The Effect of Natural LCAT Mutations on the Biogenesis of HDL

Panagiotis Fotakis, Jan Albert Kuivenhoven, Eugene Dafnis, Dimitris Kardassis, Vassilis I. Zannis*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3348-3359
Number of pages12
JournalBiochemistry
Volume54
Issue number21
DOIs
Publication statusPublished - 2-Jun-2015

Keywords

  • APOLIPOPROTEIN-A-I
  • LECITHIN-CHOLESTEROL ACYLTRANSFERASE
  • HIGH-DENSITY-LIPOPROTEIN
  • FISH-EYE DISEASE
  • DOMINANTLY INHERITED HYPOALPHALIPOPROTEINEMIA
  • DIET-INDUCED ATHEROSCLEROSIS
  • APOA-I
  • DEFICIENT MICE
  • LECITHINCHOLESTEROL ACYLTRANSFERASE
  • HYDROPHOBIC RESIDUES

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