Chiesa G, Hobbs H H, Koschinsky M L, Lawn R M, Maika S D, Hammer R E
Department of Internal Medicine, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas 75235.
J Biol Chem. 1992 Dec 5;267(34):24369-74.
Lipoprotein(a) (Lp(a)) is an atherosclerosis-causing lipoprotein that circulates in human plasma as a complex of low density lipoprotein (LDL) and apolipoprotein(a) (apo(a)). It is not known whether apo(a) attaches to LDL within hepatocytes prior to secretion or in plasma subsequent to secretion. Here we describe the development of a line of mice expressing the human apo(a) transgene under the control of the murine transferrin promoter. The apo(a) was secreted into the plasma, but circulated free of lipoproteins. When human (h)-LDL was injected intravenously, the circulating apo(a) rapidly associated with the lipoproteins, as determined by nondenaturing gel electrophoresis. Human HDL and mouse LDL had no such effect. When h-VLDL was injected, there was a delayed association of apo(a) with the lipoprotein fraction which suggests that apo(a) preferentially associated with a metabolic product of VLDL. The complex of apo(a) with LDL formed both in vivo and in vitro was resistant to boiling in the presence of detergents and denaturants, but was resolved upon disulfide reduction. These studies suggest that apo(a) fails to associate with mouse lipoproteins due to structural differences between human and mouse LDL, and that Lp(a) formation can occur in plasma through the association of apo(a) with circulating LDL.
脂蛋白(a)[Lp(a)]是一种致动脉粥样硬化的脂蛋白，它在人血浆中以低密度脂蛋白(LDL)和载脂蛋白(a)[apo(a)]的复合物形式循环。目前尚不清楚apo(a)是在分泌前在肝细胞内与LDL结合，还是在分泌后在血浆中与LDL结合。在此，我们描述了在小鼠转铁蛋白启动子控制下表达人apo(a)转基因的小鼠品系的培育。apo(a)分泌到血浆中，但以游离脂蛋白的形式循环。静脉注射人(h)-LDL后，通过非变性凝胶电泳测定，循环中的apo(a)迅速与脂蛋白结合。人HDL和小鼠LDL没有这种作用。注射h-VLDL后，apo(a)与脂蛋白部分的结合延迟，这表明apo(a)优先与VLDL的代谢产物结合。在体内和体外形成的apo(a)与LDL的复合物在去污剂和变性剂存在下耐煮沸，但在二硫键还原后可解离。这些研究表明，由于人和小鼠LDL之间的结构差异，apo(a)无法与小鼠脂蛋白结合，并且Lp(a)的形成可通过apo(a)与循环中的LDL结合在血浆中发生。
