xCT deficiency aggravates acetaminophen-induced hepatotoxicity under inhibition of the transsulfuration pathway
xCT deficiency aggravates acetaminophen-induced hepatotoxicity under inhibition of the transsulfuration pathway
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DOI：
10.1080/10715762.2017.1282157
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发表时间：
2017-01-01
影响因子：
3.3
通讯作者：
Fujii, Junichi
中科院分区：
文献类型：
--
作者：
Kang, Eun Sil;Lee, Jaeyong;Fujii, Junichi
胱氨酸是半胱氨酸（Cys）的一种氧化形式，通过xCT蛋白输入细胞，该蛋白也与谷氨酸作为对抗氨基酸的输出有关。在目前的研究中，我们试图合理化xCT在雄性小鼠肝脏中的作用。虽然xCT在普通小鼠的肝脏中不表达，但在对乙酰氨基酚（AAP）引起的谷胱甘肽耗竭条件下可诱导表达。为了区分xCT和反式硫化途径对胱氨酸供应的作用，我们使用了半胱甘氨酸c-裂解酶抑制剂丙基甘氨酸（PPG）。该抑制剂显著加重了aap引起的肝损伤，xCT（-/-）小鼠的死亡率比xCT（+/+）小鼠增加得更大。虽然PPG预处理对肝脏状况或Cys水平没有影响，但对PPG预处理小鼠给予AAP可将xCT（+/+）和xCT（-/-）小鼠的Cys和谷胱甘肽水平降低到非常低的水平。这些发现表明，当谷胱甘肽水平较低时，转硫途径在补充胱氨酸中起主要作用。此外，Akr1a消融引起的抗坏血酸不足，在xCT缺乏的情况下，进一步加重了aap诱导的肝损伤，表明谷胱甘肽和抗坏血酸协同起保护肝脏的作用。综上所述，虽然转硫途径在向肝脏氧化还原系统供应Cys方面起主要作用，但在紧急情况下，通过补偿Cys供应系统诱导xCT。
Cystine, an oxidized form of cysteine (Cys), is imported into cells via the protein xCT, which is also associated with the export of glutamate as the counter amino acid. In the current study, we attempted to rationalize roles of xCT in the livers of male mice. While xCT was not expressed in the livers of ordinary mice, it was induced under conditions of glutathione depletion, caused by the administration of acetaminophen (AAP). To differentiate the role between xCT and the trans-sulfuration pathway on the supply of Cys, we employed an inhibitor of the enzyme cystathionine c-lyase, propargylglycine (PPG). This inhibitor caused a marked aggravation in AAP-induced hepatic damage and the mortality of the xCT (-/-) mice was increased to a greater extent than that for the xCT(+/+) mice. While a PPG pretreatment had no effect on liver condition or Cys levels, the administration of AAP to the PPG-pretreated mice reduced the levels of Cys as well as glutathione to very low levels in both the xCT(+/+) and xCT(-/-) mice. These findings indicate that the transsulfuration pathway plays a major role in replenishing Cys when glutathione levels are low. Moreover, an ascorbic acid insufficiency, induced by Akr1a ablation, further aggravated the AAP-induced liver damage in the case of the xCT deficiency, indicating that glutathione and ascorbic acid function cooperatively in protecting the liver. In conclusion, while the transsulfuration pathway plays a primary role in supplying Cys to the redox system in the liver, xCT is induced in cases of emergencies, by compensating for Cys supply systems.