Effects of mutant apolipoprotein A-I on the reverse cholesterol transport

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It is widely assumed that high density lipoproteins (HDL) exert their antiatherogenic role by contributing to the reverse transport of excess cholesterol from peripheral cells to the liver and steoidogenic organs. In complexes with HDL,apolipoprotein (apo) A-I acts as the most potent activator of the plasma enzume lecithin : chlesterol acyltransferase (LCAT) and increases cholesterol efflux from peripheral tissues. In our laboratory, ten different apo A-I mutations were characterized. In this project, functional consequences of the mutation were examined by expressing the mutated and wild-type recombinant proapo (r-proapo) A-I cDNAs in E.coli. We produced four different mutations of r-proapo A-I,proapo A-I (Tyr100His) Karatsu, proapo A-I (Trp108Arg) Tsushima, proapo A-I (Vall56Glu) Oita, proapo A-I (Glu235*0) Nichinan Cholesterol efflux to r-proapo A-I (Glu235*0) Nichinan from mouse peritoneal macrophages converted with [^3H] cholesterol-labeled acetylated LDL was decreased by 54% when compared that of normal r-proapo A-I.In vivo turnover studies in normal rabbits demonstrated that the r-proapo A-I Nichinan was rapidly cleared by 22% compared with normal r-proapo A-I.We conclude that the apo A-I (Glu235*0) Nichinan induced a critical structural change of the carboxyl-terminal domain of apo A-I for cellular cholesterol efflux and increased catabolism of the apo A-I,resulting in low HDL cholesterol level. We are going to continue the next experiment for functional analysis of mutant apo A-I.