PMID- 10037685
OWN - NLM
STAT- MEDLINE
DCOM- 19990330
LR  - 20190508
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 274
IP  - 10
DP  - 1999 Mar 5
TI  - Liver-specific inactivation of the abetalipoproteinemia gene completely abrogates
      very low density lipoprotein/low density lipoprotein production in a viable
      conditional knockout mouse.
PG  - 6051-5
AB  - 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 useful in vivo
      model for studying the role of MTP in apoB biosynthesis and the biogenesis of
      apoB-containing lipoproteins.
FAU - Chang, B H
AU  - Chang BH
AD  - Departments of Cell Biology and Medicine, Baylor College of Medicine, Houston,
      Texas 77030, USA.
FAU - Liao, W
AU  - Liao W
FAU - Li, L
AU  - Li L
FAU - Nakamuta, M
AU  - Nakamuta M
FAU - Mack, D
AU  - Mack D
FAU - Chan, L
AU  - Chan L
LA  - eng
GR  - HL-16512/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Apolipoproteins B)
RN  - 0 (Carrier Proteins)
RN  - 0 (Lipoproteins, LDL)
RN  - 0 (Lipoproteins, VLDL)
RN  - 0 (microsomal triglyceride transfer protein)
SB  - IM
MH  - Abetalipoproteinemia/*genetics/*metabolism
MH  - Animals
MH  - Apolipoproteins B/genetics
MH  - Carrier Proteins/*genetics
MH  - Disease Models, Animal
MH  - Lipoproteins, LDL/*biosynthesis/genetics
MH  - Lipoproteins, VLDL/*biosynthesis/genetics
MH  - Liver/metabolism
MH  - Mice
MH  - Mice, Knockout
EDAT- 1999/02/26 00:00
MHDA- 1999/02/26 00:01
CRDT- 1999/02/26 00:00
PHST- 1999/02/26 00:00 [pubmed]
PHST- 1999/02/26 00:01 [medline]
PHST- 1999/02/26 00:00 [entrez]
AID - 10.1074/jbc.274.10.6051 [doi]
PST - ppublish
SO  - J Biol Chem. 1999 Mar 5;274(10):6051-5. doi: 10.1074/jbc.274.10.6051.