van Vlijmen B J, van 't Hof H B, Mol M J, van der Boom H, van der Zee A, Frants R R, Hofker M H, Havekes L M
TNO Prevention and Health, Gaubius Laboratory, Leiden, The Netherlands.
J Clin Invest. 1996 Mar 1;97(5):1184-92. doi: 10.1172/JCI118532.
Apolipoprotein E3-Leiden (APOE3-Leiden) transgenic mice have been studied to identify factors modulating chylomicron and VLDL remnant lipoprotein metabolism. Transient elevated levels of VLDL/LDL-sized lipoproteins occurred in these mice with maximal levels during the period of rapid growth (optimum at 45 d of age). After about 100 d of age, serum cholesterol and triglyceride levels stabilized to slightly elevated levels as compared to control mice. The expression of the APOE3-Leiden transgene was not age-dependent. In young mice the in vivo hepatic production of VLDL-triglycerides was 50% increased as compared to older mice. This is sustained by in vivo VLDL-apo B turnover studies showing increased (75%) VLDL-apo B secretion rates in young mice, whereas the VLDL-apo B clearance rate appeared not to be age dependent. On a high fat/cholesterol diet, females displayed significantly higher cholesterol levels than males (10 versus 7.0 mmol/liter, respectively). Serum levels of VLDL/LDL sized lipoproteins increased upon administration of estrogens, whereas administration of testosterone gave the opposite result. As compared to male mice, in female mice the hepatic VLDL-triglyceride production rate was significantly elevated. Injection of estrogen in males also resulted in increased VLDL-triglyceride production, although not statistically significant. In vivo VLDL-apo B turnover experiments showed that the VLDL secretion rate tended to be higher in females. Although, the fractional catabolic rate of VLDL-apo B is not different between males and females, administration of estrogens in males resulted in a decreased clearance rate of VLDL, whereas administration of testosterone in females resulted in an increased clearance rate of VLDL. The latter presumably due to an inhibiting effect of testosterone on the expression of the APOE3-Leiden transgene. We conclude that hyperlipidemia in APOE3-Leiden transgenic mice is strongly affected by age via its effect on hepatic VLDL production rate, whereas gender influences hyperlipidemia by modulating both hepatic VLDL production and clearance rate.
已对载脂蛋白E3-莱顿（APOE3-莱顿）转基因小鼠进行研究，以确定调节乳糜微粒和极低密度脂蛋白（VLDL）残粒脂蛋白代谢的因素。这些小鼠中出现了短暂的VLDL/低密度脂蛋白（LDL）大小的脂蛋白水平升高，在快速生长期间（45日龄时达到最佳）达到最高水平。约100日龄后，与对照小鼠相比，血清胆固醇和甘油三酯水平稳定在略高的水平。APOE3-莱顿转基因的表达不依赖于年龄。与老年小鼠相比，幼年小鼠体内VLDL-甘油三酯的肝脏生成增加了50%。体内VLDL-载脂蛋白B周转率研究支持了这一点，该研究表明幼年小鼠的VLDL-载脂蛋白B分泌率增加了（75%），而VLDL-载脂蛋白B清除率似乎不依赖于年龄。在高脂/高胆固醇饮食下，雌性小鼠的胆固醇水平显著高于雄性小鼠（分别为10 mmol/L和7.0 mmol/L）。给予雌激素后，VLDL/LDL大小的脂蛋白血清水平升高，而给予睾酮则产生相反的结果。与雄性小鼠相比，雌性小鼠的肝脏VLDL-甘油三酯生成率显著升高。给雄性小鼠注射雌激素也导致VLDL-甘油三酯生成增加，但无统计学意义。体内VLDL-载脂蛋白B周转率实验表明，雌性小鼠的VLDL分泌率往往更高。虽然，VLDL-载脂蛋白B的分解代谢率在雄性和雌性之间没有差异，但给雄性小鼠注射雌激素会导致VLDL清除率降低，而给雌性小鼠注射睾酮会导致VLDL清除率增加。后者可能是由于睾酮对APOE3-莱顿转基因表达的抑制作用。我们得出结论，APOE3-莱顿转基因小鼠的高脂血症通过其对肝脏VLDL生成率的影响而受到年龄的强烈影响，而性别则通过调节肝脏VLDL的生成和清除率来影响高脂血症。
