Apolipoprotein B is synthesized by the intestine and the liver in mammals, where it serves as the main structural component in the formation of
chylomicrons and
very low density lipoproteins, respectively.
Apolipoprotein B is also expressed in mammalian fetal membranes. To examine the consequences of
apolipoprotein B deficiency in mice, we used gene targeting in mouse embryonic stem cells to generate mice containing an insertional disruption of the 5' region of the
apolipoprotein B gene. Mice that were heterozygous for the disrupted
apolipoprotein B allele had an approximately 20% reduction in plasma
cholesterol levels, markedly reduced plasma concentrations of the pre-beta and beta-migrating
lipoproteins, and an approximately 70% reduction in plasma
apolipoprotein B levels. When fed a diet rich in fat and
cholesterol, heterozygous mice were protected from diet-induced
hypercholesterolemia; these mice, which constitute an animal model for
hypobetalipoproteinemia, should be useful for studying the effects of decreased
apolipoprotein B expression on
atherogenesis. The breeding of heterozygous mice yielded no viable homozygous
apolipoprotein B knockout mice. Most homozygous embryos were resorbed by midgestation (before gestational day 11.5); several embryos that survived until later in gestation exhibited exencephalus. The embryonic lethal phenotype was rescued by complementation with a human
apolipoprotein B transgene--i.e., human
apolipoprotein B transgenic mice that were homozygous for the murine
apolipoprotein B knockout mutation were viable. Our findings indicate that
apolipoprotein B plays an essential role in mouse embryonic development.