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The Effect of Natural LCAT Mutations on the Biogenesis of HDL

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journal contribution
posted on 02.06.2015, 00:00 by Panagiotis Fotakis, Jan Albert Kuivenhoven, Eugene Dafnis, Dimitris Kardassis, Vassilis I. Zannis
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.