Dietary lipid stress aggravates obstructive lung injury involving epithelial IGF-1-Akt dysfunction and epithelial-endothelial crosstalk

We integrated a βENaC-transgenic muco-obstructive lung disease model, an elastase-induced emphysema model, whole-lung transcriptomics, epithelial and endothelial cell systems, and a health-screening cohort. A high-fat diet (HFD) increased body weight, glycemia, and adiposity in both wild-type and βENaC-transgenic mice, but further enlarged distal airspaces and reduced FEV0.1/FVC in βENaC-transgenic mice.

Transcriptomic and tissue analyses revealed remodeling of lipid-handling, PI3K-Akt, and vascular programs, accompanied by reduced Akt phosphorylation, increased FOXO1 abundance and Fasl expression, and increased TUNEL positivity in epithelial regions. Palmitate attenuated IGF-1-induced Akt activation in bronchial epithelial cells, whereas IGF-1 receptor inhibition reproduced Akt suppression and apoptosis-related responses without recapitulating the full HFD phenotype.