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脂质氧化和肝纤维化通过ENPP1 mRNA m6A修改的表皮转录学调节
Feng Sun1,2, Juan Wang1,2, Yang Yang3
1Department of Clinical Pharmacology, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, China.
Cellular and molecular life sciences : CMLS
|September 9, 2024
概括
不调节的脂质氧化驱动肝纤维化,通过促进肝星细胞的增殖. 威尔姆斯瘤1关联蛋白 (WTAP) 通过甲基化乙核酸酸酶/化酶 (ENPP1) mRNA来增强这一过程,从而增加脂质氧化.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 肝病学 肝病学是一种肝病学.
背景情况:
- 不调节的脂质氧化与病态细胞增殖和迁移有关.
- 肝纤维化中脂质氧化的精确分子机制仍然不清楚,尽管纤维细胞活性增加.
研究的目的:
- 阐明脂质氧化在肝纤维化中的作用和调节机制.
- 调查参与肝星细胞增殖和肝纤维化期间迁移的分子参与者.
主要方法:
- 利用细胞培养,动物模型和人类临床样本来研究肝纤维化.
- 研究了ecto-核酸酸酶/化酶 (ENPP1),威尔姆斯瘤1关联蛋白 (WTAP) 和N6-甲基氨酸 (m6A) 修饰的表达和功能.
主要成果:
- 增加ENPP1表达增加了脂质氧化,促进肝星细胞 (HSC) 增殖和迁移,导致肝纤维化.
- 通过WTAP介导的ENPP1mRNA的m6A甲基化增强了通过YTH域家族蛋白1 (YTHDF1) 的翻译.
- ENPP1直接与HILPDA相互作用,放大脂质氧化和高质细胞活性;相反,ENPP1抑制逆转了这些效应. 在人类纤维性肝组织中观察到WTAP,YTHDF1,ENPP1,HILPDA,m6A和脂质氧化水平升高.
结论:
- 一个涉及WTAP催化ENPP1的m6A甲基化,依赖于YTHDF1的新途径增强了脂质氧化.
- 这种机制促进HSC的增殖和迁移,有助于肝纤维化病变.
- 这些发现突出了通过调节脂质氧化通路来治疗肝纤维化的新治疗点.
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