oxidation (FAO) in ex-vivo csARNT+/- working hearts, increased PPARα protein content and increased PPARα target gene expression.To study the mechanism by which ARNT regulates PPARα, luciferase reporter assays revealed that ARNT knockdown resulted in increased PPARα promoter activity and deletion of the second hypoxia response element (HRE) upstream of the initiation site removed the inhibitory effect of ARNT on the PPARα promoter, suggesting that this site is likely involved in the regulation of the gene. ARNT binding to this sequence was confirmed by chromatin immunoprecipitation analysis. Moreover, a reduction in HIF-2α, but not HIF-1α or AHR, also significantly increased the levels of PPARα. These results suggest that the effects of ARNT deletion on PPARα are, at least partially, through its association with HIF-2α and through the binding of this complex to the second HRE upstream of the PPARα initiation site. Finally, mice with double deletion of ARNT and PPARα demonstrated rescue of the cardiac dysfunction phenotype, improved survival, and complete reversal of FA accumulation. Conclusion: Reduction in ARNT levels leads to cardiomyopathy by increasing lipid accumulation through a PPARα pathway. Thus, ARNT is a critical regulator of fatty acid metabolism in the heart, and a potential target for the treatment of diabetic cardiomyopathy.
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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) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 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".