Knockout of the mouse apolipoprotein B gene results in embryonic lethality in homozygotes and protection against diet-induced hypercholesterolemia in …

RV Farese Jr, SL Ruland, LM Flynn… - Proceedings of the …, 1995 - National Acad Sciences
RV Farese Jr, SL Ruland, LM Flynn, RP Stokowski, SG Young
Proceedings of the National Academy of Sciences, 1995National Acad Sciences
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 …
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.
National Acad Sciences