Long-chain Acylcarnitines Reduce Lung Function by Inhibiting Pulmonary Surfactant.
Identifieur interne : 000D22 ( Main/Exploration ); précédent : 000D21; suivant : 000D23Long-chain Acylcarnitines Reduce Lung Function by Inhibiting Pulmonary Surfactant.
Auteurs : Chikara Otsubo [États-Unis] ; Sivakama Bharathi [États-Unis] ; Radha Uppala [États-Unis] ; Olga R. Ilkayeva ; Dongning Wang ; Kevin Mchugh [États-Unis] ; Ye Zou [États-Unis] ; Jieru Wang [États-Unis] ; John F. Alcorn [États-Unis] ; Yi Y. Zuo [États-Unis] ; Matthew D. Hirschey ; Eric S. Goetzman [États-Unis]Source :
- The Journal of biological chemistry [ 1083-351X ] ; 2015.
Descripteurs français
- KwdFr :
- Animaux, Carnitine (analogues et dérivés), Carnitine (génétique), Carnitine (métabolisme), Humains, Long-chain-acyl-CoA dehydrogenase (génétique), Long-chain-acyl-CoA dehydrogenase (métabolisme), Lésion pulmonaire (anatomopathologie), Lésion pulmonaire (génétique), Lésion pulmonaire (métabolisme), Phospholipides (génétique), Phospholipides (métabolisme), Poumon (anatomopathologie), Poumon (métabolisme), Souris, Souris knockout, Surfactants pulmonaires (métabolisme).
- MESH :
- analogues et dérivés : Carnitine.
- anatomopathologie : Lésion pulmonaire, Poumon.
- génétique : Carnitine, Long-chain-acyl-CoA dehydrogenase, Lésion pulmonaire, Phospholipides.
- métabolisme : Carnitine, Long-chain-acyl-CoA dehydrogenase, Lésion pulmonaire, Phospholipides, Poumon, Surfactants pulmonaires.
- Animaux, Humains, Souris, Souris knockout.
English descriptors
- KwdEn :
- Acyl-CoA Dehydrogenase, Long-Chain (genetics), Acyl-CoA Dehydrogenase, Long-Chain (metabolism), Animals, Carnitine (analogs & derivatives), Carnitine (genetics), Carnitine (metabolism), Humans, Lung (metabolism), Lung (pathology), Lung Injury (genetics), Lung Injury (metabolism), Lung Injury (pathology), Mice, Mice, Knockout, Phospholipids (genetics), Phospholipids (metabolism), Pulmonary Surfactants (metabolism).
- MESH :
- chemical , analogs & derivatives : Carnitine.
- chemical , genetics : Acyl-CoA Dehydrogenase, Long-Chain, Carnitine, Phospholipids.
- chemical , metabolism : Acyl-CoA Dehydrogenase, Long-Chain, Carnitine, Phospholipids, Pulmonary Surfactants.
- genetics : Lung Injury.
- metabolism : Lung, Lung Injury.
- pathology : Lung, Lung Injury.
- Animals, Humans, Mice, Mice, Knockout.
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.
