High fat diet obesity exacerbates acute lung injury induced dysregulation of fatty acid oxidation in alveolar epithelial type 2 cells.
Academic Article
Overview
abstract
Obesity is a risk factor for acute respiratory distress syndrome (ARDS). We previously showed 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 (AEC2) 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. Cpt1aloxp/loxpSftpcCreERT2+/- 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 compared to lean mice after hyperoxia. AEC2 from obese mice exhibited more severe mitochondrial bioenergetic failure and reduced ATP production after hyperoxia compared to lean mice. Consistent with prior 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 Cpt1aloxp/loxpSftpcCreERT2+/- mice were not protected from increased lung injury. In a reanalysis of a human single-cell lung atlas of COVID19 ARDS, the downregulation of the FAO signature in AEC2 was significant only in obese, and not lean, ARDS patients compared to controls. These findings demonstrate a previously underappreciated effect of diet on AEC2 function in acute lung injury.
