Rohlmann A, Gotthardt M, Hammer R E, Herz J
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Howard Hughes Medical Institute, Dallas, Texas 75235, USA.
J Clin Invest. 1998 Feb 1;101(3):689-95. doi: 10.1172/JCI1240.
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.
多功能低密度脂蛋白（LDL）受体相关蛋白（LRP）被推测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、纤维蛋白溶解到神经元再生和存活。由于LRP对胚胎发育至关重要，因此通过传统的基因敲除方法无法在体内证明LRP对这些复杂过程中每一个的生理意义。在这里，我们使用Cre/loxP重组系统在成年小鼠中实现了LRP基因的诱导性、组织特异性和定量破坏。在低密度脂蛋白受体缺陷小鼠的肝脏中使LRP失活导致循环中富含胆固醇的残余脂蛋白积累。在正常动物中，这导致肝脏中LDL受体的代偿性上调。条件性基因靶向因此使我们能够分离出LRP的特定生理功能用于体内分析，并为肝脏中另一条不依赖LDL受体的胆固醇清除途径提供了明确的证据。