DOI: 10.1074/jbc.M115.655837
PubMed: 26240137
Affiliations:
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Le document en format XML
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Alcorn</name><affiliation wicri:level="2"><nlm: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.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>From the Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh</wicri:cityArea></affiliation></author><author><name sortKey="Zuo, Yi Y" sort="Zuo, Yi Y" uniqKey="Zuo Y" first="Yi Y" last="Zuo">Yi Y. 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Ilkayeva</name><affiliation><nlm:affiliation>Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina 27701, and.</nlm:affiliation><wicri:noCountry code="subField">and</wicri:noCountry></affiliation></author><author><name sortKey="Wang, Dongning" sort="Wang, Dongning" uniqKey="Wang D" first="Dongning" last="Wang">Dongning Wang</name><affiliation><nlm:affiliation>Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina 27701, and.</nlm:affiliation><wicri:noCountry code="subField">and</wicri:noCountry></affiliation></author><author><name sortKey="Mchugh, Kevin" sort="Mchugh, Kevin" uniqKey="Mchugh K" first="Kevin" last="Mchugh">Kevin Mchugh</name><affiliation wicri:level="2"><nlm: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.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>From the Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh</wicri:cityArea></affiliation></author><author><name sortKey="Zou, Ye" sort="Zou, Ye" uniqKey="Zou Y" first="Ye" last="Zou">Ye Zou</name><affiliation wicri:level="2"><nlm:affiliation>Department of Mechanical Engineering, University of Hawaii at Manoa, Honolulu, Hawaii 96822.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Hawaï</region></placeName><wicri:cityArea>Department of Mechanical Engineering, University of Hawaii at Manoa, Honolulu</wicri:cityArea></affiliation></author><author><name sortKey="Wang, Jieru" sort="Wang, Jieru" uniqKey="Wang J" first="Jieru" last="Wang">Jieru Wang</name><affiliation wicri:level="2"><nlm: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.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>From the Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh</wicri:cityArea></affiliation></author><author><name sortKey="Alcorn, John F" sort="Alcorn, John F" uniqKey="Alcorn J" first="John F" last="Alcorn">John F. Alcorn</name><affiliation wicri:level="2"><nlm: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.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Pennsylvanie</region></placeName><wicri:cityArea>From the Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh</wicri:cityArea></affiliation></author><author><name sortKey="Zuo, Yi Y" sort="Zuo, Yi Y" uniqKey="Zuo Y" first="Yi Y" last="Zuo">Yi Y. Zuo</name><affiliation wicri:level="2"><nlm:affiliation>Department of Mechanical Engineering, University of Hawaii at Manoa, Honolulu, Hawaii 96822.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Hawaï</region></placeName><wicri:cityArea>Department of Mechanical Engineering, University of Hawaii at Manoa, Honolulu</wicri:cityArea></affiliation></author><author><name sortKey="Hirschey, Matthew D" sort="Hirschey, Matthew D" uniqKey="Hirschey M" first="Matthew D" last="Hirschey">Matthew D. Hirschey</name><affiliation><nlm:affiliation>Sarah W. Stedman Nutrition and Metabolism Center, Duke University Medical Center, Durham, North Carolina 27701, and.</nlm:affiliation><wicri:noCountry code="subField">and</wicri:noCountry></affiliation></author><author><name sortKey="Goetzman, Eric S" sort="Goetzman, Eric S" uniqKey="Goetzman E" first="Eric S" last="Goetzman">Eric S. Goetzman</name><affiliation wicri:level="1"><nlm: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.