Dietary lipids attenuate IGF-1-Akt and injure epithelial-endothelial injury program that accelerates obstructive lung disease
Ogasawara, C.; Nohara, H.; Kishimoto, T.; Kawano, K.; Watanabe, K.; Oniki, K.; Fujiwara, Y.; Nakashima, R.; Kamei, S.; Takahashi, N.; Hayashi, M.; Fukuyama, A.; Uemura, M.; Ueno-Shuto, K.; Saruwatari, J.; Otake, K.; Ogata, Y.; Mizukami, Y.; Suico, M. A.; Kai, H.; Shuto, T.
Show abstract
Metabolic lipotoxicity injures multiple organs, but its impact on the lung remains unclear. Here we show that a high-fat diet (HFD) accelerates obstructive pathology in {beta}ENaC-transgenic mice and worsens elastase-induced emphysema. Lung transcriptomics reveal repression and rewiring of PI3K-Akt survival circuitry; in both models, phospho-Akt is reduced, FOXO1 is increased, and epithelial apoptosis is induced. Streptozotocin-induced diabetes does not impair lung mechanics, indicating that hyperglycemia or insulin deficiency alone is insufficient. HFD elevates circulating free fatty acids, and palmitate blunts IGF-1-dependent Akt activation in primary human bronchial epithelium. Palmitate also activates endothelium and suppresses junctional genes both directly and via epithelial conditioned media, consistent with epithelial-to-endothelial injury signaling; in vivo, HFD reduces CD34 endothelial cells in susceptible lungs. In men with airflow obstruction, obesity and fatty liver are associated with lower FEV. Together, these findings define pulmonary lipotoxicity as a lipid-driven epithelial-endothelial injury program that accelerates obstructive lung disease.
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