Low levels of
cholesterol are protective against development of
coronary artery disease. Heterozygous hypobetalipoproteinemic individuals expressing truncated
apolipoprotein (
apo)B as a result of mutation in the
apob gene have low levels of
cholesterol and
apoB in their plasma. To study the molecular mechanism of low levels of
apoB in these individuals, we employed a previously reported knock out mouse model generated by targeted modification of the
apob gene. The heterozygous,
apoB-100/B-81, mice express full length and truncated
apoB, B-81, and have 20 and 35% lower levels of total
cholesterol and
apoB, respectively, when compared to WT (
apoB-100/B-100) mice. The majority of the truncated
apoB, B-81, fractionated in the VLDL- density range. The mechanism of low levels of
apoB in B-100/B-81 mice was examined. Total hepatic
apoB mRNA levels decreased by 15%, primarily due to lower levels of apoB-81
mRNA. Since
apoB mRNA transcription rates were similar in B-100/B-100 and B-100/B-81 mice, low levels of mutant apoB-81
mRNA occurred by enhanced degradation of
apoB mRNA transcript containing premature translational stop
codon.
ApoB synthesis measured on isolated hepatocytes decreased in B-100/B-81 mice by 35%, while
apoB-48,
apoE, and apoAI syntheses remained unchanged. Metabolic studies using whole animal showed a 32% decrease in
triglyceride secretion rates, consistent with the
apoB secretion rates. Inhibition of receptor-mediated clearance of apoB-81-containing particles resulted in greater relative accumulation of apoB-81 in plasma than
apoB-100, suggesting enhanced clearance of apoB-81-containing particles. These results demonstrate that low levels of
apoB in heterozygous hypobetalipoproteinemic mice occurs by low rates of
apoB secretion, and increased clearance of truncated
apoB. Similar mechanisms appear to contribute to low levels of
apoB in hypobetalipoproteinemic humans.