</nlm:affiliation><country wicri:rule="url">États-Unis</country><wicri:regionArea>From the Department of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224</wicri:regionArea><wicri:noRegion>Pennsylvania 15224</wicri:noRegion></affiliation></author></analytic><series><title level="j">The Journal of biological chemistry</title><idno type="eISSN">1083-351X</idno><imprint><date when="2015" type="published">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Acyl-CoA Dehydrogenase, Long-Chain (genetics)</term><term>Acyl-CoA Dehydrogenase, Long-Chain (metabolism)</term><term>Animals</term><term>Carnitine (analogs & derivatives)</term><term>Carnitine (genetics)</term><term>Carnitine (metabolism)</term><term>Humans</term><term>Lung (metabolism)</term><term>Lung (pathology)</term><term>Lung Injury (genetics)</term><term>Lung Injury (metabolism)</term><term>Lung Injury (pathology)</term><term>Mice</term><term>Mice, Knockout</term><term>Phospholipids (genetics)</term><term>Phospholipids (metabolism)</term><term>Pulmonary Surfactants (metabolism)</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Animaux</term><term>Carnitine (analogues et dérivés)</term><term>Carnitine (génétique)</term><term>Carnitine (métabolisme)</term><term>Humains</term><term>Long-chain-acyl-CoA dehydrogenase (génétique)</term><term>Long-chain-acyl-CoA dehydrogenase (métabolisme)</term><term>Lésion pulmonaire (anatomopathologie)</term><term>Lésion pulmonaire (génétique)</term><term>Lésion pulmonaire (métabolisme)</term><term>Phospholipides (génétique)</term><term>Phospholipides (métabolisme)</term><term>Poumon (anatomopathologie)</term><term>Poumon (métabolisme)</term><term>Souris</term><term>Souris knockout</term><term>Surfactants pulmonaires (métabolisme)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Carnitine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Acyl-CoA Dehydrogenase, Long-Chain</term><term>Carnitine</term><term>Phospholipids</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Acyl-CoA Dehydrogenase, Long-Chain</term><term>Carnitine</term><term>Phospholipids</term><term>Pulmonary Surfactants</term></keywords><keywords scheme="MESH" qualifier="analogues et dérivés" xml:lang="fr"><term>Carnitine</term></keywords><keywords scheme="MESH" qualifier="anatomopathologie" xml:lang="fr"><term>Lésion pulmonaire</term><term>Poumon</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Lung Injury</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Carnitine</term><term>Long-chain-acyl-CoA dehydrogenase</term><term>Lésion pulmonaire</term><term>Phospholipides</term></keywords><keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Lung</term><term>Lung Injury</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Carnitine</term><term>Long-chain-acyl-CoA dehydrogenase</term><term>Lésion pulmonaire</term><term>Phospholipides</term><term>Poumon</term><term>Surfactants pulmonaires</term></keywords><keywords scheme="MESH" qualifier="pathology" xml:lang="en"><term>Lung</term><term>Lung Injury</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Humans</term><term>Mice</term><term>Mice, Knockout</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Animaux</term><term>Humains</term><term>Souris</term><term>Souris knockout</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">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. </div></front></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Hawaï</li><li>Pennsylvanie</li></region></list><tree><noCountry><name sortKey="Hirschey, Matthew D" sort="Hirschey, Matthew D" uniqKey="Hirschey M" first="Matthew D" last="Hirschey">Matthew D. Hirschey</name><name sortKey="Ilkayeva, Olga R" sort="Ilkayeva, Olga R" uniqKey="Ilkayeva O" first="Olga R" last="Ilkayeva">Olga R. Ilkayeva</name><name sortKey="Wang, Dongning" sort="Wang, Dongning" uniqKey="Wang D" first="Dongning" last="Wang">Dongning Wang</name></noCountry><country name="États-Unis"><region name="Pennsylvanie"><name sortKey="Otsubo, Chikara" sort="Otsubo, Chikara" uniqKey="Otsubo C" first="Chikara" last="Otsubo">Chikara Otsubo</name></region><name sortKey="Alcorn, John F" sort="Alcorn, John F" uniqKey="Alcorn J" first="John F" last="Alcorn">John F. Alcorn</name><name sortKey="Bharathi, Sivakama" sort="Bharathi, Sivakama" uniqKey="Bharathi S" first="Sivakama" last="Bharathi">Sivakama Bharathi</name><name sortKey="Goetzman, Eric S" sort="Goetzman, Eric S" uniqKey="Goetzman E" first="Eric S" last="Goetzman">Eric S. Goetzman</name><name sortKey="Mchugh, Kevin" sort="Mchugh, Kevin" uniqKey="Mchugh K" first="Kevin" last="Mchugh">Kevin Mchugh</name><name sortKey="Uppala, Radha" sort="Uppala, Radha" uniqKey="Uppala R" first="Radha" last="Uppala">Radha Uppala</name><name sortKey="Wang, Jieru" sort="Wang, Jieru" uniqKey="Wang J" first="Jieru" last="Wang">Jieru Wang</name><name sortKey="Zou, Ye" sort="Zou, Ye" uniqKey="Zou Y" first="Ye" last="Zou">Ye Zou</name><name sortKey="Zuo, Yi Y" sort="Zuo, Yi Y" uniqKey="Zuo Y" first="Yi Y" last="Zuo">Yi Y. Zuo</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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