Inducible inactivation of hepatic LRP gene by Cre-mediated recombination confirms role of LRP in clearance of chylomicron remnants
Inducible inactivation of hepatic LRP gene by Cre-mediated recombination confirms role of LRP in clearance of chylomicron remnants
复制标题
DOI：
10.1172/jci1240
复制
发表时间：
1998-02-01
影响因子：
15.9
通讯作者：
Herz, J
中科院分区：
文献类型：
--
作者：
Rohlmann, A;Gotthardt, M;Herz, J
多功能低密度脂蛋白（LDL）受体相关蛋白（LRP）被认为参与了许多不同的生理和病理过程，从血浆脂蛋白的稳态、动脉粥样硬化和纤维蛋白溶解到神经元的再生和存活。由于LRP对胚胎发育至关重要，因此通过常规基因敲除方法不可能在体内证明LRP对这些复杂过程中的每一个的生理意义。我们利用Cre/loxP重组系统对成年小鼠LRP基因进行了可诱导的、组织特异性的、定量的破坏。LRP在LDL受体缺陷小鼠肝脏中的失活导致了富含胆固醇的残余脂蛋白在循环中的积累。在正常动物中，这引起肝脏中LDL受体的代偿性上调，因此条件性基因靶向使我们能够分离LRP的特定生理功能用于体内分析，并为肝脏中另一种LDL受体非依赖性胆固醇清除途径提供了明确的证据。
The multifunctional low density lipoprotein (LDL) receptor-related protein (LRP) has been postulated to participate in a number of diverse physiological and pathological processes ranging from the homeostasis of plasma lipoproteins, atherosclerosis, and fibrinolysis to neuronal regeneration and survival. It has not been possible to demonstrate in vivo the physiological significance of LRP for each of these complex processes by a conventional gene knockout approach because LRP is essential for embryonic development. Here we have used the Cre/loxP recombination system to achieve inducible, tissue-specific and quantitative disruption of the LRP gene in adult mice, Inactivation of LRP in the livers of LDL receptor-deficient mice resulted in the accumulation of cholesterol-rich remnant lipoproteins in the circulation. In normal animals, this caused a compensatory upregulation of the LDL receptor in the liver, Conditional gene targeting has thus allowed us to isolate a specific physiological function of LRP for in vivo analysis and has provided unequivocal evidence for another LDL receptor-independent cholesterol clearance pathway in liver.