DIET-INDUCED HYPERCHOLESTEROLEMIA AND ATHEROSCLEROSIS IN HETEROZYGOUS APOLIPOPROTEIN E-DEFICIENT MICE

Apolipoprotein (ape) E is a ligand for the receptor-mediated uptake of lipoprotein remnant particles. Complete absence of ape E in humans leads to a severe form of type III hyperlipoproteinemia. We have used targeted inactivation in murine embryonic stem cells, as also described by others, to specifically study the effects of heterozygous Apoe gene loss on the development of hyperlipidemia. After 6 weeks on a severe semi-synthetic atherogenic diet, heterozygous null mutants, with only one functional Apoe allele, developed hypercholesterolemia as compared with controls (10.1 mM vs. 4.7 mM serum cholesterol). Interestingly, serum cholesterol levels in female heterozygotes were doubled as compared with male heterozygotes(15.0 mM vs. 7.5 mM). On this diet, heterozygous apo E deficient mice also showed an increased susceptibility to atherosclerosis, depending on gender (mean lesion area per section of 9524 mu m(2) vs. 61388 mu m(2) for males and females, respectively), whereas wild-type mice displayed far fewer lesions (354 mu m(2) and 9196 mu m(2) for males and females, respectively). This study indicates that a subnormal expression-level of the Apoe gene leads to hypercholesterolemia and, consequently, to an increased susceptibility to the development of atherosclerosis.