Apolipoprotein A-IFIN (Leu159 [right arrow] Arg) Mutation Affects Lecithin: Cholesterol Acyltransferase Activation and Subclass Distribution of HDL but Not Cholesterol Efflux From Fibroblasts

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 17; no. 11; pp. 3021 - 3032
• Main Authors: Miettinen, Helena E, Jauhiainen, Matti, Gylling, Helena, Ehnholm, Sonja, Palomaki, Ari, Miettinen, Tatu A, Kontula, Kimmo
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.11.1997; Hagerstown, MD Lippincott
• Subjects: Adolescent; Adult; Aged; Apolipoprotein A-I - genetics; Apolipoprotein A-I - metabolism; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Carrier Proteins - metabolism; Cholesterol - metabolism; Cholesterol Ester Transfer Proteins; Enzyme Activation; Female; Fibroblasts - metabolism; Genotype; Glycoproteins; Humans; Lipoproteins, HDL - classification; Lipoproteins, HDL - metabolism; Male; Medical sciences; Membrane Proteins - metabolism; Middle Aged; Particle Size; Pedigree; Phosphatidylcholine-Sterol O-Acyltransferase - metabolism; Phosphatidylcholines - metabolism; Phospholipid Transfer Proteins; Phospholipids - metabolism; Point Mutation; Proteolipids - metabolism; Human; Acyltransferases; Enzyme; Transferases; Apolipoprotein AI; Cardiovascular disease; Cholesterol; Vascular disease; Countercurrent; Cholesterol HDL; Atherosclerosis; Risk factor; Mutation; Transport; Fibroblast; Sterol O-acyltransferase
• ISSN: 1079-5642; 1524-4636

We showed earlier that the apolipoprotein A-I Leu159 [right arrow] Arg mutation (apoA-IFin) results in dominantly inherited hypoalphalipoproteinemia. In the present study we investigated the effect of the apoA-IFin mutation on lipoprotein profile, apoA-I kinetics, lecithin:cholesterol acyltransferase (LCAT) activation, and cholesterol efflux in vitro. Carriers (n = 9) of the apoA-IFin 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-IFin protein to activate LCAT was reduced to 40% of that of the wild-type apoA-I. The impact of the apoA-IFin protein on cholesterol efflux was examined in vitro using [() 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-IFin or wild-type apoA-I isoform 1) combined with phospholipid. ApoA-IFin did not impair phospholipid binding or cholesterol efflux from fibroblasts to any of the acceptors used. Only one of the nine apoA-IFin carriers appears to have evidence of clinically manifested atherosclerosis. In conclusion, although the apoA-IFin 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-IFin was found to be associated with several lipoprotein composition rearrangements and increased catabolism of apoA-I. (Arterioscler Thromb Vasc Biol. 1997;17:3021-3032.)