title: Long-chain Acylcarnitines Reduce Lung Function by Inhibiting Pulmonary Surfactant.
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.
authors.affiliation: From the Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
authors.forename: Chikara
authors.initials: C
authors.lastname: Otsubo
authors.affiliation: From the Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
authors.forename: Sivakama
authors.initials: S
authors.lastname: Bharathi
authors.affiliation: From the Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
authors.forename: Radha
authors.initials: R
authors.lastname: Uppala
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina 27701, and.
authors.forename: Olga R
authors.initials: OR
authors.lastname: Ilkayeva
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina 27701, and.
authors.forename: Dongning
authors.initials: D
authors.lastname: Wang
authors.affiliation: From the Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
authors.forename: Kevin
authors.initials: K
authors.lastname: McHugh
authors.affiliation: Department of Mechanical Engineering, University of Hawaii at Manoa, Honolulu, Hawaii 96822.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zou
authors.affiliation: From the Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
authors.forename: Jieru
authors.initials: J
authors.lastname: Wang
authors.affiliation: From the Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
authors.forename: John F
authors.initials: JF
authors.lastname: Alcorn
authors.affiliation: Department of Mechanical Engineering, University of Hawaii at Manoa, Honolulu, Hawaii 96822.
authors.forename: Yi Y
authors.initials: YY
authors.lastname: Zuo
authors.affiliation: Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina 27701, and.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hirschey
authors.affiliation: From the Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224, Eric.goetzman@chp.edu.
authors.forename: Eric S
authors.initials: ES
authors.lastname: Goetzman
mesh_terms: D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D055370:Lung Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D010743:Phospholipids / Q000235:genetics / Q000378:metabolism*; D011663:Pulmonary Surfactants / Q000378:metabolism*
chemical_list: D010743:Phospholipids; D011663:Pulmonary Surfactants; C116917:acylcarnitine; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D002331:Carnitine
keywords: acyl-CoA dehydrogenase; acylcarnitine; fatty acid oxidation; gene knockout; lung; mildronate; mitochondria; pulmonary surfactant