Familial hypobetalipoproteinemia (FHbeta), a syndrome characterized by low plasma
cholesterol levels, is caused by mutations in the apo-B gene that interfere with
the synthesis of apo-B100. FHbeta mutations frequently lead to the synthesis of
a truncated form of apo-B, which typically is present in plasma at >
5% of the levels of apo-B100. Although many FHbeta mutations have been
characterized, the basic mechanisms causing the low plasma levels of truncated
apo-B variants have not been defined. We used gene targeting to create a mutant
allele that exclusively yields a truncated apo-B, apo-B83. In mice heterozygous
for the Apob83 allele, plasma levels and the size and density distribution of
apo-B83-containing lipoproteins were strikingly similar to those observed in
humans with FHbeta and an apo-B83 mutation. Analysis of mice carrying the Apob83
mutation revealed two mechanisms for the low plasma levels of apo-B83. First,
Apob83 mRNA levels and apo-B83 secretion were reduced 76 and 72%, respectively.
Second, apo-B83 was removed rapidly from the plasma, compared with apo-B100.
This mouse model provides a new level of understanding of FHbeta and adds new
insights into apo-B metabolism.