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J. Biol. Chem., Vol. 282, Issue 13, 9628-9634, March 30, 2007

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ABCA3 as a Lipid Transporter in Pulmonary Surfactant Biogenesis^*

Nobuhiro Ban, Yoshihiro Matsumura, Hiromichi Sakai, Yasukazu Takanezawa, Mayumi Sasaki^¶, Hiroyuki Arai, and Nobuya Inagaki^¶1

From the 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, the Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan, and the ^¶Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, and CREST-JST, Kyoto 606-8507, Japan

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.

Received for publication, December 22, 2006 , and in revised form, January 29, 2007.

^* This work was supported by scientific research grants and Grant-in-aid 15GS0301 for Creative Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; CREST (Core Research for Evolutional Science and Technology) of Japan Science and Technology Agency; and the 21st Century Center of Excellence Program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure and a video.

¹ To whom correspondence should be addressed: Dept. of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606–8507, Japan. Tel.: 81-75-751-3562; Fax: 81-75-771-6601; E-mail: inagaki{at}metab.kuhp.kyoto-u.ac.jp.

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