Long-chain Acylcarnitines Reduce Lung Function by Inhibiting Pulmonary Surfactant |
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Authors: | Chikara Otsubo Sivakama Bharathi Radha Uppala Olga R Ilkayeva Dongning Wang Kevin McHugh Ye Zou Jieru Wang John F Alcorn Yi Y Zuo Matthew D Hirschey Eric S Goetzman |
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Institution: | From the ‡Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh, Children''s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.;§Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina 27701, and ;¶Department of Mechanical Engineering, University of Hawaii at Manoa, Honolulu, Hawaii 96822 |
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Abstract: | The role of mitochondrial energy metabolism in maintaining lung function is not understood. We previously observed reduced lung function in mice lacking the fatty acid oxidation enzyme long-chain acyl-CoA dehydrogenase (LCAD). Here, we demonstrate that long-chain acylcarnitines, a class of lipids secreted by mitochondria when metabolism is inhibited, accumulate at the air-fluid interface in LCAD−/− lungs. Acylcarnitine accumulation is exacerbated by stress such as influenza infection or by dietary supplementation with l-carnitine. Long-chain acylcarnitines co-localize with pulmonary surfactant, a unique film of phospholipids and proteins that reduces surface tension and prevents alveolar collapse during breathing. In vitro, the long-chain species palmitoylcarnitine directly inhibits the surface adsorption of pulmonary surfactant as well as its ability to reduce surface tension. Treatment of LCAD−/− mice with mildronate, a drug that inhibits carnitine synthesis, eliminates acylcarnitines and improves lung function. Finally, acylcarnitines are detectable in normal human lavage fluid. Thus, long-chain acylcarnitines may represent a risk factor for lung injury in humans with dysfunctional fatty acid oxidation. |
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Keywords: | fatty acid oxidation gene knockout lung mitochondria pulmonary surfactant acyl-CoA dehydrogenase acylcarnitine mildronate |
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