Sterol Regulatory Element-Binding Protein-1 Determines Plasma Remnant Lipoproteins and Accelerates Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice
Sterol Regulatory Element-Binding Protein-1 Determines Plasma Remnant Lipoproteins and Accelerates Atherosclerosis in Low-Density Lipoprotein Receptor-Deficient Mice
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DOI：
10.1161/atvbaha.110.219659
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发表时间：
2011-08-01
影响因子：
8.7
通讯作者：
Shimano, Hitoshi
中科院分区：
文献类型：
--
作者：
Karasawa, Tadayoshi;Takahashi, Akimitsu;Shimano, Hitoshi
目的：甾醇调节元件结合蛋白-1 （SREBP-1）具有营养调控作用，是调节脂肪生成酶的关键转录因子。本研究的目的是评估SREBP-1在血脂异常和动脉粥样硬化中的作用。方法与结果：将肝脏过表达SREBP-1c转基因小鼠和srebp -1缺陷小鼠与低密度脂蛋白受体（LDLR）缺陷小鼠杂交，分析其血脂和动脉粥样硬化的变化。ldlr缺陷小鼠肝脏SREBP-1c过表达引起餐后高甘油三酯血症，血浆中极低密度脂蛋白（VLDL）胆固醇升高，高密度脂蛋白胆固醇降低，导致主动脉粥样硬化形成加速。相反，缺乏SREBP-1可抑制低密度脂蛋白缺陷小鼠的西方饮食诱导的高脂血症，并改善动脉粥样硬化。相反，骨髓特异性SREBP-1缺乏不会改变动脉粥样硬化的发展。SREBP-1c转基因小鼠肝脏分泌的新生VLDL颗粒大小增加，srebp -1缺陷小鼠肝脏分泌的新生VLDL颗粒大小减少，同时磷脂转移蛋白表达分别上调和下调。结论：肝脏SREBP-1c决定血浆甘油三酯和残余胆固醇，并参与高血脂状态下动脉粥样硬化。肝脏SREBP-1c也调节新生VLDL颗粒的大小。（中华动脉血栓与血管杂志，2011;31:1788-1795。）
Objective-Sterol regulatory element-binding protein-1 (SREBP-1) is nutritionally regulated and is known to be a key transcription factor regulating lipogenic enzymes. The goal of this study was to evaluate the roles of SREBP-1 in dyslipidemia and atherosclerosis.Methods and Results-Transgenic mice that overexpress SREBP-1c in the liver and SREBP-1-deficient mice were crossed with low-density lipoprotein receptor (LDLR)-deficient mice, and the plasma lipids and atherosclerosis were analyzed. Hepatic SREBP-1c overexpression in LDLR-deficient mice caused postprandial hypertriglyceridemia, increased very-low-density lipoprotein (VLDL) cholesterol, and decreased high-density lipoprotein cholesterol in plasma, which resulted in accelerated aortic atheroma formation. Conversely, absence of SREBP-1 suppressed Western diet-induced hyperlipidemia in LDLR-deficient mice and ameliorated atherosclerosis. In contrast, bone marrow-specific SREBP-1 deficiency did not alter the development of atherosclerosis. The size of nascent VLDL particles secreted from the liver was increased in SREBP-1c transgenic mice and reduced in SREBP-1-deficient mice, accompanied by upregulation and downregulation of phospholipid transfer protein expression, respectively.Conclusion-Hepatic SREBP-1c determines plasma triglycerides and remnant cholesterol and contributes to atherosclerosis in hyperlipidemic states. Hepatic SREBP-1c also regulates the size of nascent VLDL particles. (Arterioscler Thromb Vasc Biol. 2011;31:1788-1795.)