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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE264369 | GEO | 2025/04/18

REPOSITORIES: GEO

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Project description:Background: Obesity has become a worldwide concern. Acute respiratory distress syndrome (ARDS) comprises 10.4% of total intensive care unit admissions and is associated with very high mortality. ARDS incidence is increased in obese patients. Exposure of rodents to hyperoxia mimics many of the clinical and pathologic features observed in patients with ARDS. The aim of this study was to determine the impact of high fat diet-induced obesity on the susceptibility to hyperoxic acute lung injury in mice. Methods: Male C57BL/6 mice received 60% fat versus ingredient matched 10% fat diet. Mice were exposed to >95% oxygen to induce lung damage. RNA was isolated from lung homogenates and by comparing RNA sequencing results with mouse Mitocarta, an inventory of genes encoding proteins with mitochondrial localization, we identified fatty acid synthase (FASN), an enzyme catalyzing de novo fatty acid synthesis, as one of the mitochondrial genes significantly changed with diet and with hyperoxia. We generated mice deficient in FASN in alveolar epithelial cells by using a tamoxifen inducible Cre recombinase construct (FASNflox/flox SPC Cre+/-) and subjected them to hyperoxia and high fat diet. Results: Mice receiving 60% fat diet had significantly higher weight, serum cholesterol and fasting glucose. High fat diet mice had significantly reduced survival and increased lung damage, as assessed by BAL protein and LDH, histology and TUNEL staining. By RNA sequencing of lung homogenates we identified FASN as one of the mitochondrial genes significantly reduced in mice receiving 60% compared to 10% fat diet and further reduced with hyperoxia. We confirmed that FASN protein levels in the lung of high fat diet mice were lower by immunoblotting and immunohistochemistry. After 48 hours of hyperoxia FASNflox/flox SPC Cre+/- mice displayed increased levels of BAL protein and LDH and more severe histologic lung injury. FASNflox/flox SPC Cre+/- mice remained more prone to lung injury after hyperoxic exposure even when they received 60% fat diet. Conclusions: These results demonstrate that obesity increases the severity of hyperoxia induced acute lung injury in mice by altering FASN levels in the lung of high fat diet fed rodents. To our knowledge, this is the first study to show that high fat diet leads to altered FASN expression in the lung and that both high fat diet and reduced FASN in alveolar epithelial cells lead to increased lung injury under hyperoxic conditions.

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

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