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J Biol Chem. 2014 Apr 11;289(15):10668-79. doi: 10.1074/jbc.M113.540260. Epub 2014 Mar 3.

Long-chain acyl-CoA dehydrogenase deficiency as a cause of pulmonary surfactant dysfunction.

Author information

1
From the Department of Pediatrics, University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh of University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.

Abstract

Long-chain acyl-CoA dehydrogenase (LCAD) is a mitochondrial fatty acid oxidation enzyme whose expression in humans is low or absent in organs known to utilize fatty acids for energy such as heart, muscle, and liver. This study demonstrates localization of LCAD to human alveolar type II pneumocytes, which synthesize and secrete pulmonary surfactant. The physiological role of LCAD and the fatty acid oxidation pathway in lung was subsequently studied using LCAD knock-out mice. Lung fatty acid oxidation was reduced in LCAD(-/-) mice. LCAD(-/-) mice demonstrated reduced pulmonary compliance, but histological examination of lung tissue revealed no obvious signs of inflammation or pathology. The changes in lung mechanics were found to be due to pulmonary surfactant dysfunction. Large aggregate surfactant isolated from LCAD(-/-) mouse lavage fluid had significantly reduced phospholipid content as well as alterations in the acyl chain composition of phosphatidylcholine and phosphatidylglycerol. LCAD(-/-) surfactant demonstrated functional abnormalities when subjected to dynamic compression-expansion cycling on a constrained drop surfactometer. Serum albumin, which has been shown to degrade and inactivate pulmonary surfactant, was significantly increased in LCAD(-/-) lavage fluid, suggesting increased epithelial permeability. Finally, we identified two cases of sudden unexplained infant death where no lung LCAD antigen was detectable. Both infants were homozygous for an amino acid changing polymorphism (K333Q). These findings for the first time identify the fatty acid oxidation pathway and LCAD in particular as factors contributing to the pathophysiology of pulmonary disease.

KEYWORDS:

Acyl-CoA Dehydrogenase; Fatty Acid Oxidation; Genetic Diseases; Lung; Mitochondrial Metabolism; Pulmonary Surfactant

PMID:
24591516
PMCID:
PMC4036448
DOI:
10.1074/jbc.M113.540260
[Indexed for MEDLINE]
Free PMC Article

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