title: Natural human apoA-I mutations L141RPisa and L159RFIN alter HDL structure and functionality and promote atherosclerosis development in mice.
abstract: OBJECTIVE
  Mutations in human apolipoprotein A-I (apoA-I) are associated with low high-density lipoprotein (HDL) cholesterol levels and pathological conditions such as premature atherosclerosis and amyloidosis. In this study we functionally characterized two natural human apoA-I mutations, L141RPisa and L159RFIN, in vivo.
  
  
  METHODS
  We generated transgenic mice expressing either wild-type (WT) or the two mutant forms of human apoA-I on a mouse apoA-I(-/-) background and analyzed for abnormalities in their lipid and lipoprotein profiles. HDL structure and functionality, as well as atherosclerosis development following a 14-week high-fat diet were assessed in these mice.
  
  
  RESULTS
  The expression of either apoA-I mutant was associated with markedly reduced serum apoA-I (<10% of WT apoA-I), total and HDL-cholesterol levels (∼20% and ∼7% of WT apoA-I, respectively) and the formation of few small size HDL particles with preβ2 and α3, α4 electrophoretic mobility. HDL particles containing either of the two apoA-I mutants exhibited attenuated anti-oxidative properties as indicated by their inability to prevent low-density lipoprotein oxidation, and by decreased activities of paraoxonase-1 and platelet-activating factor acetylhydrolase. However, the apoA-I(L141R)Pisa or apoA-I(L159R)FIN-containing HDL particles demonstrated increased capacity to promote ATP-Binding Cassette Transporter A1-mediated cholesterol efflux from macrophages. Expression of apoA-I(L141R)Pisa or apoA-I(L159R)FIN mutations in mice was associated with increased diet-induced atherosclerosis compared to either WT apoA-I transgenic or apoA-I(-/-) mice.
  
  
  CONCLUSIONS
  These findings suggest that natural apoA-I mutations L141RPisa and L159RFIN affect the biogenesis and the functionality of HDL in vivo and predispose to diet-induced atherosclerosis in the absence of any other genetic defect.
authors.affiliation: Department of Biochemistry, University of Crete Medical School, 71003 Heraklion, Crete, Greece; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology - Hellas, Nikolaou Plastira 100, 70013 Heraklion, Crete, Greece.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Tiniakou
authors.affiliation: Biomedical Research Foundation, Academy of Athens, Soranou Ephessiou 4, 11527 Athens, Greece.
authors.forename: Zoi
authors.initials: Z
authors.lastname: Kanaki
authors.affiliation: Biomedical Research Foundation, Academy of Athens, Soranou Ephessiou 4, 11527 Athens, Greece.
authors.forename: Spiros
authors.initials: S
authors.lastname: Georgopoulos
authors.affiliation: Institute of Biosciences and Applications, National Center for Scientific Research "Demokritos", Patriarchou Grigoriou & Neapoleos 27, 15310, Athens, Greece.
authors.forename: Angeliki
authors.initials: A
authors.lastname: Chroni
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Centre for Drug Research, Einsteinweg 55, 2333 Leiden, the Netherlands.
authors.forename: Miranda
authors.initials: M
authors.lastname: Van Eck
authors.affiliation: Department of Biochemistry, University of Crete Medical School, 71003 Heraklion, Crete, Greece; Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston MA 02118, USA.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Fotakis
authors.affiliation: Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston MA 02118, USA.
authors.forename: Vassilis I
authors.initials: VI
authors.lastname: Zannis
authors.affiliation: Department of Biochemistry, University of Crete Medical School, 71003 Heraklion, Crete, Greece; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology - Hellas, Nikolaou Plastira 100, 70013 Heraklion, Crete, Greece. Electronic address: kardasis@imbb.forth.gr.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Kardassis
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000821:Animal Feed; D000818:Animals; D000975:Antioxidants / Q000737:chemistry; D016632:Apolipoprotein A-I / Q000235:genetics*; D043303:Aryldialkylphosphatase / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood*; D015180:Electrophoresis, Gel, Two-Dimensional; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood*; D008077:Lipoproteins, LDL / Q000235:genetics*; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D010972:Platelet Activating Factor / Q000378:metabolism
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000975:Antioxidants; D016632:Apolipoprotein A-I; D043303:Aryldialkylphosphatase; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D010972:Platelet Activating Factor; C577833:Abca1 protein, mouse; C505693:APOA1 protein, human; C099252:oxidized low density lipoprotein; C560867:PON1 protein, mouse
keywords: Animal models; Atherosclerosis; HDL biogenesis; High-density lipoprotein; Mutations; apoA-I(L141R)(Pisa); apoA-I(L159R)(FIN); apolipoprotein A-I