Effects of diet and hyperlipidemia on levels and distribution of circulating lysophosphatidic acid
Effects of diet and hyperlipidemia on levels and distribution of circulating lysophosphatidic acid
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DOI：
10.1194/jlr.m093096
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发表时间：
2019-11-01
影响因子：
6.5
通讯作者：
Morris, Andrew J.
中科院分区：
文献类型：
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作者：
Kraemer, Maria;Mao, Guogen;Morris, Andrew J.
溶血磷脂酸（LPAs）是甘油3-磷酸的生物活性烃基取代衍生物。LPA代谢和信号传导与冠状动脉疾病的遗传风险有关这些过程的遗传和药理学抑制减弱实验性动脉粥样硬化。LPA在动脉粥样硬化中蓄积，这可能是与LDL相关的结果。LDL相关LPA的来源、调节和生物活性尚不清楚。我们研究了实验性高脂血症对小鼠循环LPA水平和分布的影响。大多数血浆LPA与正常饲料喂养的野生型小鼠血浆中的白蛋白相关。LDL相关的LPA在来自高脂肪西方饮食喂养的小鼠的血浆中增加，所述小鼠在遗传上易于患高脂血症（LDL受体敲除或活化的前蛋白转化酶枯草杆菌蛋白酶/kexin 9型-过表达C57 B16）。编码产生LPA的分泌型溶血磷脂酶D（自分泌运动因子（ATX））的ENPP 2基因的脂肪特异性缺陷减弱了LPA的这些西方饮食依赖性增加。在分离的孵育血浆中观察到LDL相关LPA的ATX依赖性增加。ATX在体外直接作用于LDL相关溶血磷脂底物。来自所有人类受试者的LDL检查含有LPA，并通过降脂药物治疗降低。因此，人和小鼠血浆中含有对饮食敏感的LDL相关LPA池，可能有助于LPA的心血管疾病促进作用。
Lysophosphatidic acids (LPAs) are bioactive radyl hydrocarbon-substituted derivatives of glycerol 3-phosphate. LPA metabolism and signaling are implicated in heritable risk of coronary artery disease. Genetic and pharmacological inhibition of these processes attenuate experimental atherosclerosis. LPA accumulates in atheromas, which may be a consequence of association with LDLs. The source, regulation, and biological activity of LDL-associated LPA are unknown. We examined the effects of experimental hyperlipidemia on the levels and distribution of circulating LPA in mice. The majority of plasma LPA was associated with albumin in plasma from wild-type mice fed normal chow. LDL-associated LPA was increased in plasma from high-fat Western diet-fed mice that are genetically prone to hyperlipidemia (LDL receptor knockout or activated proprotein convertase subtilisin/kexin type 9-overexpressing C57Bl6). Adipose-specific deficiency of the ENPP2 gene encoding the LPA-generating secreted lysophospholipase D, autotaxin (ATX), attenuated these Western diet-dependent increases in LPA. ATX-dependent increases in LDL-associated LPA were observed in isolated incubated plasma. ATX acted directly on LDL-associated lysophospholipid substrates in vitro. LDL from all human subjects examined contained LPA and was decreased by lipid-lowering drug therapies. Human and mouse plasma therefore contains a diet-sensitive LDL-associated LPA pool that might contribute to the cardiovascular disease-promoting effects of LPA.