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Expression and Biological Activity of ABCA1 in Alveolar Epithelial Cells

¹ Institute for Environmental Medicine, Philadelphia; ² Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania; ³ Will Rogers Institute Pulmonary Research Center, University of Southern California, Los Angeles, California; and ⁴ Children's Hospital of Philadelphia, Philadelphia, Pennsylvania

Correspondence and requests for reprints should be addressed to Sandra R. Bates, Ph.D., 1 John Morgan Bldg., Institute for Environmental Medicine, 3620 Hamilton Walk, University of Pennsylvania, Philadelphia, PA 19104. E-mail: batekenn{at}mail.med.upenn.edu

The mechanisms used by alveolar type I pneumocytes for maintenance of the lipid homeostasis necessary to sustain these large squamous cells are unknown. The processes may involve the ATP-binding cassette transporter A1 (ABCA1), a transport protein shown to be crucial in apolipoprotein A-I (apoA-I)–mediated mobilization of cellular cholesterol and phospholipid. Immunohistochemical data demonstrated the presence of ABCA1 in lung type I and type II cells and in cultured pneumocytes. Type II cells isolated from rat lungs and cultured for 5 days in 10% serum trans-differentiated toward cells with a type I–like phenotype which reacted with the type I cell–specific monoclonal antibody VIIIB2. Upon incubation of the type I–like pneumocytes with agents that up-regulate the ABCA1 gene (9-cis-retinoic acid [9cRA] and 22-hydroxycholesterol [22-OH, 9cRA/22-OH]), ABCA1 protein levels were enhanced to maximum levels after 8 to 16 hours and remained elevated for 24 hours. In the presence of apoA-I and 9cRA/22-OH, efflux of radioactive phospholipid and cholesterol from pneumocytes was stimulated 3- to 20-fold, respectively, over controls. Lipid efflux was inhibited by Probucol. Sucrose density gradient analysis of the media from stimulated cells incubated with apoA-I identified heterogeneous lipid particles that isolated at a density between 1.063 and 1.210 g/ml, with low or high apoA-I content. Thus, pneumocytes with markers for the type I phenotype contained functional ABCA1 protein, released lipid to apoA-I protein, and were capable of producing particles resembling nascent high-density lipoprotein, indicating an important role for ABCA1 in the maintenance of lung lipid homeostasis.

Key Words: lung • cholesterol • high-density lipoprotein • apolipoprotein A-I • phospholipids

CLINICAL RELEVANCE Type I pneumocytes cover most of the internal surface of the alveolar space. This article describes the role of the ABCA1 transporter in these cells for the maintenance of lipid homeostasis and for the formation of nascent high density lipoprotein particles.