Disruption of LDL receptor gene in transgenic SREBP-1a mice unmasks hyperlipidemia resulting from production of lipid-rich VLDL
Disruption of LDL receptor gene in transgenic SREBP-1a mice unmasks hyperlipidemia resulting from production of lipid-rich VLDL
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DOI：
10.1172/jci6246
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发表时间：
1999-04-01
影响因子：
15.9
通讯作者：
Goldstein, JL
中科院分区：
文献类型：
--
作者：
Horton, JD;Shimano, H;Goldstein, JL
在肝脏中过表达核型固醇调节元件结合蛋白-1a(SREBP-1a)的转基因小鼠(TGBP-1a小鼠)先前被证明过度产生胆固醇和脂肪酸，并在肝细胞中积累大量的胆固醇和甘油三酯。尽管肝脏产生了过量的脂质，但血浆胆固醇(类似于45 mg/dl)和甘油三酯(类似于55 mg/dl)水平并未升高，这可能是由于低密度脂蛋白(LDL)受体降解了富含脂肪的颗粒。为了验证这一假设，在目前的研究中，我们用低密度脂蛋白受体基因敲除小鼠培育了TGBP-1a小鼠。正如之前报道的那样，LDLR-/-小鼠的血浆胆固醇(类似于215 mg/dl)和甘油三酯(类似于155 mg/dl)有中等程度的升高。相比之下，双突变TGBP-1a；LDLR-/-小鼠的血浆胆固醇(类似于1050 mg/dl)和甘油三酯(类似于900 mg/dl)显著增加。这些脂质主要包含在较大的极低密度脂蛋白(VLDL)颗粒中，这些颗粒相对富含胆固醇和载脂蛋白E；新鲜从TGBP-1a和TGBP-1a分离的肝细胞；LDLR-/-小鼠过度产生胆固醇和脂肪酸，并将大量这些脂类分泌到介质中。TGBP-1a小鼠肝脏的电子显微镜照片显示，在分泌途径中有大量扩大的脂蛋白。我们得出结论，TGBP-1a小鼠产生大量富含脂肪的脂蛋白，但这些颗粒不会在血浆中积累，因为它们是通过低密度脂蛋白受体的作用而降解的。
Transgenic mice that overexpress the nuclear form of sterol regulatory element binding protein-1a (SREBP-1a) in liver (TgBP-1a mice) were shown previously to overproduce cholesterol and fatty acids and to accumulate massive amounts of cholesterol and triglycerides in hepatocytes. Despite the hepatic overproduction of lipids, the plasma levels of cholesterol (similar to 45 mg/dl) and triglycerides (similar to 55 mg/dl) were not elevated, perhaps owing to degradation of lipid-enriched particles by low-density lipoprotein (LDL) receptors. To test this hypothesis, in the current studies we bred TgBP-1a mice with LDL receptor knockout mice. As reported previously, LDLR-/- mice manifested a moderate elevation in plasma cholesterol (similar to 215 mg/dl) and triglycerides (similar to 155 mg/dl). In contrast, the doubly mutant TgBP-1a;LDLR-/- mice exhibited marked increases in plasma cholesterol(similar to 1,050 mg/dl) and triglycerides (similar to 900 mg/dl). These lipids were contained predominantly within large very-low-density lipoprotein (VLDL) particles that were relatively enriched in cholesterol and apolipoprotein E. Freshly isolated hepatocytes from TgBP-1a and TgBP-1a; LDLR-/- mice overproduced cholesterol and fatty acids and secreted increased amounts of these lipids into the medium. Electron micrographs of livers from TgBP-1a mice showed large amounts of enlarged lipoproteins within the secretory pathway. We conclude that the TgBP-1a mice produce large lipid-rich lipoproteins, but these particles do not accumulate in plasma because they are degraded through the action of LDL receptors.