A Txnrd1-dependent metabolic switch alters hepatic lipogenesis, glycogen storage, and detoxification

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• 作者：Sonya V. Iverson ; Sofi Eriksson ; Jianqiang Xu ; Justin R. Prigge ; Emily A. Talago ; Tesia A. Meade ; Erin S. Meade ; Mario R. Capecchi ; Elias S.J. Arn¨¦r ; Edward E. Schmidt
• 关键词：Abcc ; ATP-binding cassette subfamily C multidrug-resistance transporters ; ALT ; alanine transaminase ; Aox1 ; aldehyde oxidase-1 ; APAP ; acetaminophen (paracetamol) ; BSO ; buthionine sulfoximine ; Cre ; bacteriophage P1 cyclization recombinase ; CYP ; cytochrome P
• 刊名：Free Radical Biology and Medicine
• 出版年：2013
• 出版时间：October, 2013
• 年：2013
• 卷：63
• 期：Complete
• 页码：369-380
• 全文大小：13824 K

文摘

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.