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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:3021-3032.)
© 1997 American Heart Association, Inc.

Articles

Apolipoprotein A-I_FIN (Leu159Arg) Mutation Affects Lecithin

Cholesterol Acyltransferase Activation and Subclass Distribution of HDL but Not Cholesterol Efflux From Fibroblasts

Helena E. Miettinen; Matti Jauhiainen; Helena Gylling; Sonja Ehnholm; Ari Palomäki; Tatu A. Miettinen; ; Kimmo Kontula

From the Department of Medicine, University of Helsinki, Helsinki, Finland (H.E.M., H.G., T.A.M, K.K); the Department of Biochemistry, National Public Health Institute, Helsinki, Finland (M.J., S.E.); and the Department of Cardiology, Central Hospital of Hämeenlinna, Finland (A.P.).

Correspondence to Helena E. Miettinen, MD, Department of Medicine, University of Helsinki, Meilahti Hospital, Haartmaninkatu 4, 00290 Helsinki, Finland. E-mail Helena.Miettinen{at}helsinki.fi

Abstract We showed earlier that the apolipoprotein A-I Leu159Arg 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 (HDL₂-type) and the presence of small 7.8- to 8.9-nm (mostly HDL₃-type) particles only. HDL₃-type particles from both the mutation carriers and nonaffected family members were similarly converted to large, HDL₂-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 [³H]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.

Key Words: reverse cholesterol transport • HDL • apolipoprotein A-I kinetics • coronary artery disease • mutation

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