Jong M C, Dahlmans V E, van Gorp P J, Breuer M L, Mol M J, van der Zee A, Frants R R, Hofker M H, Havekes L M
TNO-Prevention and Health, Gaubius Laboratory, Leiden, Netherlands.
Arterioscler Thromb Vasc Biol. 1996 Aug;16(8):934-40. doi: 10.1161/01.atv.16.8.934.
Transgenic mice overexpressing human APOE3Leiden are highly susceptible to diet-induced hyperlipoproteinemia and atherosclerosis due to a defect in hepatic uptake of remnant lipoproteins. In addition to the human APOE3Leiden gene, these mice carry the human APOC1 gene (APOE3Leiden-C1). To investigate the possible effect of simultaneous expression of the human APOC1 gene, we examined the phenotypic expression in these APOE3Leiden-C1 mice in relation to transgenic mice expressing the APOE3Leiden gene without the APOC1 gene (APOE3Leiden-HCR). APOE3Leiden-C1 and APOE3Leiden-HCR mice had comparable liver expression for the APOE3Leiden transgene and high total cholesterol levels on a sucrose-based diet compared with control mice (4.3 and 4.3 versus 2.1 mmol/L). In addition, on this diet APOE3Leiden-C1 mice displayed significantly higher serum triglyceride levels than APOE3Leiden-HCR mice and control mice (4.4 versus 0.6 and 0.2 mmol/L). Elevated triglyceride and cholesterol levels were mainly in the VLDL-sized lipoproteins. In vivo turnover studies with endogenously triglyceride-labeled VLDL showed a reduced VLDL triglyceride fractional catabolic rate for APOE3Leiden-C1 and APOE3Leiden-HCR mice compared with control mice (3.5 and 11.0 versus 20.4 pools per hour). To study whether the difference in fractional catabolic rates between the two transgenic strains was due to an inhibiting effect of apoC1 on the extrahepatic lipolysis or hepatic-mediated uptake of VLDL, turnover experiments were performed in functionally hepatectomized mice. Strikingly, both APOE3Leiden-C1 and APOE3Leiden-HCR mice showed a decreased lipolytic rate of VLDL triglyceride in the extrahepatic circulation compared with control mice (1.5 and 1.8 versus 6.3 pools per hour). We conclude that next to an impaired hepatic uptake, overexpression of the APOE3Leiden gene influences the extrahepatic lipolysis of VLDL triglycerides, whereas simultaneous overexpression of the APOC1 gene leads to a further decrease in hepatic clearance of VLDL.
由于肝脏对残余脂蛋白摄取存在缺陷，过表达人载脂蛋白E3莱顿（APOE3Leiden）的转基因小鼠对饮食诱导的高脂蛋白血症和动脉粥样硬化高度敏感。除了人APOE3Leiden基因外，这些小鼠还携带人载脂蛋白C1（APOC1）基因（APOE3Leiden-C1）。为了研究人APOC1基因同时表达可能产生的影响，我们检测了这些APOE3Leiden-C1小鼠与只表达APOE3Leiden基因而不表达APOC1基因的转基因小鼠（APOE3Leiden-HCR）相比的表型表达。与对照小鼠相比，APOE3Leiden-C1和APOE3Leiden-HCR小鼠的APOE3Leiden转基因在肝脏中的表达相当，且在基于蔗糖的饮食下总胆固醇水平较高（分别为4.3和4.3 mmol/L，而对照小鼠为2.1 mmol/L）。此外，在这种饮食条件下，APOE3Leiden-C1小鼠的血清甘油三酯水平显著高于APOE3Leiden-HCR小鼠和对照小鼠（分别为4.4、0.6和0.2 mmol/L）。甘油三酯和胆固醇水平升高主要存在于极低密度脂蛋白（VLDL）大小的脂蛋白中。对内源性甘油三酯标记的VLDL进行的体内周转研究表明，与对照小鼠相比，APOE3Leiden-C1和APOE3Leiden-HCR小鼠的VLDL甘油三酯分解代谢率分数降低（分别为每小时3.5和11.0池，而对照小鼠为20.4池）。为了研究这两种转基因品系之间分解代谢率分数的差异是否是由于载脂蛋白C-1对肝外脂肪分解或肝脏介导的VLDL摄取的抑制作用，我们在功能性肝切除的小鼠中进行了周转实验。令人惊讶的是，与对照小鼠相比，APOE3Leiden-C1和APOE3Leiden-HCR小鼠肝外循环中VLDL甘油三酯的脂肪分解率均降低（分别为每小时1.5和1.8池，而对照小鼠为6.3池）。我们得出结论，除了肝脏摄取受损外，APOE*3Leiden基因的过表达会影响VLDL甘油三酯的肝外脂肪分解，而APOC1基因的同时过表达会导致VLDL肝脏清除率进一步降低。
