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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:1821.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Hepatic ATP-Binding Cassette Transporter A1 Is a Key Molecule in High-Density Lipoprotein Cholesteryl Ester Metabolism in Mice

Roshni R. Singaraja; Bjorn Stahmer; May Brundert; Martin Merkel; Joerg Heeren; Nagat Bissada; Martin Kang; Jenelle M. Timmins; Rajasekhar Ramakrishnan; John S. Parks; Michael R. Hayden; Franz Rinninger

From the University of British Columbia (R.R.S., N.B., M.K., M.R.H.), Vancouver, Canada; University Hospital Eppendorf (B.S., M.B., M.M., J.H., F.R.), Hamburg, Germany; Wake Forest University (J.M.T., J.S.P.), Winston-Salem, NC; and Columbia University (R.R.), New York, NY.

Correspondence to Franz Rinninger, University Hospital Eppendorf, Department of Medicine, Martinistrasse 52, 20246 Hamburg, Germany. E-mail Rinninger{at}uke.uni-hamburg.de

Objective— Mutations in ATP-binding cassette transporter A1 (ABCA1), the cellular lipid transport molecule mutated in Tangier disease, result in the rapid turnover of high-density lipoprotein (HDL)–associated apolipoproteins that presumably are cleared by the kidneys. However, the role of ABCA1 in the liver for HDL apolipoprotein and cholesteryl ester (CE) catabolism in vivo is unknown.

Methods and Results— Murine HDL was radiolabeled with ¹²⁵I in its apolipoprotein and with [³H]cholesteryl oleyl ether in its CE moiety. HDL protein and lipid metabolism in plasma and HDL uptake by tissues were investigated in ABCA1-overexpressing bacterial artificial chromosome (BAC)–transgenic (BAC⁺) mice and in mice harboring deletions of total (ABCA1^–/–) and liver-specific ABCA1 (ABCA1^–L/–L). In BAC⁺ mice with elevated ABCA1 expression, fractional catabolic rates (FCRs) of both the protein and the lipid tracer were significantly decreased in plasma and in the liver, yielding a diminished hepatic selective CE uptake from HDL. In contrast, ABCA1^–/– or ABCA1^–L/–L mice had significantly increased plasma and liver FCRs for both HDL tracers. An ABCA1 deficiency was associated with increased selective HDL CE uptake by the liver under all experimental conditions.

Conclusions— Hepatic ABCA1 has a critical role for HDL catabolism in plasma and for HDL selective CE uptake by the liver.

The role of ABCA1 in HDL metabolism was investigated with doubly radiolabeled HDL. In mice with transgenic expression of ABCA1 or in mice with deletions of this transport protein, it is shown that ABCA1 has a substantial effect on HDL turnover in plasma and on HDL catabolism by the liver.

Key Words: ABCA1 • HDL • selective uptake • cholesteryl ester

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