Pulmonary arterial hypertension induces a metabolic and inflammatory hepatopathy

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Abstract

BACKGROUND Right ventricular failure (RVF) is a major determinant of mortality in pulmonary arterial hypertension (PAH), and hepatic dysfunction predicts adverse outcomes. However, the cell-specific effects of PAH/RVF on the human liver remain poorly defined.METHODS We performed single-nucleus RNA-seq (snRNA-seq) of autopsy-derived liver tissue from 5 patients with PAH and 4 healthy individuals (non-PAH) treated as controls and compared these findings with publicly available snRNA-seq datasets from nonalcoholic steatohepatitis (NASH) and Fontan-associated liver disease (FALD). Transcriptomic analyses were integrated with histologic assessment, mitochondrion-enriched proteomics, and correlations with clinical markers of PAH/RVF severity.RESULTS PAH livers showed cell-specific metabolic, inflammatory, and fibrotic remodeling distinct from NASH and FALD. PAH hepatocytes exhibited a hypoxia-adapted, Warburg-like metabolic phenotype with reduced fatty acid metabolism, gluconeogenesis, cytochrome P450 activity, and ketone metabolism. PAH endothelial cells demonstrated increased glycolytic pathway activity and altered adhesion/barrier signaling. PAH hepatic stellate cells (HSCs) displayed HIF-1 and PI3K/Akt pathway activation, increased IL-6 expression, and histologic evidence of perivascular fibrotic remodeling. PAH macrophages showed complement activation with reduced JAK/STAT signaling. HSC HIF-1 activity correlated with clinical markers of PAH/RVF severity.CONCLUSION PAH induces a distinct metabolic and inflammatory hepatopathy characterized by hepatocyte metabolic reprogramming, HSC activation, macrophage complement signaling, and suppressed ketone metabolism. These findings support PAH-associated hepatopathy as a disease-specific end-organ phenotype linked to RVF severity.FUNDING NIH grants F31 HL170585, R01 HL158795, and R01 HL162927.

Authors

Madelyn J. Blake, Sally E. Prins, Jeffrey Blake, Lynn M. Hartweck, Jenna B. Mendelson, Steeve Provencher, Sandra Breuils-Bonnet, Sebastien Bonnet, Kurt W. Prins