apoE3[K146N/R147W] acts as a dominant negative apoE form that prevents remnant clearance and inhibits the biogenesis of HDL.
The K146N/R147W substitutions in apoE3 were described in patients with a dominant form of type III hyperlipoproteinemia. The effects of these mutations on the in vivo functions of apoE were studied by adenovirus-mediated gene transfer in different mouse models. Expression of the apoE3[K146N/R147W] mutant in apoE-deficient (apoE(-/-)) or apoA-I-deficient (apoA-I(-/-))×apoE(-/-) mice exacerbated the hypercholesterolemia and increased plasma apoE and triglyceride levels. In apoE(-/-) mice, the apoE3[K146N/R147W] mutant displaced apoA-I from the VLDL/LDL/HDL region and caused the accumulation of discoidal apoE-containing HDL. The WT apoE3 cleared the cholesterol of apoE(-/-) mice without induction of hypertriglyceridemia and promoted formation of spherical HDL. A unique property of the truncated apoE3[K146N/R147W]202 mutant, compared with similarly truncated apoE forms, is that it did not correct the hypercholesterolemia. The contribution of LPL and LCAT in the induction of the dyslipidemia was studied. Treatment of apoE(-/-) mice with apoE3[K146N/R147W] and LPL corrected the hypertriglyceridemia, but did not prevent the formation of discoidal HDL. Treatment with LCAT corrected hypertriglyceridemia and generated spherical HDL. The combined data indicate that the K146N/R147W substitutions convert the full-length and the truncated apoE3[K146N/R147W] mutant into a dominant negative ligand that prevents receptor-mediated remnant clearance, exacerbates the dyslipidemia, and inhibits the biogenesis of HDL.
Molecular Genetics, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118 Department of BiochemistryUniversity of Crete Medical School, Heraklion, Crete, Greece 71110 Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, Heraklion, Crete, Greece 71003.
Panagiotis
P
Fotakis
Molecular Genetics, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118.
Alexander
A
Vezeridis
National Center for Scientific Research "Demokritos" Athens, Greece 15310.
Ioannis
I
Dafnis
National Center for Scientific Research "Demokritos" Athens, Greece 15310.
Angeliki
A
Chroni
Department of BiochemistryUniversity of Crete Medical School, Heraklion, Crete, Greece 71110 Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, Heraklion, Crete, Greece 71003.
Dimitris
D
Kardassis
Molecular Genetics, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118.
Vassilis I
VI
Zannis
D019943:Amino Acid Substitution; D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015228:Hypertriglyceridemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020125:Mutation, Missense; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism
D053318:Apolipoprotein E3; D008075:Lipoproteins, HDL; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D008071:Lipoprotein Lipase
apolipoprotein E3; dominant type III hyperlipoproteinemia; gene transfer; high density lipoprotein; hypertriglyceridemia; lecithin:cholesterol acyl transferase; lipoprotein lipase; recombinant adenovirus