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Published ahead of print on March 23, 2004, doi:10.1165/rcmb.2004-0038OC

Am. J. Respir. Cell Mol. Biol., Volume 31, Number 2, August 2004, 227-233

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Submitted on February 4, 2004
Revised on March 22, 2004

OXYSTEROLS TRIGGER ABCA1-MEDIATED BASOLATERAL SURFACTANT EFFLUX

Marianna Agassandian1, Satya N Mathur2, Jiming Zhou1, F. Jeffrey Field2, and Rama K Mallampalli3*

1 Department of Medicine, University of Iowa, Iowa City, IA, USA, 2 Department of Medicine, University of Iowa, Iowa City, IA, USA; Department of Veterans Affairs Medical Center, University of Iowa, Iowa City, IA, USA, 3 Department of Medicine, University of Iowa, Iowa City, IA, USA; Department of Veterans Affairs Medical Center, University of Iowa, Iowa City, IA, USA; Department of Biochemistry, University of Iowa, Iowa City, IA, USA

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

Surfactant is an apically-secreted surface-active material containing primarily disaturated phosphatidylcholine (DSPtdCho) that is released from alveolar epithelia into the alveolus. Surfactant deficiency is an important aspect of inflammatory lung disease and may result from extravasation of serum lipoproteins into the alveolus. We investigated whether one bioactive component of modified lipoproteins, oxysterols, might reduce surfactant PtdCho availability by altering its trafficking. The oxysterol, 22-hydroxycholesterol (22HC), in combination with its obligate partner, 9 cis-retinoic acid (RA), decreased surfactant PtdCho levels, in part, by stimulating basolateral phospholipid export in murine lung epithelia. 22HC/RA stimulated basolateral PtdCho efflux in cells via transcriptional activation of the ATP-binding cassette transporter 1 (ABCA1) gene. This effect was mediated by a DR-4 locus within the ABCA1 promoter. ABCA1 knockdown studies using ABCA1 siRNA or the ABCA1 inhibitor, glyburide, selectively attenuated 22HC/RA -driven basolateral PtdCho efflux. 22HC/RA significantly increased export of PtdCho molecular species containing saturated (16:0) fatty-acyl species typical of DSPtdCho. Overexpression of ABCA1 mimicked 22HC/RA effects by increasing cellular PtdCho efflux whereas mutagenesis of ABCA1 at Trp590 attenuated PtdCho release. The results indicate the existence of an oxysterol-activated basolateral exit pathway for surfactant that might impact the availability of phospholipid destined for apical secretion.




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