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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. |
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