Published Online
on August 28, 2006

A more recent version of this article appeared on September 19, 2006

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Submitted on February 18, 2006
Revised on July 10, 2006
Accepted on July 13, 2006

Both Hepatic and Extrahepatic ABCA1 Have Discrete and Essential Functions in the Maintenance of Plasma High-Density Lipoprotein Cholesterol Levels In Vivo

Roshni R. Singaraja PhD, Miranda Van Eck PhD, Nagat Bissada MD, Francesca Zimetti PhD, Heidi L. Collins PhD, Reeni B. Hildebrand BS, Anna Hayden , Liam R. Brunham BS, Martin H. Kang BS, Jean-Charles Fruchart PhD, Theo J.C. Van Berkel PhD, John S. Parks PhD, Bart Staels PhD, George H. Rothblat PhD, Catherine Fiévet PhD, and Michael R. Hayden MBChB, PhD^*

From the Center for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada (R.R.S., N.B., A.H., L.R.B., M.H.K., M.R.H.); Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, Leiden, the Netherlands (M.V.E., R.B.H., T.J.C.V.B.); Division of Gastroenterology and Nutrition, Children’s Hospital of Philadelphia, Philadelphia, Pa (F.Z., H.L.C., G.H.R.); Institut Pasteur, Département d’Athérosclérose, INSERM U545, Université de Lille 2, Lille, France (J.F., B.S., C.F.); and Department of Pathology, Lipid Sciences Research Center, Wake Forest University School of Medicine, Winston-Salem, NC (J.P.).

^* To whom correspondence should be addressed. E-mail: mrh{at}cmmt.ubc.ca.

Background--Extrahepatic tissues have long been considered critical contributors of cholesterol to nascent HDL particles in the reverse cholesterol transport pathway, in which ABCA1 plays the crucial role. Recent studies, however, including both overexpression and deletion of ABCA1 selectively in the liver, have highlighted the primary role of the liver in the maintenance of HDL levels in vivo.

Methods and Results--The availability of mice with complete deletion of ABCA1 (total knockout [TKO]) and with liver-specific deletion of ABCA1 (LSKO) has enabled us to dissect the discrete roles of hepatic relative to extrahepatic ABCA1 in HDL biogenesis. Delivery of adenoviral ABCA1 resulted in selective expression of physiological levels of ABCA1 in the livers of both LSKO and TKO mice, resulting in increased HDL cholesterol (HDL-C). Expression of ABCA1 in the liver of LSKO mice resulted in plasma HDL-C levels that were similar to those in wild-type mice and significantly above those seen in similarly treated TKO mice. HDL particles from ABCA1-expressing LSKO mice were larger and contained significantly increased cholesterol compared with TKO mice. Infusion of human apolipoprotein A-I/phospholipid reconstituted HDL particles normalized plasma HDL-C levels in LSKO mice but had no effect on HDL-C levels in TKO mice.

Conclusions--Although hepatic ABCA1 appears crucial for phospholipid transport, extrahepatic tissues play an important role in cholesterol transfer to nascent HDL particles. These data highlight the discrete and specific roles of both liver and extrahepatic ABCA1 in HDL biogenesis in vivo and indicate that ABCA1 shows lipid cargo selectivity depending on its site of expression.

Key words: cholesterol • lipids • lipoproteins

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