Dueland S, France D, Wang S L, Trawick J D, Davis R A
Department of Biology, San Diego State University, CA 92182-0057, USA.
J Lipid Res. 1997 Jul;38(7):1445-53.
C57BL/6 mice are susceptible to diet-induced atherosclerosis, whereas BALB/c mice are resistant. The susceptibility of C57BL/6 mice has been linked to decreased plasma HDL cholesterol in response to a diet containing fat, cholesterol, and cholic acid. Feeding C57BL/6 mice a diet consisting of fat and cholesterol, but no cholic acid, increased plasma high density lipoprotein (HDL) cholesterol. The increase in HDL was associated with increases in both plasma apolipoprotein (apo)A-I and hepatic apoA-I mRNA. Supplementation of the cholesterol-rich diet with cholic acid inhibited the stimulatory effect of cholesterol on hepatic apoA-I mRNA expression, resulting in similar hepatic apoA-I mRNA levels compared to chow-fed mice. Atherosclerosis-resistant BALB/c mice were also resistant to diet-induced changes in plasma HDL, apoA-I, and hepatic apoA-I mRNA levels. Previous studies showed that the diets changed both the activity and mRNA encoding the liver specific enzyme 7alpha-hydroxylase (1993.J. Lipid Res. 34: 923-931). In both strains of mice, hepatic expression of apoA-I and 7alpha-hydroxylase mRNA varied in parallel. Whereas susceptible C57BL/6 mice also showed a significant correlation between HDL cholesterol and expression of 7alpha-hydroxylase, no such correlation was observed in BALB/c mice, suggesting that genetic differences in HDL metabolism, not hepatic apoA-I synthesis, are responsible for the strain specific differences in plasma HDL levels. The finding that lecithin: cholesterol acyltransferase (LCAT) activity was significantly decreased in C57BL/6 mice, but not in BALB/ c mice fed the atherogenic diet, further supports this conclusion. Additional studies show that McArdle hepatoma cells stably expressing plasmid-derived rat 7alpha-hydroxylase recapitulated the parallel linear relationship between 7alpha-hydroxylase and apoA-I mRNA expression observed in both strains of mice. These data link hepatic apoA-I mRNA expression to hepatic cholesterol/bile acid metabolism.
C57BL/6小鼠易患饮食诱导的动脉粥样硬化，而BALB/c小鼠则具有抗性。C57BL/6小鼠的易感性与喂食含脂肪、胆固醇和胆酸的饮食后血浆高密度脂蛋白（HDL）胆固醇降低有关。给C57BL/6小鼠喂食由脂肪和胆固醇组成但不含胆酸的饮食，可增加血浆高密度脂蛋白（HDL）胆固醇。HDL的增加与血浆载脂蛋白（apo）A-I和肝脏apoA-I mRNA的增加有关。用胆酸补充富含胆固醇的饮食可抑制胆固醇对肝脏apoA-I mRNA表达的刺激作用，导致与喂食普通饲料的小鼠相似的肝脏apoA-I mRNA水平。抗动脉粥样硬化的BALB/c小鼠对饮食诱导的血浆HDL、apoA-I和肝脏apoA-I mRNA水平变化也具有抗性。先前的研究表明，这些饮食改变了肝脏特异性酶7α-羟化酶的活性和编码该酶的mRNA（1993年。《脂质研究杂志》34: 923 - 931）。在两种品系的小鼠中，apoA-I和7α-羟化酶mRNA的肝脏表达呈平行变化。虽然易感的C57BL/6小鼠的HDL胆固醇与7α-羟化酶的表达之间也存在显著相关性，但在BALB/c小鼠中未观察到这种相关性，这表明HDL代谢的遗传差异而非肝脏apoA-I的合成导致了血浆HDL水平的品系特异性差异。在喂食致动脉粥样硬化饮食的C57BL/6小鼠中卵磷脂胆固醇酰基转移酶（LCAT）活性显著降低，而在BALB/c小鼠中未降低，这一发现进一步支持了这一结论。额外的研究表明，稳定表达质粒衍生的大鼠7α-羟化酶的McArdle肝癌细胞重现了在两种品系小鼠中观察到的7α-羟化酶与apoA-I mRNA表达之间的平行线性关系。这些数据将肝脏apoA-I mRNA表达与肝脏胆固醇/胆汁酸代谢联系起来。
