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J Biol Chem, Vol. 275, Issue 16, 12156-12163, April 21, 2000

Single Repeat Deletion in ApoA-I Blocks Cholesterol Esterification and Results in Rapid Catabolism of Delta 6 and Wild-type ApoA-I in Transgenic Mice*

Mary G. Sorci-ThomasDagger §, Mike Thomas§, Linda Curtiss||, and Mark LandrumDagger

From the Dagger  Departments of Pathology and § Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157 and the || Departments of Immunology and Vascular Biology, The Scripps Research Institute, La Jolla, California 92037

The deletion mutation Delta 6 apolipoprotein A-I lacks residues 143-164 or repeat 6 in the mature apoA-I protein. In vitro studies show this mutation dramatically reduces the rate of lecithin:cholesterol acyltransferase (LCAT) catalyzed cholesterol esterification. The present study was initiated to investigate the effect of this mutation on in vivo high density lipoprotein (HDL) cholesterol esterification and metabolism. Transgenic mice expressing human Delta 6 apoA-I (TgDelta 6 +/+) were created and then crossed with apoA-I knockout mice (-/-) to generate mice expressing only human Delta 6 apoA-I (TgDelta 6 -/-). Human Delta 6 apoA-I was associated with homogeneous sized alpha -HDL, when wild-type mouse apoA-I was present (in TgDelta 6 +/+ and +/- mice). However, in the absence of endogenous mouse apoA-I, Delta 6 apoA-I was found exclusively in cholesterol ester-poor HDL, and lipid-free HDL fractions. This observation coincides with the 6-fold lower cholesterol ester mass in TgDelta 6 -/- mouse plasma compared with control. Structural studies show that despite the structural perturbation of a domain extending from repeat 5 to repeat 8 (137-178), Delta 6 apoA-I binds to spherical unilamellar vesicles with only 2-fold less binding affinity. In summary, these data show a domain corresponding to apoA-I repeat 6 is responsible for providing an essential conformation for LCAT catalyzed generation of cholesterol esters. Deletion of apoA-I repeat 6 not only blocks normal levels of cholesterol esterification but also exerts a dominant inhibition on the ability of wild-type apoA-I to activate LCAT in vivo.

* This work was supported by Public Health Service Grants HL-49373 (to M. S. T.) and HL-43815 (to L. K. C.) from the National Institutes of Health. Transgenic mouse production was supported in part by NCI, National Institutes of Health Grant CAA13148 to the University of Alabama at Birmingham Comprehensive Cancer Center.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

An Established Investigator of the American Heart Association. To whom correspondence should be addressed: Dept. of Pathology/Comparative Medicine, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157. Tel.: 336-716-2147; Fax: 336-716-6279; E-mail: msthomas@wfubmc.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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