ABCA3 as a lipid transporter in pulmonary surfactant biogenesis.
ABCA3 protein is expressed predominantly at the limiting membrane of the lamellar bodies in alveolar type II cells, and mutations in the ABCA3 gene cause lethal respiratory distress in newborn infants. To investigate the function of ABCA3 protein, we generated Abca3-deficient mice by targeting Abca3. Full-term Abca3(-/-) newborn pups died within an hour after birth because of acute respiratory failure. Ultrastructural analysis revealed abnormally dense lamellar body-like organelles and no normal lamellar bodies in Abca3(-/-) alveolar type II cells. TLC and electrospray ionization mass spectrometry analyses of lipids in the pulmonary interstitium showed that phosphatidylcholine and phosphatidylglycerol, which contain palmitic acid and are abundant in normal surfactant lipids, were dramatically decreased in Abca3(-/-) lung. These findings indicate that ABCA3 plays an essential role in pulmonary surfactant lipid metabolism and lamellar body biogenesis, probably by transporting these lipids as substrates.
Ban
Nobuhiro
N
Department of Physiology, Akita University School of Medicine, and Core Research for Evolutional Science and Technology (CREST) of Japan Science and Technology Agency (JST), Akita 010-8543, Japan.
Matsumura
Yoshihiro
Y
Department of Physiology, Akita University School of Medicine, and Core Research for Evolutional Science and Technology (CREST) of Japan Science and Technology Agency (JST), Akita 010-8543, Japan.
Sakai
Hiromichi
H
Department of Physiology, Akita University School of Medicine, and Core Research for Evolutional Science and Technology (CREST) of Japan Science and Technology Agency (JST), Akita 010-8543, Japan.
Takanezawa
Yasukazu
Y
Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
Sasaki
Mayumi
M
Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, and CREST-JST, Kyoto 606-8507, Japan.
Arai
Hiroyuki
H
Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
Inagaki
Nobuya
N
Department of Physiology, Akita University School of Medicine, and Core Research for Evolutional Science and Technology (CREST) of Japan Science and Technology Agency (JST), Akita 010-8543, Japan; Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, and CREST-JST, Kyoto 606-8507, Japan. Electronic address: inagaki@metab.kuhp.kyoto-u.ac.jp.
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D050356:Lipid Metabolism / Q000502:physiology*; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011663:Pulmonary Surfactants / Q000378:metabolism*; D013379:Substrate Specificity / Q000502:physiology
D018528:ATP-Binding Cassette Transporters; C512026:Abca3 protein, mouse; D011663:Pulmonary Surfactants