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Journal of Lipid Research, Vol. 45, 1758-1767, September 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Upregulation of surfactant synthesis triggers ABCA1-mediated basolateral phospholipid efflux

Jiming Zhou^*, Yong You^*, Alan J. Ryan^*, and Rama K. Mallampalli^1,,

^* Departments of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Biochemistry, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242
Department of Veterans Affairs Medical Center, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242

¹ To whom correspondence should be addressed. e-mail: rama-mallampalli{at}uiowa.edu

Alveolar type II lung epithelia produce surfactant, an essential surface-active material highly enriched with disaturated phosphatidylcholine (DSPC), which requires a key regulatory enzyme, CTP:phosphocholine cytidylyltransferase (CCT), for its synthesis before its export apically into the alveolus. In this study, we examined whether surfactant phosphatidylcholine (PC) synthesis and export are physiologically linked. Stable overexpression of CCT in lung epithelial cell lines increased rates of PC synthesis and cellular DSPC mass without altering total cellular PC content. Overexpression of CCT was associated with i) increased basolateral, rather than apical, PC export catalyzed by ABCA1; ii) basolateral export of significant levels of unsaturated (nonsurfactant) PC; and iii) transcriptional activation of the ABCA1 gene via a liver X receptor/retinoic acid receptor-independent pathway. Cells exposed to PC vesicles exhibited a dose-dependent increase in ABCA1 transcriptional activity.

These data provide the first evidence that surfactant PC synthesis is linked to its export via a basolateral lipid efflux pathway. This pathway is mediated, in part, by a phospholipid sensor, ABCA1, that appears to partake in the autoregulation of both cellular content and composition of PC, thereby providing a potentially novel exit route for a newly synthesized pool of PC distinct from surfactant.

Abbreviations: CCT, CTP:phosphocholine cytidylyltransferase; CDP-choline, cytidine diphosphocholine; DOPC, 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine; DR-4, direct repeat separated by four nucleotides; DPPC, dipalmitoyl phosphatidylcholine; DSPC, disaturated phosphatidylcholine; ECL, enhanced chemiluminescence; GPC, glycerophosphocholine; 22HC, 22-hydroxycholesterol; LXR, liver X receptor; PC, phosphatidylcholine; POPC, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; RA, 9-cis retinoic acid; RXR, retinoid X receptor

Supplementary key words CTP:phosphocholine cytidylyltransferase • phosphatidylcholine • ATP binding cassette transporter 1 • human lung adenocarcinoma cell line • overexpression

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