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J Biol Chem, Vol. 275, Issue 11, 7515-7520, March 17, 2000
From the Microsomal triglyceride transfer
protein (MTP) transfers lipids to apolipoprotein B (apoB) within the
endoplasmic reticulum, a process that involves direct interactions
between apoB and the large subunit of MTP. Recent studies with
heterozygous MTP knockout mice have suggested that half-normal levels
of MTP in the liver reduce apoB secretion. We hypothesized that reduced
apoB secretion in the setting of half-normal MTP levels might be caused
by a reduced MTP:apoB ratio in the endoplasmic reticulum, which would reduce the number of apoB-MTP interactions. If this hypothesis were
true, half-normal levels of MTP might have little impact on lipoprotein
secretion in the setting of half-normal levels of apoB synthesis (since
the ratio of MTP to apoB would not be abnormally low) and might cause
an exaggerated reduction in lipoprotein secretion in the setting of
apoB overexpression (since the MTP:apoB ratio would be even lower). To
test this hypothesis, we examined the effects of heterozygous MTP
deficiency on apoB metabolism in the setting of normal levels of apoB
synthesis, half-normal levels of apoB synthesis (heterozygous
Apob deficiency), and increased levels of apoB synthesis
(transgenic overexpression of human apoB). Contrary to our
expectations, half-normal levels of MTP reduced the plasma apoB100
levels to the same extent (~25-35%) at each level of apoB
synthesis. In addition, apoB secretion from primary hepatocytes was
reduced to a comparable extent at each level of apoB synthesis. Thus,
these results indicate that the concentration of MTP within the
endoplasmic reticulum rather than the MTP:apoB ratio is the critical
determinant of lipoprotein secretion. Finally, we found that
heterozygosity for an apoB knockout mutation lowered plasma apoB100
levels more than heterozygosity for an MTP knockout allele. Consistent
with that result, hepatic triglyceride accumulation was greater in
heterozygous apoB knockout mice than in heterozygous MTP knockout mice.
A Deficiency of Microsomal Triglyceride Transfer Protein Reduces
Apolipoprotein B Secretion*
§¶
,§,,,§**,§,,, and§¶§§
Gladstone Institute of Cardiovascular
Disease, § Cardiovascular Research Institute, and
¶ Department of Medicine, University of California, San Francisco,
California 94141-9100 and Department of
Nutritional Sciences, University of California,
Berkeley, California 94720-3104
*
This work was supported in part by National Institutes of
Health Grant (NIH) HL47660, an NIH-supported Cardiovascular Research Institute Molecular/Cellular Cardiology training grant position (to
G. L.), an Howard Hughes Medical Institute Postdoctoral Fellowship for
Physicians (to G.L.), and grants from the University of California Tobacco-related Disease Research Program (to M. M. V. and
S. G. Y.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
The first two authors contributed equally to this project.
**
Current address: Bayer AG, Cardiovascular Research Institute, 42096 Wuppertal, Germany.
§§
To whom correspondence should be addressed: Gladstone Institute
of Cardiovascular Disease, P. O. Box 419100, San Francisco, CA
94141-9100. Tel.: 415-826-7500; Fax: 415-285-5632; E-mail: syoung@gladstone.ucsf.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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