A Txnrd1-dependent metabolic switch alters hepatic lipogenesis, glycogen storage, and detoxification.
A Txnrd1-dependent metabolic switch alters hepatic lipogenesis, glycogen storage, and detoxification.
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DOI：
10.1016/j.freeradbiomed.2013.05.028
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发表时间：
2013-10
影响因子：
7.4
通讯作者：
Schmidt EE
中科院分区：
文献类型：
--
作者：
Iverson SV;Eriksson S;Xu J;Prigge JR;Talago EA;Meade TA;Meade ES;Capecchi MR;Arnér ES;Schmidt EE
除了帮助维持细胞内还原环境外，硫氧还蛋白（Trx）系统还影响生物能量学和药物代谢。我们发现，编码Trx还原酶-1 （TrxR1）的Txnrd1的肝细胞特异性破坏导致代谢开关，其中脂肪生成基因被抑制，门静脉周围肝细胞充满糖原。这些肝脏也过度表达生物合成谷胱甘肽和将糖原转化为udp -葡萄糖酸盐的机制；他们储存谷胱甘肽- s转移酶和udp -葡萄糖醛酸转移酶；而且它们过度表达外源性出口商。这种重新排列的代谢谱表明，突变的肝细胞可能被预先调节，以更有效地解毒某些外源挑战。肝细胞将前毒素对乙酰氨基酚（APAP，扑热息痛）转化为细胞毒性n -乙酰基-对苯醌亚胺（NAPQI）。APAP防御包括APAP的葡萄糖醛酸化或NAPQI的谷胱甘肽化，允许外源性出口物去除。我们发现NAPQI直接灭活TrxR1，但txnrd1缺失的肝脏对apap诱导的肝毒性具有抗性。txnrd1缺失的肝脏对APAP攻击没有更有效的基因表达反应；然而，它们的组成代谢状态支持更强大的谷胱甘肽生物合成-，谷胱甘肽酰化-和葡萄糖醛酸化系统。在APAP攻击后，这有效地维持了GSH系统并减轻了损害。
Besides helping to maintain a reducing intracellular environment, the thioredoxin (Trx) system impacts bioenergetics and drug-metabolism. We show that hepatocyte-specific disruption of Txnrd1, encoding Trx reductase-1 (TrxR1), causes a metabolic switch in which lipogenic genes are repressed and periportal hepatocytes become engorged with glycogen. These livers also overexpress machinery for biosynthesis of glutathione and conversion of glycogen into UDP-glucuronate; they stockpile glutathione-S-transferases and UDP-glucuronyl-transferases; and they overexpress xenobiotic exporters. This realigned metabolic profile suggested that the mutant hepatocytes might be preconditioned to more effectively detoxify certain xenobiotic challenges. Hepatocytes convert the pro-toxin acetaminophen (APAP, paracetamol) into cytotoxic N-acetyl-p-benzoquinone imine (NAPQI). APAP defenses include glucuronidation of APAP or glutathionylation of NAPQI, allowing removal by xenobiotic exporters. We found that NAPQI directly inactivates TrxR1, yet Txnrd1-null livers were resistant to APAP-induced hepatotoxicity. Txnrd1-null livers did not have more effective gene expression responses to APAP challenge; however their constitutive metabolic state supported more robust GSH biosynthesis-, glutathionylation-, and glucuronidation-systems. Following APAP challenge, this effectively sustained the GSH system and attenuated damage.
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影响因子：
3.7
作者：
Anestål K;Prast-Nielsen S;Cenas N;Arnér ES
通讯作者：
Arnér ES
AMPK信号传导对硫氧还蛋白相互作用的蛋白质基因敲除小鼠中禁食的信号传导响应减少。
影响因子：
3.5
作者：
Andres AM;Ratliff EP;Sachithanantham S;Hui ST
通讯作者：
Hui ST
DOI：
10.1124/jpet.110.176321
发表时间：
2011-04-01
影响因子：
3.5
作者：
Agarwal, Rakhee;MacMillan-Crow, Lee Ann;Hinson, Jack A.
通讯作者：
Hinson, Jack A.
影响因子：
4.8
作者：
Chutkow, William A.;Lee, Richard T.
通讯作者：
Lee, Richard T.
影响因子：
7.4
作者：
Bondareva, Alla A.;Capecchi, Mario R.;Schmidt, Edward E.
通讯作者：
Schmidt, Edward E.