Farese RV Jr, Ruland SL, Flynn LM, Stokowski RP, Young SG:
Knockout of the mouse apolipoprotein B gene results in embryonic
lethality in homozygotes and protection against diet-induced
hypercholesterolemia in heterozygotes.
Proceedings of the National Academy of Sciences of the United States of
America 1995 Feb 28;92(5):1774-8
ABSTRACT
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.
