Liver-specific knockout of arginase-1 leads to a profound phenotype similar to inducible whole body arginase-1 deficiency.
Liver-specific knockout of arginase-1 leads to a profound phenotype similar to inducible whole body arginase-1 deficiency.
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DOI：
10.1016/j.ymgmr.2016.10.003
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发表时间：
2016-12
影响因子：
1.9
通讯作者：
Funk, Colin D.
中科院分区：
文献类型：
--
作者：
Ballantyne, Laurel L.;Sin, Yuan Yan;Al-Dirbashi, Osama Y.;Li, Xinzhi;Hurlbut, David J.;Funk, Colin D.
精氨酸酶-1（Arg 1）在肝脏尿素循环的远端步骤中将精氨酸转化为尿素和鸟氨酸。我们以前产生了一个他莫昔芬诱导的Arg 1缺陷小鼠模型（Arg 1-Cre），破坏Arg 1在整个身体的表达，并导致致死性基因破坏后2周。在这里，我们评估肝脏选择性Arg 1丢失是否足以概括在全球Arg 1基因敲除小鼠中观察到的表型，以及评估基因递送或肝细胞移植挽救表型的有效性。通过使用腺相关病毒（AAV）-甲状腺素结合球蛋白（TBG）启动子-Cre重组酶载体给予Arg 1“floxed”小鼠（Arg 1fl/fl）来诱导肝脏选择性Arg 1缺失。使用表达Arg 1增强的绿色荧光蛋白（Arg 1-eGFP）转基因的AAV载体进行基因递送，而在部分肝切除术后脾内注射野生型（WT）C57 BL/6肝细胞用于细胞递送以“拯救”他莫昔芬处理的Arg 1-Cre小鼠。结果表明，肝脏选择性丢失Arg 1（> 90%缺陷）导致类似于全身敲除Arg 1的表型，在Cre诱导的基因破坏后3周具有致死性。Arg 1-eGFP AAV的递送拯救了超过一半的Arg 1整体敲除雄性小鼠（存活> 4个月），但即使融合蛋白的肝脏表达和酶活性达到WT动物中观察到的水平，仍有相当大比例的小鼠死于酶缺乏。从移植的WT肝细胞到敲除肝脏中可以实现显著的Arg 1酶活性，但不足以挽救致死表型。这引起了一个与Arg 1的肝脏特异性表达有关的难题。一方面，该器官中表达的缺失似乎是解释小鼠遗传性疾病致死表型的必要和充分条件。另一方面，基因和细胞定向治疗表明，拯救肝外Arg 1表达也可能是必要的疾病纠正。需要进一步的研究，以阐明详细的发病机制Arg 1-缺陷。
Arginase-1 (Arg1) converts arginine to urea and ornithine in the distal step of the urea cycle in liver. We previously generated a tamoxifen-inducible Arg1 deficient mouse model (Arg1-Cre) that disrupts Arg1 expression throughout the whole body and leads to lethality ≈ 2 weeks after gene disruption. Here, we evaluate if liver-selective Arg1 loss is sufficient to recapitulate the phenotype observed in global Arg1 knockout mice, as well as to gauge the effectiveness of gene delivery or hepatocyte transplantation to rescue the phenotype. Liver-selective Arg1 deletion was induced by using an adeno-associated viral (AAV)-thyroxine binding globulin (TBG) promoter-Cre recombinase vector administered to Arg1 “floxed” mice; Arg1fl/fl). An AAV vector expressing an Arg1-enhanced green fluorescent protein (Arg1-eGFP) transgene was used for gene delivery, while intrasplenic injection of wild-type (WT) C57BL/6 hepatocytes after partial hepatectomy was used for cell delivery to “rescue” tamoxifen-treated Arg1-Cre mice. The results indicate that liver-selective loss of Arg1 (> 90% deficient) leads to a phenotype resembling the whole body knockout of Arg1 with lethality ≈ 3 weeks after Cre-induced gene disruption. Delivery of Arg1-eGFP AAV rescues more than half of Arg1 global knockout male mice (survival > 4 months) but a significant proportion still succumb to the enzyme deficiency even though liver expression and enzyme activity of the fusion protein reach levels observed in WT animals. Significant Arg1 enzyme activity from engrafted WT hepatocytes into knockout livers can be achieved but not sufficient for rescuing the lethal phenotype. This raises a conundrum relating to liver-specific expression of Arg1. On the one hand, loss of expression in this organ appears to be both necessary and sufficient to explain the lethal phenotype of the genetic disorder in mice. On the other hand, gene and cell-directed therapies suggest that rescue of extra-hepatic Arg1 expression may also be necessary for disease correction. Further studies are needed in order to illuminate the detailed mechanisms for pathogenesis of Arg1-deficiency.
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影响因子：
5.3
作者：
Iyer, RK;Yoo, PK;Cederbaum, SD
通讯作者：
Cederbaum, SD
影响因子：
5.1
作者：
通讯作者：
--
DOI：
10.1152/ajpgi.00167.2006
发表时间：
2007-04-01
影响因子：
4.5
作者：
Dawra, Rajinder;Sharif, Rifat;Saluja, Ashok K.
通讯作者：
Saluja, Ashok K.
影响因子：
64.5
作者：
Chantranupong L;Scaria SM;Saxton RA;Gygi MP;Shen K;Wyant GA;Wang T;Harper JW;Gygi SP;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
4.2
作者：
Iyer, R;Jenkinson, CP;Cederbaum, S
通讯作者：
Cederbaum, S