Familial hypobetalipoproteinemia (FH ␤), 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. FH ␤ mutations frequently lead to the synthesis of a truncated form of apo-B, which typically is present in plasma at Ͻ 5% of the levels of apo-B100. Although many FH ␤ 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 Apob 83 allele, plasma levels and the size and density distribution of apo-B83-containing lipoproteins were strikingly similar to those observed in humans with FH ␤ and an apo-B83 mutation. Analysis of mice carrying the Apob 83 mutation revealed two mechanisms for the low plasma levels of apo-B83. First, Apob 83 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 FH ␤ and adds new insights into apo-B metabolism.

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