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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:40.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Overexpression of Apolipoprotein F Reduces HDL Cholesterol Levels In Vivo

William R. Lagor; Robert J. Brown; Sue-Anne Toh; John S. Millar; Ilia V. Fuki; Margarita de la Llera-Moya; Tiffany Yuen; George Rothblat; Jeffrey T. Billheimer; Daniel J. Rader

From the Institute for Translational Medicine and Therapeutics and Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia.

Correspondence to Daniel J. Rader, MD, University of Pennsylvania School of Medicine, 654 Biomedical Research Building II/III, 421 Curie Blvd, Philadelphia, PA 19104. E-mail rader{at}mail.med.upenn.edu

Objective— Apolipoprotein F (ApoF) is a protein component of several lipoprotein classes including HDL. It is also known as lipid transfer inhibitor protein (LTIP) based on its ability to inhibit lipid transfer between lipoproteins ex vivo. We sought to investigate the role of ApoF in HDL metabolism.

Methods and Results— Adeno-associated viruses (AAV) based on serotype 8, were used to overexpress either murine or human ApoF in mice. Overexpression of murine ApoF significantly reduced total cholesterol levels by 28% (P<0.001), HDL by 27% (P<0.001), and phospholipid levels by 19% (P<0.001). Overexpression of human ApoF had similar effects. Human ApoF was nearly exclusively HDL-associated in mice. In agreement with this finding, greater than 90% of the ApoF in human plasma was found on HDL₃, with only a small amount on LDL. Overexpression of mouse ApoF accelerated the plasma clearance of [³H]-cholesteryl ether labeled HDL. Plasma from mice overexpressing ApoF showed improved macrophage cholesterol efflux on a per HDL-C basis.

Conclusions— ApoF overexpression reduces HDL cholesterol levels in mice by increasing clearance of HDL-CE. ApoF may be an important determinant of HDL metabolism and reverse cholesterol transport.

Adeno-associated viral vectors were used to overexpress human or mouse ApoF in mice. ApoF overexpression reduced HDL cholesterol levels, and improved clearance of HDL cholesteryl ester from the plasma. The data suggests ApoF is an important gene affecting HDL metabolism.

Key Words: apolipoprotein F • lipid transfer inhibitor protein • adeno-associated virus • HDL cholesterol • reverse cholesterol transport