Regulation of the apolipoprotein B in heterozygous hypobetalipoproteinemic knock-out mice expressing truncated apoB, B81. Low production and enhanced clearance of apoB cause low levels of apoB

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