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J Biol Chem, Vol. 274, Issue 10, 6051-6055, March 5, 1999
From the Departments of Cell Biology and Medicine, Baylor College
of Medicine, Houston, Texas 77030
Conventional knockout of the microsomal
triglyceride transfer protein large subunit (
MTP) gene is embryonic
lethal in the homozygous state in mice. We have produced a conditional
MTP knockout mouse by inserting loxP sequences flanking exons 5 and 6 by gene targeting. Homozygous floxed mice were born live with normal
plasma lipids. Intravenous injection of an adenovirus harboring Cre
recombinase (AdCre1) produced deletion of exons 5 and 6 and disappearance of MTP mRNA and immunoreactive protein in a
liver-specific manner. There was also disappearance of plasma
apolipoprotein (apo) B-100 and marked reduction in apoB-48 levels.
Wild-type mice showed no response, and heterozygous mice, an
intermediate response, to AdCre1. Wild-type mice doubled their plasma
cholesterol level following a high cholesterol diet. This
hypercholesterolemia was abolished in AdCre1-treated
MTP
/ mice, the result of a complete absence of
very low/intermediate/low density lipoproteins and a slight reduction
in high density lipoprotein. Heterozygous mice showed an intermediate
lipoprotein phenotype. The rate of accumulation of plasma triglyceride
following Triton WR1339 treatment in MTP/ mice was
<10% that in wild-type animals, indicating a failure of
triglyceride-rich lipoprotein production. Pulse-chase experiments using
hepatocytes isolated from wild-type and MTP/ mice
revealed a failure of apoB secretion in MTP/
animals. Therefore, the liver-specific inactivation of the MTP gene
completely abrogates apoB-100 and very low/intermediate/low density
lipoprotein production. These conditional knockout mice are a useful
in vivo model for studying the role of MTP in apoB biosynthesis and the biogenesis of apoB-containing lipoproteins.
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