High-fat diet obesity exacerbates acute lung injury-induced dysregulation of fatty acid oxidation in alveolar epithelial type 2 cells.

Obesity is a risk factor for acute respiratory distress syndrome (ARDS). We previously showed that obesity is linked to increased lung injury and bronchoalveolar lavage fluid (BALF) fatty acids in a hyperoxic model of ARDS. We sought to expand our understanding of this association and examined the effect of obesity on β-oxidation (FAO), the mitochondrial process of breaking down fatty acids, in alveolar epithelial type 2 cells (AEC2s) in hyperoxia-induced ARDS. AEC2 were isolated from mice receiving 60% versus 10% fat diet. Carnitine palmitoyltransferase 1A (CPT1A) mediates the transport of fatty acids into mitochondria for subsequent FAO. Cpt1a(loxp/loxp)Sftpc(CreERT2+/-) mice were generated with AEC2-specific CPT1A downregulation. Obesity was associated with intracellular lipid accumulation and increased expression of CPT1A in AEC2 after hyperoxia. Mitochondrial FAO; however, was significantly transcriptionally downregulated in AEC2 of obese mice compared with lean mice after hyperoxia. AEC2 from obese mice exhibited more severe mitochondrial bioenergetic failure and reduced ATP production after hyperoxia compared with lean mice. Consistent with earlier reports linking FAO perturbation to surfactant impairment, we also observed that high-fat diet was associated with reduced surfactant-related phospholipids in hyperoxic AEC2 and increased BALF surface tension, although obese Cpt1a(loxp/loxp)Sftpc(CreERT2+/-) mice were not protected from increased lung injury. In a reanalysis of a human single-cell lung atlas of COVID-19 ARDS, the downregulation of the FAO signature in AEC2 was significant only in obese, and not lean, patients with ARDS compared with controls. These findings demonstrate a previously underappreciated effect of diet on AEC2 function in acute lung injury.NEW & NOTEWORTHY High-fat diet obesity is linked to increased lung injury and bronchoalveolar lavage fluid (BALF) fatty acids in a hyperoxic ARDS model. In the present study, obesity not only upregulated intracellular lipids and effectors of fatty acid mitochondrial import but also was associated with downregulated fatty acid oxidation and reduced ATP production in alveolar epithelial type 2 cells after injury. Hyperoxic AEC2 from obese mice had reduced phospholipids, and obese mice had increased BALF surface tension after injury.