Arylacetamide deacetylase regulates hepatic iron homeostasis to protect against carbon tetrachloride-induced ferroptosis

IF 4.8 2区 医学 Q1 TOXICOLOGY Archives of Toxicology Pub Date : 2024-10-05 DOI:10.1007/s00204-024-03873-5
Soshi Shinohara, Seijo Uchijima, Keiya Hirosawa, Mai Nagaoka, Masataka Nakano, Miki Nakajima, Tatsuki Fukami
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Abstract

Arylacetamide deacetylase (AADAC) catalyzes the hydrolysis of small molecules containing ester and amide bonds. Recently, it has been reported that AADAC can suppress reactive oxygen species production in cancer cells. This study aimed to elucidate the possibility that AADAC protects against drug-induced liver injury accompanied by oxidative stress and to explore its molecular mechanisms. Intraperitoneal administration of carbon tetrachloride induced significantly more severe liver injury in Aadac knockout (KO) mice (plasma alanine aminotransferase level: 19,381 ± 10,578 U/L) than in wild-type (WT) mice (7219 ± 4729 U/L). More severe liver injury in Aadac KO mice was accompanied by higher hepatic malondialdehyde and antioxidant gene mRNA levels than those in WT mice. The increase in plasma alanine aminotransferase levels in Aadac KO mice was substantially suppressed by pretreatment with the ferroptosis inhibitors deferoxamine or ferrostatin-1, suggesting that Aadac deficiency increases susceptibility to ferroptosis. Immunoprecipitation followed by proteomic analysis revealed that AADAC interacts with ceruloplasmin (CP), which oxidizes ferrous iron to ferric iron. Hepatic CP activity was significantly lower in Aadac KO mice than that in WT mice, resulting in elevated hepatic ferrous iron levels in Aadac KO mice. Overexpression of human AADAC in Huh-7 cells significantly attenuated carbon tetrachloride-induced cytotoxicity by suppressing ferrous iron accumulation, suggesting that AADAC interacts with CP to suppress hepatic ferrous iron accumulation. The hepatoprotective role of Aadac in ferroptosis was also observed in mice with acetaminophen-induced liver injury. This study demonstrates a novel function of AADAC in protecting against ferroptosis induced by hepatotoxicants, carbon tetrachloride and acetaminophen.

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芳基乙酰胺去乙酰化酶调节肝脏铁稳态,防止四氯化碳诱导的铁变态反应。
芳基乙酰胺脱乙酰酶(AADAC)催化水解含有酯键和酰胺键的小分子。最近有报道称,AADAC 可抑制癌细胞中活性氧的产生。本研究旨在阐明 AADAC 可防止药物诱导的肝损伤(伴有氧化应激)的可能性,并探索其分子机制。腹腔注射四氯化碳诱导的Aadac基因敲除(KO)小鼠肝损伤(血浆丙氨酸氨基转移酶水平:19381 ± 10578 U/L)比野生型(WT)小鼠(7219 ± 4729 U/L)严重得多。与 WT 小鼠相比,Aadac KO 小鼠肝损伤更严重,肝丙二醛和抗氧化基因 mRNA 水平更高。Aadac KO小鼠血浆丙氨酸氨基转移酶水平的升高在使用铁蛋白沉积抑制剂去铁胺或铁前列素-1预处理后被大大抑制,这表明Aadac缺乏会增加对铁蛋白沉积的易感性。免疫沉淀后的蛋白质组分析表明,AADAC 与将亚铁氧化为铁的脑磷脂蛋白(CP)相互作用。Aadac KO小鼠肝脏CP活性明显低于WT小鼠,导致Aadac KO小鼠肝脏亚铁水平升高。在Huh-7细胞中过表达人AADAC可通过抑制亚铁积累而明显减轻四氯化碳诱导的细胞毒性,这表明AADAC与CP相互作用抑制肝脏亚铁积累。在对乙酰氨基酚诱导的肝损伤小鼠中,也观察到了 Aadac 在铁变态反应中的保肝作用。这项研究证明了 AADAC 在保护肝脏免受四氯化碳和对乙酰氨基酚等肝毒性物质诱导的铁中毒作用方面的新功能。
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来源期刊
Archives of Toxicology
Archives of Toxicology 医学-毒理学
CiteScore
11.60
自引率
4.90%
发文量
218
审稿时长
1.5 months
期刊介绍: Archives of Toxicology provides up-to-date information on the latest advances in toxicology. The journal places particular emphasis on studies relating to defined effects of chemicals and mechanisms of toxicity, including toxic activities at the molecular level, in humans and experimental animals. Coverage includes new insights into analysis and toxicokinetics and into forensic toxicology. Review articles of general interest to toxicologists are an additional important feature of the journal.
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