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J. Biol. Chem., Vol. 282, Issue 20, 14868-14874, May 18, 2007

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Enhanced ApoA-I-dependent Cholesterol Efflux by ABCA1 from Sphingomyelin-deficient Chinese Hamster Ovary Cells^*

Kohjiro Nagao, Kei Takahashi, Kentaro Hanada, Noriyuki Kioka, Michinori Matsuo, and Kazumitsu Ueda¹

From the Laboratory of Cellular Biochemistry, Division of Applied Life Sciences, Kyoto University Graduate School of Agriculture, Kyoto 606-8502, Japan and Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan

ATP binding cassette protein A1 (ABCA1) plays a major role in cholesterol homeostasis and high density lipoprotein (HDL) metabolism. It is proposed that ABCA1 reorganizes the plasma membrane and generates more loosely packed domains that facilitate apoA-I-dependent cholesterol efflux. In this study, we examined the effects of the cellular sphingomyelin level on HDL formation by ABCA1 by using a Chinese hamster ovary-K1 mutant cell line, LY-A, which has a missense mutation in the ceramide transfer protein CERT. When LY-A cells were cultured in Nutridoma-BO medium and sphingomyelin content was reduced, apoA-I-dependent cholesterol efflux by ABCA1 from LY-A cells increased 1.65-fold compared with that from LY-A/CERT cells stably transfected with human CERT cDNA. Exogenously added sphingomyelin significantly reduced the apoA-I-dependent efflux of cholesterol from LY-A cells, confirming that the decrease in sphingomyelin content in the plasma membrane stimulates cholesterol efflux by ABCA1. The amount of cholesterol available to cold methyl--cyclodextrin (MCD) extraction from LY-A cells was increased by 40% by the expression of ABCA1 and was 1.6-fold higher than that from LY-A/CERT cells. This step in ABCA1 function, making cholesterol available to cold MCD, was independent of apoA-I. These results suggest that the function of ABCA1 could be divided into two steps: (i) a flopping step to move phosphatidylcholine and cholesterol from the inner to outer leaflet of the plasma membrane, where cholesterol becomes available to cold MCD extraction, and (ii) a loading step to load phosphatidylcholine and cholesterol onto apoA-I to generate HDL.

Received for publication, December 7, 2006 , and in revised form, March 14, 2007.

^* This work was supported by Grant-in-aid for Scientific Research and Creative Scientific Research 15GS0301 from the Ministry of Education, Culture, Sports, Science, and Technology, Japan, and grants from the Bio-oriented Technology Research Advancement Institution and the Pharmaceutical and Medical Devices Agency. 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.

¹ To whom correspondence should be addressed. Tel.: 81-75-753-6124; Fax: 81-75-753-6104; E-mail: uedak{at}kais.kyoto-u.ac.jp.

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