Low therapeutic threshold for hepatocyte replacement in murine phenylketonuria
Low therapeutic threshold for hepatocyte replacement in murine phenylketonuria
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DOI：
10.1016/j.ymthe.2005.03.025
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发表时间：
2005-08-01
影响因子：
12.4
通讯作者：
Harding, CO
中科院分区：
文献类型：
--
作者：
Hamman, K;Clark, H;Harding, CO
哺乳动物中的苯丙氨酸稳态主要由肝脏苯丙氨酸羟化酶（PAH）活性控制。遗传性 PAH 缺乏症（苯丙酮尿症或 PKU）会导致小鼠和人类出现高苯丙氨酸血症。低水平的残余肝脏 PAH 活性确保了接近正常的饮食蛋白质耐受性和正常的血清苯丙氨酸水平，但正常苯丙氨酸清除率的精确阈值尚不清楚。我们在选择性生长条件下采用肝细胞移植来研究预防小鼠高苯丙氨酸血症所需的表达 PAH 的肝细胞的最小数量。小鼠的血清苯丙氨酸水平保持正常，这些小鼠表现出几乎完全由缺乏 PAH 的肝细胞进行肝脏重建。
Phenylalanine homeostasis in mammals is primarily controlled by liver phenylalanine hydroxylase (PAH) activity. Inherited PAH deficiency (phenylketonuria or PKU) leads to hyperphenylalaninemia in both mice and humans. A low level of residual liver PAH activity ensures near-normal dietary protein tolerance with normal serum phenylalanine level, but the precise threshold for normal phenylalanine clearance is unknown. We employed hepatocyte transplantation under selective growth conditions to investigate the minimal number of PAH-expressing hepatocytes necessary to prevent hyperphenylalaninemia in mice. Serum phenylalanine levels remained normal in mice exhibiting nearly complete liver repopulation with PAH-deficient hepatocytes (