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J. Biol. Chem., Vol. 275, Issue 42, 32807-32815, October 20, 2000
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From the Division of Atherosclerosis, Nutrition and Lipid Research,
Department of Medicine, Washington University School of Medicine,
St. Louis, Missouri 63110
Nonphysiological truncations of apolipoprotein
(apo) B-100 cause familial hypobetalipoproteinemia (FHBL) in humans and
mice. An elucidation of the mechanisms underlying the FHBL phenotypes may provide valuable information on the metabolism of apo B-containing lipoproteins and the structure-function relationship of apo B. To
generate a faithful mouse model of human FHBL, a subtle mutation was
introduced into the mouse apo B gene by targeting embryonic stem
cells using homologous recombination followed by removal of the
selection marker gene by Cre-loxP-mediated site-specific recombination.
The engineered mice bear a premature stop codon at residue 1767 and a
42-base pair loxP inserted into intron 24 of the apo B gene, thus
closely resembling the apo B-38.9-producing mutation in humans. Apo
B-38.9 was the sole apo B protein in homozygote (apob38.9/38.9) plasma. In heterozygotes
(apob+/38.9), apo B-100 and apo B-48
were reduced by 75 and 40%, respectively, and apo B-38.9 represented
20% of total circulating apo B. Hepatic apo B-38.9 mRNA levels
were reduced by 40%. In cultured
apob+/38.9 hepatocytes, apo B-100 was
produced in trace quantities, and the synthesis rate of apo B-38.9
relative to apo B-48 was reduced by 40%. However, almost
equimolar amounts of apo B-38.9 and apo B-48 were secreted into the
media. Pulse-chase studies revealed that apo B-38.9 was secreted
at a faster rate and more efficiently than apoB-48. Nevertheless, both
apob+/38.9 and
apob38.9/38.9 mice had reduced hepatic triglyceride
secretion rates and fatty livers. Thus, low mRNA levels or
defective secretion of apo B-38.9 may not be responsible for the FHBL
phenotypes caused by the apo B-38.9 mutation. Rather, a reduced
capacity of apo B-38.9 for triglyceride transport may account for the
fatty livers in these mice.
A Targeted Apolipoprotein B-38.9-producing Mutation Causes
Fatty Livers in Mice Due to the Reduced Ability of Apolipoprotein
B-38.9 to Transport Triglycerides*
,
*
This work was supported by National Institutes of Health
Grants R37 HL-424460 and RO1 HL-59515 and a grant from the Alan and Edith Wolf charitable fund.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.
To whom correspondence should be addressed: Division of
Atherosclerosis, Nutrition and Lipid Research, Dept. of Medicine, Washington University School of Medicine, Box 8046, 660 S. Euclid Ave.,
St. Louis, MO 63110. Tel.: 314-747-4352; Fax: 314-362-3513; E-mail:
zchen@im.wustl.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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