Studies on a model animal for atherogenic lipoproteins and atherosclerosis

为探讨肝脏甘油三酯合成增强对致动脉粥样硬化脂蛋白生成的影响，建立了SREBP-lc反式和低密度脂蛋白受体缺陷双突变小鼠(BP1c/LDLRKO)。BP1c/LDLRKO表现出血浆甘油三酯和胆固醇的升高，尤其是在饲喂时。琼脂糖凝胶电泳法显示，与对照组相比，LDLR KO组小鼠体内残存脂蛋白的含量增加，而LIDL胆固醇的含量降低。肝脏Northern印迹分析表明，SREBP-1c过表达诱导了Fas、ACC和SCO等成脂酶基因的表达。生脂基因表达的激活可增加肝脏餐后甘油三酯的合成和富含甘油三酯的脂蛋白的产生，而这些脂蛋白是在没有LDLR转化为血浆中残留的脂蛋白时积累的。由于这些致动脉粥样硬化脂蛋白的积聚，BP1c/LDLRKO在8个月龄时，即使在正常饮食的情况下，也能在主动脉窦周围形成动脉粥样硬化。这些小鼠是研究餐后高脂血症和代谢综合征的良好模型。

To investigate effects of enhanced hepatic trigylcerides synthesis on production of atherogenic lipoproteins, SREBP-lc transgeni and LDL receptor-deficient doubly mutant mice (BP1c/LDLRKO). were generated and their plasma lipoproteins were studied BP1c/LDLRKO showed incrases in plasma triglycerides and cholesterol especially at feeding. On agarose electrophoresis, broa beta band, suggesting presence of remnant lipoproteins was increased and LIDL cholesterol was inversely decreased as compared to controls of LDLR KO mice. Northern blot analysis of livers showed that over-expression of SREBP-lc induced expression of lipogenic enzyme genes such as FAS, ACC, and SCO. Activation of lipogenic gene expression could incrase hepatic postprandia synthesis of triglycerides and production of TG rich lipoproteins, which were accumulated in the absence of LDLR converting to remnant lipoproteins in plasma. Due to the accumulation of these atherogenic lipoproteins, BP1c/LDLRKO exhibited atherorm formation around aortic sinus at age of 8 months even on a regular diet. These mice are a good model for postprandial hyperlipidemia and metabolic syndrome.