The Arg123-Tyr166 central domain of human ApoAI is critical for lecithin:cholesterol acyltransferase-induced hyperalphalipoproteinemia and HDL remodeling in transgenic mice.
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 HDL(3) to HDL(2), 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-beta-HDL and of pre-alpha-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.
Holvoet
P
P
Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium. paul.holvoet@med.kuleuven.ac.be
De Geest
B
B
Van Linthout
S
S
Lox
M
M
Danloy
S
S
Raes
K
K
Collen
D
D
D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics*; D001053:Apolipoproteins / Q000097:blood; D002678:Chimera; D008076:Cholesterol, HDL / Q000097:blood; D018014:Gene Transfer Techniques; D005838:Genotype; D006801:Humans; D006951:Hyperlipoproteinemias / Q000139:chemically induced* / Q000235:genetics*; D008074:Lipoproteins / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood*; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000097:blood / Q000235:genetics
D016632:Apolipoprotein A-I; D001053:Apolipoproteins; D008076:Cholesterol, HDL; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D007862:Phosphatidylcholine-Sterol O-Acyltransferase