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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 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

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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 3

Fatty acid synthase is reduced in the lungs of mice receiving high-fat diet and further reduced with hyperoxia.

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Fatty acid synthase is reduced in the lungs of mice receiving high-fat d...
(A) Differential lung expression by RNA-Seq of genes associated with mitochondrial function as determined by per mouse MitoCarta (an inventory of genes encoding proteins with mitochondrial localization) that were significantly different between the 60% and 10% fat diet mice. (B) Relative gene expression levels of fatty acid synthase (Fasn) from RNA-Seq of whole-lung homogenates from mice fed 60% and 10% fat diet exposed for 48 hours to hyperoxia or room air (n = 3 mice per group; the fold change of fragments per kilobase of transcript per million (FPKM) fragments sequenced was calculated relative to control, Benjamini-Hochberg method, *adjusted P < 0.05). (C) Western blot analysis for FASN in lungs with β-actin loading control. Densitometry analysis shown on the bottom (n = 2 per group for room air and n = 5 per group for hyperoxia, Mann-Whitney U test, *P < 0.05). (D) Representative section of FASN-stained lungs (n = 2 per group for room air and n = 7 per group for hyperoxia; original magnification, ×40). Data are expressed as mean ± SEM.

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