Regulation of the apolipoprotein B in heterozygous hypobetalipoproteinemicknock-out mice expressing truncated apoB, B81. Low production and enhancedclearance of apoB cause low levels of apoB

Low levels of cholesterol are protective against development of coronary ar tery disease. Heterozygous hypobetalipoproteinemic individuals expressing t runcated apolipoprotein (apo)B as a result of mutation in the apob gene hav e low levels of cholesterol and apoB in their plasma. To study the molecula r mechanism of low levels of apoB in these individuals, we employed a previ ously reported knock out mouse model generated by targeted modification of the apob gene. The heterozygous, apoB-100/B-81, mice express full length an d truncated apoB, B-81, and have 20 and 35% lower levels of total cholester ol and apoB, respectively, when compared to WT (apoB-100/B-100) mice. The m ajority 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. Tota l 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 en hanced degradation of apoB mRNA transcript containing premature translation al 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 tr iglyceride secretion rates, consistent with the apoB secretion rates. Inhib ition of receptor-mediated clearance of apoB-81-containing particles result ed in greater relative accumulation of apoB-81 in plasma than apoB-100, sug gesting enhanced clearance of apoB-81-containing particles. These results d emonstrate that low levels of apoB in heterozygous hypobetalipoproteinemic mice occurs by low rates of apoB secretion, and increased clearance of trun cated apoB. Similar mechanisms appear to contribute to low levels of apoB i n hypobetalipoproteinemic humans.