Maeda Hiroshi, Miura Kouichi, Aizawa Kenichi, Bat-Erdene Oyunjargal, Sashikawa-Kimura Miho, Noguchi Eri, Watanabe Masako, Yamada Naoya, Osaka Hitoshi, Morimoto Naoki, Yamamoto Hironori
Department of Medicine, Division of Gastroenterology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke 329-0498, Tochigi, Japan.
Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke 329-0498, Tochigi, Japan.
Antioxidants (Basel). 2024 Jul 2;13(7):805. doi: 10.3390/antiox13070805.
The role of ferroptosis in steatohepatitis development is largely unknown. We investigated (1) whether hepatocyte ferroptosis occurs in a gene-modified steatohepatitis model without modifying dietary components, (2) whether ferroptosis occurs at an early stage of steatohepatitis, and (3) whether apomorphine, recently reported as a ferroptosis inhibitor, can ameliorate steatohepatitis. Hepatocyte-specific PTEN KO mice were used. Huh 7 and primary cultured hepatocytes isolated from the mice were used in this study. The number of dead cells increased in 10-week-old PTEN KO mice. This cell death was suppressed by the administration of ferroptosis inhibitor ferrostatin-1 for 2 weeks. Apomorphine also ameliorated the severity of steatohepatitis. Treatment with ferroptosis inhibitors, including apomorphine, decreases the level of lipid peroxidase. Apomorphine suppressed cell death induced by RSL-3 (a ferroptosis inducer), which was not suppressed by apoptosis or necroptosis inhibitors. Apomorphine showed a radical trapping capacity with much more potent activity than ferrostatin-1 and Trolox, a soluble form of vitamin E. In addition, apomorphine activated nrf2 and its downstream genes, including HO-1 and xCT. In conclusion, ferroptosis occurs in steatohepatitis from an early stage in PTEN KO mice. In addition, apomorphine ameliorates the severity of steatohepatitis by inhibiting ferroptosis.
铁死亡在脂肪性肝炎发展中的作用很大程度上尚不清楚。我们研究了：（1）在不改变饮食成分的基因修饰脂肪性肝炎模型中，肝细胞铁死亡是否发生；（2）铁死亡是否发生在脂肪性肝炎的早期阶段；（3）最近报道作为铁死亡抑制剂的阿扑吗啡是否能改善脂肪性肝炎。使用了肝细胞特异性PTEN基因敲除小鼠。本研究使用了从小鼠分离出的Huh 7细胞和原代培养肝细胞。10周龄的PTEN基因敲除小鼠中死亡细胞数量增加。给予铁死亡抑制剂铁抑素-1 2周可抑制这种细胞死亡。阿扑吗啡也改善了脂肪性肝炎的严重程度。包括阿扑吗啡在内用铁死亡抑制剂治疗可降低脂质过氧化物酶水平。阿扑吗啡抑制了由RSL-3（一种铁死亡诱导剂）诱导的细胞死亡，而凋亡或坏死性凋亡抑制剂不能抑制这种细胞死亡。阿扑吗啡表现出自由基捕获能力，其活性比铁抑素-1和维生素E的可溶形式Trolox更强。此外，阿扑吗啡激活了nrf2及其下游基因，包括HO-1和xCT。总之，铁死亡在PTEN基因敲除小鼠脂肪性肝炎的早期阶段就已发生。此外，阿扑吗啡通过抑制铁死亡改善了脂肪性肝炎严重程度。
