title: Deletions of helices 2 and 3 of human apoA-I are associated with severe dyslipidemia following adenovirus-mediated gene transfer in apoA-I-deficient mice.
abstract: The objective of this study was to determine the effect of two amino-terminal apolipoprotein A-I (apoA-I) deletions on high-density lipoprotein (HDL) biosynthesis and lipid homeostasis. Adenovirus-mediated gene transfer showed that the apoA-I[Delta(89-99)] deletion mutant caused hypercholesterolemia, characterized by increased plasma cholesterol and phospholipids, that were distributed in the very low density/intermediate density/low-density lipoprotein (VLDL/IDL/LDL) region, and normal triglycerides. The capacity of the mutant protein to promote ATP-binding cassette transporter A1- (ABCA1-) mediated cholesterol efflux and to activate lecithin:cholesterol acyltranserase (LCAT) was approximately 70-80% of the wild-type (WT) control. The phospholipid transfer protein (PLTP) activity of plasma containing the apoA-I[Delta(89-99)] mutant was decreased to 32% of the WT control. Similar analysis showed that the apoA-I[Delta(62-78)] deletion mutant in apoA-I-deficient mice caused combined hyperlipidemia characterized by increased triglycerides, cholesterol, and phospholipids in the VLDL/IDL region. There was enrichment of the VLDL/IDL with mutant apoA-I that resulted in reduction of in vitro lipolysis. The capacity of this mutant to promote ABCA1-mediated cholesterol efflux was normal, and the capacity to activate LCAT in vitro was reduced by 53%. The WT apoA-I and the apoA-I[Delta(62-78)] mutant formed spherical HDL particles, whereas the apoA-I[Delta(89-99)] mutant formed discoidal HDL particles. We conclude that alterations in apoA-I not only may have adverse effects on HDL biosynthesis but also may promote dyslipidemia due to interference of the apoA-I mutants on the overall cholesterol and triglycerides homeostasis.
authors.affiliation: Section of Molecular Genetics, Whitaker Cardiovascular Institute, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Chroni
authors.forename: Horng-Yuan
authors.initials: HY
authors.lastname: Kan
authors.forename: Adelina
authors.initials: A
authors.lastname: Shkodrani
authors.forename: Tong
authors.initials: T
authors.lastname: Liu
authors.forename: Vassilis I
authors.initials: VI
authors.lastname: Zannis
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis / Q000097:blood / Q000172:deficiency* / Q000235:genetics*; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D018014:Gene Transfer Techniques; D006801:Humans; D006868:Hydrolysis; D006937:Hypercholesterolemia / Q000097:blood / Q000235:genetics*; D008074:Lipoproteins / Q000037:antagonists & inhibitors / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood / Q000378:metabolism / Q000648:ultrastructure; D053419:Lipoproteins, IDL; D008079:Lipoproteins, VLDL / Q000037:antagonists & inhibitors / Q000097:blood; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000097:blood / Q000235:genetics; D049294:Phospholipid Transfer Proteins / Q000037:antagonists & inhibitors / Q000097:blood; D017433:Protein Structure, Secondary / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D017384:Sequence Deletion; D014280:Triglycerides / Q000037:antagonists & inhibitors / Q000097:blood
chemical_list: D016632:Apolipoprotein A-I; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D053419:Lipoproteins, IDL; D008079:Lipoproteins, VLDL; D008565:Membrane Proteins; D010446:Peptide Fragments; D049294:Phospholipid Transfer Proteins; D012333:RNA, Messenger; D014280:Triglycerides