title: The Effect of Natural LCAT Mutations on the Biogenesis of HDL.
abstract: We have investigated how the natural LCAT[T147I] and LCAT[P274S] mutations affect the pathway of biogenesis of HDL. Gene transfer of WT LCAT in LCAT(-/-) mice increased 11.8-fold the plasma cholesterol, whereas the LCAT[T147I] and LCAT[P274S] mutants caused a 5.2- and 2.9-fold increase, respectively. The LCAT[P274S] and the WT LCAT caused a monophasic distribution of cholesterol in the HDL region, whereas the LCAT[T147I] caused a biphasic distribution of cholesterol in the LDL and HDL region. Fractionation of plasma showed that the expression of WT LCAT increased plasma apoE and apoA-IV levels and shifted the distribution of apoA-I to lower densities. The LCAT[T147I] and LCAT[P274S] mutants restored partially apoA-I in the HDL3 fraction and LCAT[T147I] increased apoE in the VLD/IDL/LDL fractions. The in vivo functionality of LCAT was further assessed based on is its ability to correct the aberrant HDL phenotype that was caused by the apoA-I[L159R]FIN mutation. Co-infection of apoA-I(-/-) mice with this apoA-I mutant and either of the two mutant LCAT forms restored only partially the HDL biogenesis defect that was caused by the apoA-I[L159R]FIN and generated a distinct aberrant HDL phenotype.
authors.affiliation: †Molecular Genetics, Boston University School of Medicine, 700 Albany Street, W509, Boston, Massachusetts 02118-2394, United States.|‡Department of Biochemistry, University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology of Hellas, GR-74100 Heraklion, Greece.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Fotakis
authors.affiliation: §Department of Pediatrics, Section Molecular Genetics, Groningen, University of Groningen, University Medical Center Groningen, 9700 Groningen, The Netherlands.
authors.forename: Jan Albert
authors.initials: JA
authors.lastname: Kuivenhoven
authors.affiliation: ∥Department of Nephrology, University of Crete Medical School, GR-74100 Heraklion, Greece.
authors.forename: Eugene
authors.initials: E
authors.lastname: Dafnis
authors.affiliation: ‡Department of Biochemistry, University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Foundation of Research and Technology of Hellas, GR-74100 Heraklion, Greece.
authors.forename: Dimitris
authors.initials: D
authors.lastname: Kardassis
authors.affiliation: †Molecular Genetics, Boston University School of Medicine, 700 Albany Street, W509, Boston, Massachusetts 02118-2394, United States.
authors.forename: Vassilis I
authors.initials: VI
authors.lastname: Zannis
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood / Q000378:metabolism; D001054:Apolipoproteins A / Q000097:blood / Q000378:metabolism; D001057:Apolipoproteins E / Q000097:blood / Q000378:metabolism; D002460:Cell Line; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D006801:Humans; D008055:Lipids / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics* / Q000378:metabolism*; D017354:Point Mutation
chemical_list: D016632:Apolipoprotein A-I; D001054:Apolipoproteins A; D001057:Apolipoproteins E; D008055:Lipids; D008075:Lipoproteins, HDL; C022205:apolipoprotein A-IV; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase