LCAT can rescue the abnormal phenotype produced by the natural ApoA-I mutations (Leu141Arg)Pisa and (Leu159Arg)FIN.
To explain the etiology and find a mode of therapy of genetically determined low levels of high-density lipoprotein (HDL), we have generated recombinant adenoviruses expressing apolipoprotein A-I (apoA-I)(Leu141Arg)Pisa and apoA-I(Leu159Arg)FIN and studied their properties in vitro and in vivo. Both mutants were secreted efficiently from cells but had diminished capacity to activate lecithin/cholesterol acyltransferase (LCAT) in vitro. Adenovirus-mediated gene transfer of either of the two mutants in apoA-I-deficient (apoA-I-/-) mice resulted in greatly decreased total plasma cholesterol, apoA-I, and HDL cholesterol levels. The treatment also decreased the cholesteryl ester to total cholesterol ratio (CE/TC), caused accumulation of prebeta1-HDL and small size alpha4-HDL particles, and generated only few spherical HDL particles, as compared to mice expressing wild-type (WT) apoA-I. Simultaneous treatment of the mice with adenoviruses expressing either of the two mutants and human LCAT normalized the plasma apoA-I, HDL cholesterol levels, and the CE/TC ratio, restored normal prebeta- and alpha-HDL subpopulations, and generated spherical HDL. The study establishes that apoA-I(Leu141Arg)Pisa and apoA-I(Leu159Arg)FIN inhibit an early step in the biogenesis of HDL due to inefficient esterification of the cholesterol of the prebeta1-HDL particles by the endogenous LCAT. Both defects can be corrected by treatment with LCAT.
Koukos
Georgios
G
Molecular Genetics, Department of Medicine, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Chroni
Angeliki
A
Duka
Adelina
A
Kardassis
Dimitris
D
Zannis
Vassilis I
VI
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000257:Adenoviridae Infections; D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood / Q000172:deficiency / Q000235:genetics* / Q000302:isolation & purification; D001120:Arginine / Q000235:genetics*; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D007930:Leucine / Q000235:genetics*; D008055:Lipids / Q000097:blood; D008075:Lipoproteins, HDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D008970:Molecular Weight; D050505:Mutant Proteins / Q000302:isolation & purification / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008055:Lipids; D008075:Lipoproteins, HDL; D050505:Mutant Proteins; D012333:RNA, Messenger; D001120:Arginine; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D007930:Leucine