Fatty acid synthase downregulation contributes to acute lung injury in murine diet-induced obesity
Maria Plataki, … , Suzanne M. Cloonan, Augustine M.K. Choi
Maria Plataki, … , Suzanne M. Cloonan, Augustine M.K. Choi
Published August 8, 2019; First published July 9, 2019
Citation Information: JCI Insight. 2019;4(15):e127823. https://doi.org/10.1172/jci.insight.127823.
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Research Article Pulmonology

Fatty acid synthase downregulation contributes to acute lung injury in murine diet-induced obesity

Abstract

The prevalence of obesity is rising worldwide, and obese patients constitute a specific population in the intensive care unit. Acute respiratory distress syndrome (ARDS) incidence is increased in obese patients. Exposure of rodents to hyperoxia mimics many of the features of ARDS. In this report, we demonstrate that high-fat diet–induced obesity increases the severity of hyperoxic acute lung injury in mice in part by altering fatty acid synthase (FASN) levels in the lung. Obese mice exposed to hyperoxia had significantly reduced survival and increased lung damage. Transcriptomic analysis of lung homogenates identified Fasn as one of the most significantly altered mitochondria-associated genes in mice receiving a 60% compared with 10% fat diet. FASN protein levels in the lung of high-fat diet mice were lower by immunoblotting and immunohistochemistry. Depletion of FASN in type II alveolar epithelial cells resulted in altered mitochondrial bioenergetics and more severe lung injury with hyperoxic exposure, even upon administration of a 60% fat diet. This is the first study to our knowledge to show that a high-fat diet leads to altered FASN expression in the lung, and that both a high-fat diet and reduced FASN expression in alveolar epithelial cells promote lung injury.

Authors

Maria Plataki, LiChao Fan, Elizabeth Sanchez, Ziling Huang, Lisa K. Torres, Mitsuru Imamura, Yizhang Zhu, David E. Cohen, Suzanne M. Cloonan, Augustine M.K. Choi

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Figure 2

High-fat diet is associated with reduced survival and increased lung injury after exposure to hyperoxia.

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High-fat diet is associated with reduced survival and increased lung inj...
(A) Representative survival curve of C57BL/6J mice fed 60% versus ingredient-matched 10% fat diet exposed to >95% oxygen (n = 10 per group, log-rank test, ***P < 0.0001). (B) Bronchoalveolar lavage fluid (BALF) protein levels from mice fed 60% and 10% fat diet after 48 hours of exposure to >95% oxygen or room air (mg/mL n = 3 per group for room air and n = 8 per group for hyperoxia, ANOVA with Tukey’s post hoc correction, ***P < 0.001, similar results were obtained from at least 2 independent experiments). (C) BALF IgM levels from mice fed 60% and 10% fat diet after 48 hours of exposure to >95% oxygen or room air (ng/mL, n = 3 per group for room air and n = 8 per group for hyperoxia, ANOVA with Tukey’s post hoc correction, *P < 0.05, similar results were obtained from at least 2 independent experiments). (D) Representative image of H&E-stained lungs (n = 2 per group for room air and n = 7 per group for hyperoxia; original magnification, ×20). (E) BALF free fatty acid levels after 48 hours of hyperoxia or room air (nmol/50 μL, n = 3 per group for room air and n = 8 per group for hyperoxia, ANOVA with Tukey’s post hoc correction, *P < 0.05). (F) BALF lactate dehydrogenase (LDH) levels after 48 hours of hyperoxia or room air (relative value, n = 3 per group for room air and n = 8 per group for hyperoxia, ANOVA with Tukey’s post hoc correction, ***P < 0.001, **P < 0.01). (G) TUNEL expressed as positive cells per number of alveoli after 48 hours of hyperoxia or room air (n = 2 per group for room air and n = 7 per group for hyperoxia, ANOVA with Tukey’s post hoc correction, **P < 0.01). (H) Representative image of TUNEL-stained lungs (original magnification, ×40; arrows highlight positive cells). (I) BALF protein levels from B6.Cg-Lepob/J (ob/ob) mice and heterozygous controls (ob/+) after 48 hours of exposure to >95% oxygen or room air (mg/mL, n = 3 per group for room air and n = 8 per group for hyperoxia, ANOVA with Tukey’s post hoc correction, **P < 0.01). Data are expressed as mean ± SEM.