Abstract 4364175: Human PAH Hepatopathy Is Characterized by Metabolic and Inflammatory Alterations That Are Distinct from Other Human Hepatopathies
Bibliographic record
Abstract
Background: Right ventricular failure (RVF) is the strongest risk factor for mortality in pulmonary arterial hypertension (PAH). RVF is deadly because it leads to multi-organ dysfunction. Recent studies show that hepatic dysfunction correlates with RVF and is an important predictor of outcomes in PAH. However, the cell-specific impacts of PAH-mediated RVF in human livers are unexplored. Methods: Nuclei were isolated from autopsy-derived liver tissue from four healthy control and five PAH patients. Single-nucleus RNA sequencing (snRNAseq) was performed by 10X Genomics and analyzed in RStudio using Seurat. Publicly available snRNAseq datasets of human liver tissue from non-alcoholic steatohepatitis (NASH) and Fontan-associated liver disease (FALD) were compared to PAH. Results: 57,057 control and 71,792 PAH hepatic nuclei were analyzed via snRNAseq. Hepatocyte relative abundances were uniquely increased in PAH. Moreover, PAH induced a pro-proliferative, Warburg-like metabolic phenotype in hepatocytes, a finding mirrored by PAH endothelial cells. NASH hepatocytes and endothelial cells were characterized by a hypermetabolic phenotype, whereas FALD hepatocytes and endothelial cells only displayed suppressed oxidative phosphorylation without alterations in glycolysis. Derangements in the cytochrome P450 oxidation system were present in PAH and NASH hepatocytes, but not FALD. Pro-inflammatory signaling was observed in both PAH hepatic stellate cells and macrophage. PAH hepatic stellate cells were characterized by upregulated HIF-1 and PI3K/Akt/mTOR signaling, as opposed to PI3K/Akt/mTOR signaling alone in NASH or the combination of TGF-beta and Wnt signaling in FALD. Complement transcripts were enriched and cell-cell communication was hindered in PAH macrophages. NASH and FALD macrophages had heightened predicted intercellular interactions, with elevated complement and JAK-STAT signaling, respectively. Finally, PAH uniquely modified the expression of vasoactive genes (ENG, FLT1, GDF15) across several cell types, augmented interleukin-6 production in hepatic stellate cells, and suppressed ketone metabolism in hepatocytes. Conclusion: PAH hepatopathy is a distinct cellular and molecular phenomenon as compared to FALD and NASH. These data delineate PAH-specific therapeutic targets and nominate liver-specific alterations that may contribute to the systemic manifestations of PAH.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.031 | 0.010 |
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".