NDLI: Liver-specific Inactivation of the Abetalipoproteinemia Gene Completely Abrogates Very Low Density Lipoprotein/Low Density Lipoprotein Production in a Viable Conditional Knockout Mouse

Content Provider	Journal of Biological Chemistry (JBC)
Author	Chang, Benny Hung-Junn Liao, Wei Li, Lan Nakamuta, Makoto Mack, David Chan, Lawrence
Abstract	Conventional knockout of the microsomal triglyceride transfer protein large subunit (ℓMTP) gene is embryonic lethal in the homozygous state in mice. We have produced a conditional ℓMTP 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 ℓMTP 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 ℓMTP−/− 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 ℓMTP−/− 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 ℓMTP−/− mice revealed a failure of apoB secretion in ℓMTP−/−animals. Therefore, the liver-specific inactivation of the ℓMTP gene completely abrogates apoB-100 and very low/intermediate/low density lipoprotein production. These conditional knockout mice are a usefulin vivo model for studying the role of MTP in apoB biosynthesis and the biogenesis of apoB-containing lipoproteins.
Related Links	http://www.jbc.org/content/274/10/6051.abstract
Ending Page	6055
Starting Page	6051
Page Count	5
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	10
Volume Number	274
DOI	10.1074/jbc.274.10.6051
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	1999-03-05
Access Restriction	Open
Subject Keyword	Apolipoprotein (apo) Microsomal triglyceride transfer protein (MTP) MTP large subunit (ℓMTP) Very low density lipoproteins (VLDL) Intermediate density lipoproteins (IDL) Low density lipoproteins (LDL) High density lipoproteins (HDL) Kilobase(s) (kb) Polyacrylamide gel electrophoresis (PAGE) Fast protein liquid chromatography (FPLC) 1-(2′-deoxy-2′-fluoro-β-d-arabinofuranosyl)-5-iodouracil (FIAU) CELL BIOLOGY AND METABOLISM
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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