Dueland S, Drisko J, Graf L, Machleder D, Lusis A J, Davis R A
Atherosclerosis Research Center, University of Colorado Health Sciences Center, Denver 80262.
J Lipid Res. 1993 Jun;34(6):923-31.
Compared to BALB/c mice, inbred C57BL/6 mice are more susceptible to developing fatty streak atherosclerotic lesions when fed a cholesterol-rich diet containing taurocholate. We examined the metabolic basis for the taurocholate requirement. In contrast to widely accepted assumptions, taurocholate did not increase cholesterol absorption in either strain of mouse. However, in susceptible C57BL/6 mice, taurocholate was required to increase plasma concentrations of apoB. In both strains, the cholesterol-rich diet increased both the activity and mRNA for 7 alpha-hydroxylase, a compensatory response to maintain cholesterol homeostasis. In both strains, adding taurocholate to the diet suppressed both the activity and mRNA for 7 alpha-hydroxylase, thus blocking this important compensatory response. The cholesterol-rich diet (without taurocholate) significantly increased hepatic cholesterol content in both strains of mice, but repressed low density lipoprotein (LDL) receptor mRNA only in BALB/c mice (not in C57BL/6 mice). However, adding taurocholate to the cholesterol-rich diet did decrease LDL receptor mRNA in C57BL/6 mice. In C57BL/6, but not in BALB/c mice, there was a linear parallel relationship between 7 alpha-hydroxylase mRNA and LDL receptor mRNA. These data show the existence of strain-specific differences in the effects of dietary cholesterol and taurocholate on 7 alpha-hydroxylase and LDL receptor expression. The combined data suggest that genetic factors determine how the expression of hepatic LDL receptors responds to dietary cholesterol and taurocholate.
与BALB/c小鼠相比，近交系C57BL/6小鼠在喂食含牛磺胆酸盐的高胆固醇饮食时更易形成脂肪条纹动脉粥样硬化病变。我们研究了对牛磺胆酸盐需求的代谢基础。与广泛接受的假设相反，牛磺胆酸盐在两种品系小鼠中均未增加胆固醇吸收。然而，在易患动脉粥样硬化的C57BL/6小鼠中，需要牛磺胆酸盐来提高载脂蛋白B的血浆浓度。在两种品系中，高胆固醇饮食均增加了7α-羟化酶的活性和mRNA水平，这是维持胆固醇稳态的一种代偿反应。在两种品系中，在饮食中添加牛磺胆酸盐均抑制了7α-羟化酶的活性和mRNA水平，从而阻断了这一重要的代偿反应。高胆固醇饮食（不含牛磺胆酸盐）在两种品系小鼠中均显著增加了肝脏胆固醇含量，但仅在BALB/c小鼠中（而非C57BL/6小鼠中）抑制了低密度脂蛋白（LDL）受体mRNA水平。然而，在高胆固醇饮食中添加牛磺胆酸盐确实降低了C57BL/6小鼠的LDL受体mRNA水平。在C57BL/6小鼠中（而非BALB/c小鼠中），7α-羟化酶mRNA与LDL受体mRNA之间存在线性平行关系。这些数据表明，饮食胆固醇和牛磺胆酸盐对7α-羟化酶和LDL受体表达的影响存在品系特异性差异。综合数据表明，遗传因素决定了肝脏LDL受体表达对饮食胆固醇和牛磺胆酸盐的反应方式。
