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Inhibition of 7-dehydrocholesterol reductase prevents hepatic ferroptosis under an active state of sterol synthesis
Nature Communications ( IF 14.7 ) Pub Date : 2024-03-12 , DOI: 10.1038/s41467-024-46386-6
Naoya Yamada 1, 2, 3 , Tadayoshi Karasawa 1 , Junya Ito 4 , Daisuke Yamamuro 5 , Kazushi Morimoto 6 , Toshitaka Nakamura 3 , Takanori Komada 1 , Chintogtokh Baatarjav 1 , Yuma Saimoto 6 , Yuka Jinnouchi 6 , Kazuhisa Watanabe 7 , Kouichi Miura 8 , Naoya Yahagi 5 , Kiyotaka Nakagawa 4 , Takayoshi Matsumura 1, 7 , Ken-Ichi Yamada 6 , Shun Ishibashi 5 , Naohiro Sata 2 , Marcus Conrad 3 , Masafumi Takahashi 1
Affiliation  

Recent evidence indicates ferroptosis is implicated in the pathophysiology of various liver diseases; however, the organ-specific regulation mechanism is poorly understood. Here, we demonstrate 7-dehydrocholesterol reductase (DHCR7), the terminal enzyme of cholesterol biosynthesis, as a regulator of ferroptosis in hepatocytes. Genetic and pharmacological inhibition (with AY9944) of DHCR7 suppress ferroptosis in human hepatocellular carcinoma Huh-7 cells. DHCR7 inhibition increases its substrate, 7-dehydrocholesterol (7-DHC). Furthermore, exogenous 7-DHC supplementation using hydroxypropyl β-cyclodextrin suppresses ferroptosis. A 7-DHC-derived oxysterol metabolite, 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), is increased by the ferroptosis-inducer RSL-3 in DHCR7-deficient cells, suggesting that the ferroptosis-suppressive effect of DHCR7 inhibition is associated with the oxidation of 7-DHC. Electron spin resonance analysis reveals that 7-DHC functions as a radical trapping agent, thus protecting cells from ferroptosis. We further show that AY9944 inhibits hepatic ischemia-reperfusion injury, and genetic ablation of Dhcr7 prevents acetaminophen-induced acute liver failure in mice. These findings provide new insights into the regulatory mechanism of liver ferroptosis and suggest a potential therapeutic option for ferroptosis-related liver diseases.



中文翻译:


抑制 7-脱氢胆固醇还原酶可预防甾醇合成活跃状态下的肝铁死亡



最近的证据表明铁死亡与各种肝脏疾病的病理生理学有关。然而,人们对器官特异性调节机制知之甚少。在这里,我们证明了胆固醇生物合成的末端酶 7-脱氢胆固醇还原酶 (DHCR7) 作为肝细胞铁死亡的调节剂。 DHCR7 的遗传和药理学抑制(使用 AY9944)可抑制人肝细胞癌 Huh-7 细胞的铁死亡。 DHCR7 抑制会增加其底物 7-脱氢胆固醇 (7-DHC)。此外,使用羟丙基β-环糊精补充外源性 7-DHC 可抑制铁死亡。 7-DHC 衍生的氧化甾醇代谢物 3β,5α-二羟基胆固醇-7-en-6-one (DHCEO) 在DHCR7缺陷细胞中被铁死亡诱导剂 RSL-3 增加,表明 DHCR7 缺陷细胞中的铁死亡抑制作用DHCR7 抑制与 7-DHC 的氧化有关。电子自旋共振分析表明,7-DHC 可作为自由基捕获剂,从而保护细胞免遭铁死亡。我们进一步表明,AY9944 可抑制肝脏缺血再灌注损伤,而Dhcr7的基因消除可预防对乙酰氨基酚诱导的小鼠急性肝衰竭。这些发现为肝铁死亡的调节机制提供了新的见解,并为铁死亡相关的肝脏疾病提供了潜在的治疗选择。

更新日期:2024-03-12
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