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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1447-1455.)
© 1999 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

A Novel Mutant, ApoA-I Nichinan (Glu2350), Is Associated With Low HDL Cholesterol Levels and Decreased Cholesterol Efflux From Cells

Hua Han; Jun Sasaki; Akira Matsunaga; Hideki Hakamata; Wei Huang; Masato Ageta; Toshifumi Taguchi; Takafumi Koga; Mari Kugi; Seikoh Horiuchi; Kikuo Arakawa

From the Department of Internal Medicine, School of Medicine, Fukuoka University, Fukuoka (H. Han, J.S., A.M., W.H., T.K., K.A.); the Department of Internal Medicine, Miyazaki Prefectural Nichinan Hospital, Nichinan (M.A., T.T.); and the Department of Biochemistry, Kumamoto University, School of Medicine, Kumamoto (H. Hakamata, S.H.), Japan.

Correspondence to Jun Sasaki, MD, Department of Internal Medicine, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. E-mail mm03455{at}msat.fukuoka-u.ac.jp

Abstract—A novel variant of apolipoprotein (apo) A-I associated with low high density lipoprotein (HDL) cholesterolemia has been identified in a Japanese family during screening for apoA-I variants by isoelectric focusing (IEF) gel analysis. ApoA-I (Glu2350) Nichinan was caused by a 3-bp deletion of nucleotides 1998 through 2000 in exon 4 of the apoA-I gene. Four subjects in the family were heterozygous carriers for this mutation; the mean plasma concentrations of apoA-I and HDL cholesterol of affected family members were 30% and 32% lower, respectively, than those of unaffected family members. There were no differences in the levels of very low density lipoprotein and low density lipoprotein cholesterol, triglycerides, and other apolipoproteins between the carriers and the noncarrier family members. In the proband, plasma lecithin:cholesterol acyltransferase activity was normal. Functional consequences of the mutation were examined by expressing the mutated and wild-type proapoA-I cDNAs in Escherichia coli. Cholesterol efflux to recombinant proapoA-I Nichinan from mouse peritoneal macrophages loaded with [³H]cholesterol-labeled acetylated low density lipoprotein was decreased by 54% when compared that of normal recombinant proapoA-I. In vivo turnover studies in normal rabbits demonstrated that the recombinant proapoA-I Nichinan was rapidly cleared (22% faster) compared with normal recombinant proapoA-I. We conclude that apoA-I (Glu2350) Nichinan induced a critical structural change in the carboxyl-terminal domain of apoA-I for cellular cholesterol efflux and increased the catabolism of apoA-I, resulting in low HDL cholesterol levels.

Key Words: HDL cholesterol • apoA-I variant • cholesterol efflux • kinetics

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