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.