Genetic-dietary regulation of serum paraoxonase expression and its role in atherogenesis in a mouse model
Genetic-dietary regulation of serum paraoxonase expression and its role in atherogenesis in a mouse model
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DOI：
10.1172/jci118589
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发表时间：
1996-04-01
影响因子：
15.9
通讯作者：
Lusis, AJ
中科院分区：
文献类型：
--
作者：
Shih, DM;Gu, LJ;Lusis, AJ
为了确定导致动脉粥样硬化形成的遗传因素，我们研究了对饮食诱导的主动脉脂肪条纹病变易感（C57 BL/6 J）和耐受（C3 H/HeJ）的近交系小鼠。当维持低脂饮食时，从C57 BL/6 J（B6）和C3 H/HeJ（C3 H）系小鼠分离的HDL在动脉壁的共培养模型中保护免于LDL氧化。然而，当维持高脂肪和胆固醇的致动脉粥样硬化饮食时，从B6小鼠分离的HDL失去保护能力，而来自C3 H小鼠的HDL同样良好地保护。与HDL保护能力的丧失相关的是血清对氧磷酶活性的降低，血清对氧磷酶是HDL上携带的血清酯酶，其先前已显示在体外保护免于LDL氧化，对氧磷酶mRNA水平在B6小鼠中降低，但在C3 H中增加，表明对氧磷酶的产生受遗传控制。在一组来自B6和C3 H亲本菌株的重组近交系中，低对氧磷酶mRNA水平与主动脉病变发展分离，支持对氧磷酶在动脉粥样硬化形成中的作用。
In an effort to identify genetic factors contributing to atherogenesis, we have studied inbred strains of mice that are susceptible (C57BL/6J) and resistant (C3H/HeJ) to diet-induced aortic fatty streak lesions, When maintained on a low-fat diet, HDL isolated from both strain C57BL/6J (B6) and C3H/HeJ (C3H) mice protect against LDL oxidation in a coculture model of the artery wall. However, when maintained on an atherogenic diet high in fat and cholesterol, the HDL isolated from B6 mice lose the capacity to protect, whereas HDL from C3H mice protect equally well, Associated with the loss in the ability of HDL to protect is a decrease in the activity of serum paraoxonase, a serum esterase carried on HDL that has previously been shown to protect against LDL oxidation in vitro, The levels of paraoxonase mRNA decreased in B6 mice upon challenge with the atherogenic diet but increased in C3H, indicating that paraoxonase production is under genetic control, In a set of recombinant inbred strains derived from the B6 and C3H parental strains, low paraoxonase mRNA levels segregated with aortic lesion development, supporting a role for paraoxonase in atherogenesis.