This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Holvoet, P. Articles by Collen, D. Search for Related Content PubMed PubMed Citation Articles by Holvoet, P. Articles by Collen, D. Pubmed/NCBI databases Substance via MeSH Related Collections Animal models of human disease Genetically altered mice Gene therapy Lipid and lipoprotein metabolism

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:459.)
© 2000 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

The Arg123-Tyr166 Central Domain of Human ApoAI Is Critical for Lecithin:Cholesterol Acyltransferase–Induced Hyperalphalipoproteinemia and HDL Remodeling in Transgenic Mice

Paul Holvoet; Bart De Geest; Sophie Van Linthout; Marleen Lox; Sophie Danloy; Kathleen Raes; Désiré Collen

From the Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium.

Correspondence to Paul Holvoet, Center for Molecular and Vascular Biology, University of Leuven, Campus Gasthuisberg, O & N, Herestraat 49, B-3000 Leuven, Belgium. E-mail paul.holvoet{at}med.kuleuven.ac.be

Abstract—High density lipoprotein (HDL) metabolism and lecithin:cholesterol acyltransferase (LCAT)–induced HDL remodeling were investigated in transgenic mice expressing human apolipoprotein (apo) AI or an apoAI/apoAII chimera in which the Arg123-Tyr166 domain of apoAI was substituted with the Ser12-Ala75 domain of apoAII. Expression of apoAI and of the apoAI/apoAII chimera resulted in a respective 3.5-fold and 2.9-fold increase of HDL cholesterol. Human LCAT gene transfer into apoAI-transgenic mice resulted in a 5.1-fold increase of endogenous LCAT activity. This increase was associated with a 2.4-fold increase of the cholesterol ester–to–free cholesterol ratio of HDL, a shift from HDL₃ to HDL₂, and a 2.4-fold increase of HDL cholesterol levels. Agarose gel electrophoresis revealed that human LCAT gene transfer into human apoAI–transgenic mice resulted in an increase of pre-ß-HDL and of pre--HDL. In contrast, human LCAT gene transfer did not affect cholesterol levels and HDL distribution profile in mice expressing the apoAI/apoAII chimera. Mouse LCAT did not "see" a difference between wild-type and mutant human apoAI, whereas human LCAT did, thus localizing the species-specific interaction in the central domain of apoAI. In conclusion, the Arg123-Tyr166 central domain of apoAI is not critical for in vivo lipoprotein association. It is, however, critical for LCAT-induced hyperalphalipoproteinemia and HDL remodeling independent of the lipid-binding properties of apoAI.

Key Words: transgenic mice • adenovirus • apoAI • LCAT • HDL remodeling

This article has been cited by other articles:

				C. Christoffersen, M. Jauhiainen, M. Moser, B. Porse, C. Ehnholm, M. Boesl, B. Dahlback, and L. B. Nielsen Effect of Apolipoprotein M on High Density Lipoprotein Metabolism and Atherosclerosis in Low Density Lipoprotein Receptor Knock-out Mice J. Biol. Chem., January 25, 2008; 283(4): 1839 - 1847. [Abstract] [Full Text] [PDF]

				H.-h. Li, M. J. Thomas, W. Pan, E. Alexander, M. Samuel, and M. G. Sorci-Thomas Preparation and incorporation of probe-labeled apoA-I for fluorescence resonance energy transfer studies of rHDL J. Lipid Res., December 1, 2001; 42(12): 2084 - 2091. [Abstract] [Full Text] [PDF]

				P. Holvoet, K. Peeters, S. Lund-Katz, A. Mertens, P. Verhamme, R. Quarck, D. Stengel, M. Lox, E. Deridder, H. Bernar, et al. Arg123-Tyr166 Domain of Human ApoA-I Is Critical for HDL-Mediated Inhibition of Macrophage Homing and Early Atherosclerosis in Mice Arterioscler. Thromb. Vasc. Biol., December 1, 2001; 21(12): 1977 - 1983. [Abstract] [Full Text] [PDF]

				K.-H. Cho, D. M. Durbin, and A. Jonas Role of individual amino acids of apolipoprotein A-I in the activation of lecithin:cholesterol acyltransferase and in HDL rearrangements J. Lipid Res., March 1, 2001; 42(3): 379 - 389. [Abstract] [Full Text]

				D. C. McManus, B. R. Scott, V. Franklin, D. L. Sparks, and Y. L. Marcel Proteolytic Degradation and Impaired Secretion of an Apolipoprotein A-I Mutant Associated with Dominantly Inherited Hypoalphalipoproteinemia J. Biol. Chem., June 8, 2001; 276(24): 21292 - 21302. [Abstract] [Full Text] [PDF]