The control of intra-cellular cholesterol levels is an intricately regulated process that depends not only on the regulation of lipid uptake and cellular sterol synthesis but also on a mechanism that permits cells to efflux cholesterol to apolipoprotein and lipoprotein acceptor molecules. The best evidence for the importance of this efflux pathway in human physiology comes from studies of patient's with Tangier disease. Recent work has shown that the genetic defect in Tangier disease maps to a locus encoding a member of the ABCA family of ATP- binding cassette transporters (ABCA1) and that this transporter is required for normal, apolipoprotein-stimulated cholesterol efflux. In vivo, the reverse cholesterol transport pathway is thought to be initiated when a lipid-poor HDL binds to a cell and stimulates the removal of cellular lipids, at least in part, via this ABCA1-mediated process. As the pharmacologic tools for manipulating the reverse cholesterol transport pathway are far less sophisticated and effective than those available for reducing the levels of pro-atherogenic lipoproteins, insights gained from investigating ABCA1's function have the potential to lead to new clinical therapeutics. In this proposal, the investigators will explore the structural requirements that underlie ABCA1 function, focusing on its membrane topology, binding interaction with ligands, and regulation by kinases. These studies of the cell biology of the ABCA1 transporter will importantly contribute not only to a molecular description of the cellular cholesterol efflux pathway but also to our growing understanding of the mechanisms by which human cholesterol homeostasis is maintained or goes awry.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL068988-01
Application #
6422596
Study Section
Special Emphasis Panel (ZRG1-SSS-T (01))
Program Officer
Applebaum-Bowden, Deborah
Project Start
2002-02-01
Project End
2007-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
1
Fiscal Year
2002
Total Cost
$327,750
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02199
Fitzgerald, Michael L; Xavier, Ramnik; Haley, Kathleen J et al. (2007) ABCA3 inactivation in mice causes respiratory failure, loss of pulmonary surfactant, and depletion of lung phosphatidylglycerol. J Lipid Res 48:621-32
Kim, Woojin Scott; Fitzgerald, Michael L; Kang, Kihwa et al. (2005) Abca7 null mice retain normal macrophage phosphatidylcholine and cholesterol efflux activity despite alterations in adipose mass and serum cholesterol levels. J Biol Chem 280:3989-95
Okuhira, Kei-ichiro; Fitzgerald, Michael L; Sarracino, David A et al. (2005) Purification of ATP-binding cassette transporter A1 and associated binding proteins reveals the importance of beta1-syntrophin in cholesterol efflux. J Biol Chem 280:39653-64
Fitzgerald, Michael L; Okuhira, Kei-Ichiro; Short 3rd, Glenn F et al. (2004) ATP-binding cassette transporter A1 contains a novel C-terminal VFVNFA motif that is required for its cholesterol efflux and ApoA-I binding activities. J Biol Chem 279:48477-85
Chroni, Angeliki; Liu, Tong; Fitzgerald, Michael L et al. (2004) Cross-linking and lipid efflux properties of apoA-I mutants suggest direct association between apoA-I helices and ABCA1. Biochemistry 43:2126-39
Fitzgerald, Michael L; Morris, Andrea L; Rhee, Jeongmi S et al. (2002) Naturally occurring mutations in the largest extracellular loops of ABCA1 can disrupt its direct interaction with apolipoprotein A-I. J Biol Chem 277:33178-87
Fukumoto, Hiroaki; Deng, Amy; Irizarry, Michael C et al. (2002) Induction of the cholesterol transporter ABCA1 in central nervous system cells by liver X receptor agonists increases secreted Abeta levels. J Biol Chem 277:48508-13