Expression and biological activity of ABCA1 in alveolar epithelial cells.
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.
Bates
Sandra R
SR
Institute for Environmental Medicine, 3620 Hamilton Walk, University of Pennsylvania, Philadelphia, PA 19104, USA. batekenn@mail.med.upenn.edu
Tao
Jian-Qin
JQ
Yu
Kevin J
KJ
Borok
Zea
Z
Crandall
Edward D
ED
Collins
Heidi L
HL
Rothblat
George H
GH
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism / Q000494:pharmacology; D018929:Cell Culture Techniques; D002454:Cell Differentiation; D002478:Cells, Cultured; D002784:Cholesterol / Q000032:analysis / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D008168:Lung / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010743:Phospholipids / Q000032:analysis / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013047:Specific Pathogen-Free Organisms; D013997:Time Factors; D015854:Up-Regulation
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D006888:Hydroxycholesterols; D010743:Phospholipids; C003585:22-hydroxycholesterol; D002784:Cholesterol