APOLIPOPROTEIN A-I-FIN (LEU159-]ARG) MUTATION AFFECTS LECITHIN - CHOLESTEROL ACYLTRANSFERASE ACTIVATION AND SUBCLASS DISTRIBUTION OF HDL BUT NOT CHOLESTEROL EFFLUX FROM FIBROBLASTS

We showed earlier that the apolipoprotein A-I Leu159-->Arg mutation (a poA-I-Fin) results in dominantly inherited hypoalphalipoproteinemia. I n the present study we investigated the effect of the apoA-I-Fin mutat ion on lipoprotein profile, apoA-I kinetics, lecithin:cholesterol acyl transferase (LCAT) activation, and cholesterol efflux in vitro. Carrie rs (n=9) of the apoA-I-Fin mutation exhibited several lipoprotein abno rmalities. The serum HDL cholesterol level was diminished to 20% of no rmal, and nondenaturing gradient gel electrophoresis of HDL showed dis appearance of particles at the 9.0- to 12-nm size range (HDL2-type) an d the presence of small 7.8- to 8.9-nm (mostly HDL3-type) particles on ly. HDL3-type particles from both the mutation carriers and nonaffecte d family members were similarly converted to large, HDL2-type particle s by phospholipid transfer protein in vitro. Studies on apoA-I kinetic s in four affected subjects favored accelerated catabolism of apoA-I. Experiments with reconstituted proteoliposomes showed that the capacit y 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 cholest erol efflux was examined in vitro using [H-3]cholesterol-loaded human fibroblasts and three different cholesterol accepters: (1) total HDL, (2) total apoA-I combined with phospholipid, and (3) apoA-I isoform (a poA-I-Fin or wild-type apoA-I isoform 1) combined with phospholipid. A poA-I-Fin did not impair phospholipid binding or cholesterol efflux fr om fibroblasts to any of the accepters used. Only one of the nine apoA -I-Fin carriers appears to have evidence of clinically manifested athe rosclerosis. In conclusion, although the apoA-I-Fin mutation does not alter the properties of apoA-I involved in promotion of cholesterol ef flux, its ability to activate LCAT in vitro is defective. In vivo, apo A-I-Fin was found to be associated with several lipoprotein compositio n rearrangements and increased catabolism of apoA-I.