Alveolar type II epithelial cell FASN maintains lipid homeostasis in experimental COPD
Alveolar epithelial type II cells (AEC2) strictly regulate lipid metabolism to maintain surfactant synthesis. A loss in AEC2 cell function and surfactant production are implicated in the pathogenesis of the smoking related lung disease, chronic obstructive pulmonary disease (COPD). It is unclear if smoking alters lipid synthesis in AEC2 cells and if altering lipid metabolism in AEC2 cells contributes to COPD development. In this study, high throughput lipidomic analysis revealed increased lipid biosynthesis in AEC2 cells isolated from mice chronically exposed to cigarette smoke (CS). Mice with a targeted deletion of the de novo lipogenesis enzyme, fatty acid synthase (FASN) in AEC2 cells (Fasni?AEC2) exposed to CS exhibited higher bronchoalveolar lavage fluid (BALF) neutrophils, higher BALF protein, more severe air-space enlargement and were more susceptible to age-induced emphysema. Fasni?AEC2 mice exposed to CS had lower levels of key surfactant phospholipids but higher levels of BALF ether phospholipids, sphingomyelins and polyunsaturated fatty acid containing-phospholipids, as well as increased BALF surface tension.  Fasni?AEC2 mice exposed to CS also had higher markers of ferroptosis in the lung. These data suggest that AEC2 cell FASN modulates the response of the lung to smoke by regulating the composition of the surfactant phospholipidome. Overall design: The lung tissue from FASN gene specifically deleted in AEC2 cells mice (n=3) and the control mice (n=3)