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.
- LECITHIN-CHOLESTEROL ACYLTRANSFERASE
- FISH-EYE DISEASE
- DOMINANTLY INHERITED HYPOALPHALIPOPROTEINEMIA
- DIET-INDUCED ATHEROSCLEROSIS
- DEFICIENT MICE
- LECITHINCHOLESTEROL ACYLTRANSFERASE
- HYDROPHOBIC RESIDUES