Apolipoprotein A-I FIN (Leu159→Arg) Mutation Affects Lecithin: Cholesterol Acyltransferase Activation and Subclass Distribution of HDL but Not Cholesterol Efflux From Fibroblasts

Abstract We showed earlier that the apolipoprotein A-I Leu159→Arg mutation (apoA-I Fin ) results in dominantly inherited hypoalphalipoproteinemia. In the present study we investigated the effect of the apoA-I Fin mutation on lipoprotein profile, apoA-I kinetics, lecithin:cholesterol acyltransferase (LCAT) activation, and cholesterol efflux in vitro. Carriers (n=9) of the apoA-I Fin mutation exhibited several lipoprotein abnormalities. The serum HDL cholesterol level was diminished to 20% of normal, and nondenaturing gradient gel electrophoresis of HDL showed disappearance of particles at the 9.0- to 12-nm size range (HDL 2 -type) and the presence of small 7.8- to 8.9-nm (mostly HDL 3 -type) particles only. HDL 3 -type particles from both the mutation carriers and nonaffected family members were similarly converted to large, HDL 2 -type particles by phospholipid transfer protein in vitro. Studies on apoA-I kinetics in four affected subjects favored accelerated catabolism of apoA-I. Experiments with reconstituted proteoliposomes showed that the capacity of apoA-I Fin protein to activate LCAT was reduced to 40% of that of the wild-type apoA-I. The impact of the apoA-I Fin protein on cholesterol efflux was examined in vitro using [ 3 H]cholesterol-loaded human fibroblasts and three different cholesterol acceptors: (1) total HDL, (2) total apoA-I combined with phospholipid, and (3) apoA-I isoform (apoA-I Fin or wild-type apoA-I isoform 1) combined with phospholipid. ApoA-I Fin did not impair phospholipid binding or cholesterol efflux from fibroblasts to any of the acceptors used. Only one of the nine apoA-I Fin carriers appears to have evidence of clinically manifested atherosclerosis. In conclusion, although the apoA-I Fin mutation does not alter the properties of apoA-I involved in promotion of cholesterol efflux, its ability to activate LCAT in vitro is defective. In vivo, apoA-I Fin was found to be associated with several lipoprotein composition rearrangements and increased catabolism of apoA-I.