Fatty acid oxidation downregulation in alveolar epithelial 2 cells promotes acute lung injury in obesity

Obesity is associated with increased risk for acute respiratory distress syndrome (ARDS). High fat diet induced obesity was linked to increased lung injury and bronchoalveolar lavage fluid (BALF) free fatty acids in a hyperoxic model of ARDS. In this study, we show significant transcriptional downregulation of fatty acid oxidation (FAO), the mitochondrial process of breaking down fatty acids, in alveolar epithelial type 2 cells (AEC2) of obese compared to lean mice after hyperoxia. AEC2 from obese mice exhibited increased intracellular lipids, more severe mitochondrial bioenergetic failure and reduced ATP production after hyperoxia compared to lean mice. FAO downregulation in AEC2 through a genetic mouse model targeting carnitine palmitoyltransferase 1A (Cpt1aloxp/loxpSftpcCreERT2+/– mice) resulted in further increased BALF fatty acids and lung injury in obese mice. High fat diet was associated with markers of impaired alveolar epithelial regeneration after hyperoxia, which include reduced surfactant AEC2 lineage markers, as well as reduced surfactant related phospholipids in hyperoxic AEC2, and increased BALF surface tension. In a reanalysis of a human molecular single-cell lung atlas of COVID19 ARDS, significant downregulation of the FAO signature in AEC2 compared to controls was observed only in ARDS patients with BMI >30, and not those with BMI <30.