Complex genetic control of HDL levels in mice in response to an atherogenic diet - Coordinate regulation of HDL levels and bile acid metabolism
Complex genetic control of HDL levels in mice in response to an atherogenic diet - Coordinate regulation of HDL levels and bile acid metabolism
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DOI：
10.1172/jci119300
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发表时间：
1997-03-15
影响因子：
15.9
通讯作者：
Lusis, AJ
中科院分区：
文献类型：
--
作者：
Machleder, D;Ivandic, B;Lusis, AJ
当用含有0.5%胆酸的高脂肪、高胆固醇饮食攻击时，近交系小鼠对动脉粥样硬化形成的易感性不同。对来自敏感品系C57 BL/6 J（B6）和抗性品系C3 H/HeJ（C3 H）和BALB/cJ的重组近交（RI）品系的研究揭示了脂肪条纹损伤大小与饮食中高密度脂蛋白（HDL）水平降低之间的关联。为了更好地了解饮食对HDL代谢和动脉粥样硬化形成的影响，我们使用完整的连锁图谱方法研究了来自B6和C3 H之间杂交的小鼠。共有185个雌性后代被分型为跨越小鼠基因组的134个遗传标记，导致标记之间的平均间隔约为10 cM。染色体1远端的一个含有载脂蛋白AII基因的基因座与食物和致动脉粥样硬化饮食中的HDL-胆固醇水平相关，但该基因座对饮食引起的HDL-胆固醇降低没有贡献。染色体3、5和11上至少有三个不同的遗传基因座显示出与饮食刺激后HDL-胆固醇降低相关的证据，由于胆汁酸（胆酸）是必需的饮食诱导的HDL水平的变化和动脉粥样硬化在这些菌株中，我们研究了胆固醇-7-α羟化酶（C7 AH）的表达。而B6小鼠表现出大幅度降低C7 AH mRNA水平的饮食反应，C3 H表现出增加。在互交小鼠中，多个位点的C7 AH mRNA水平的调节，饮食反应，其中最显着的是与染色体上的位点3，5，和11控制HDL水平的饮食反应。这些基因座均不与我们定位于近端4号染色体的C7 AH结构基因连锁。这些研究揭示了C7 AH表达和HDL水平的协调调节，并且它们表明控制HDL水平的遗传因素比先前由RI菌株的研究所提出的更复杂。我们观察到C7 AH表达的两个基因座导致这些菌株之间胆结石形成的差异。
Inbred strains of mice differ in susceptibility to atherogenesis when challenged with a high fat, high cholesterol diet containing 0.5% cholic acid. Studies of recombinant inbred (RI) strains derived from the susceptible strain C57BL/6J (B6) and the resistant strains C3H/HeJ (C3H) and BALB/cJ have revealed an association between fatty streak lesion size and a decrease in high density lipoprotein (HDL) levels on the diet. To better understand the genetic factors contributing to HDL metabolism and atherogenesis in response to the diet, we studied mice derived from an intercross between B6 and C3H using a complete linkage map approach. A total of 185 female progeny were typed for 134 genetic markers spanning the mouse genome, resulting in an average interval of about 10 cM between markers. A locus on distal chromosome 1 containing the apolipoprotein AII gene was linked to HDL-cholesterol levels on both the chow and the atherogenic diets, but this locus did not contribute to the decrease in HDL-cholesterol in response to the diet, At least three distinct genetic loci, on chromosomes 3, 5, and 11, exhibited evidence of linkage to a decrease in HDL-cholesterol after a dietary challenge, Since a bile acid (cholic acid) is required for the diet induced changes in HDL levels and for atherogenesis in these strains, we examined cholesterol-7-alpha hydroxylase (C7AH) expression. Whereas B6 mice exhibited a large decrease in C7AH mRNA levels in response to the diet, C3H showed an increase, Among the intercross mice, multiple loci contributed to the regulation of C7AH mRNA levels in response to the diet, the most notable of which coincided with the loci on chromosomes 3, 5, and 11 controlling HDL levels in response to the diet. None of these loci were linked to the C7AH structural gene which we mapped to proximal chromosome 4, These studies reveal coordinate regulation of C7AH expression and HDL levels, and they indicate that the genetic factors controlling HDL levels are more complex than previously suggested by studies of RI strains, Furthermore, we observed that two of the loci for C7AH expression contributed to differences in gallstone formation between these strains.