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 acyltran sferase (LCAT)-induced HDL remodeling were investigated in transgenic mice expressing human apolipoprotein (apo) AI or an apoAI/apoAII chimera in whic h the Arg123-Tyr166 domain of apoAI was substituted with the Ser12-Ala75 do main of apoAII. Expression of apoAI and of the apoAI/apoAII chimera resulte d 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 increa se of endogenous LCAT activity. This increase was associated with a 2.4-fol d increase of the cholesterol ester-to-free cholesterol ratio of HDL, a shi ft from HDL3 to HDL2, and a 2.4-fold increase of HDL cholesterol levels. Ag arose gel electrophoresis revealed that human LCAT gene transfer into human apoAI-transgenic mice resulted in an increase of pre-beta-HDL and of pre-a lpha-HDL, In contrast, human LCAT gene transfer did not affect cholesterol levels and HDL distribution profile in mice expressing the apoAI/apoAII chi mera. Mouse LCAT did not "see" a difference between wild-type and mutant hu man apoAI, whereas human LCAT did, thus localizing the species-specific int eraction in the central domain of apoAI, In conclusion, the Arg123-Tyr166 c entral domain of apoAI is not critical for in vivo lipoprotein association. It is, however, critical for LCAT-induced hyperalphalipoproteinemia and HD L remodeling independent of the lipid-binding properties of apoAI.