对酒精诱导肝纤维化的雄激素影响由依赖口的表观遗传开关控制
Kruti Nataraj1, Michael Schonfeld1, Adriana Rodriguez1
1Department of Internal Medicine, Kansas City VA Medical Center, Kansas City, Missouri.
Cellular and molecular gastroenterology and hepatology
|September 30, 2024
概括
男性性激素可以通过抑制Notch信号来恶化酒精相关性肝病 (ALD),但在KDM5脱甲基酶存在时可以防止纤维化. 这突出了KDM5的亮点.
科学领域:
- 表观遗传学和分子生物学
- 肝病学和肝脏疾病研究研究
- 内分泌学和性激素信号传递
背景情况:
- 与酒精相关的肝病 (ALD) 是死亡的一个重要原因.
- 人们已经认识到ALD的性别差异,但潜在的机制仍然不清楚.
- KDM5脱甲基酶和男性性激素与肝病进展有关.
研究的目的:
- 研究KDM5B/KDM5C脱甲基酶和男性性激素在ALD中的作用.
- 阐明肝纤维化的性别差异背后的表观遗传机制.
- 为了确定Notch信号在激素介导性肝病中的参与.
主要方法:
- 患有Kdm5b/Kdm5c淘汰的雄性小鼠接受了淋巴切除术或假手术.
- 给小鼠食含有酒精的西方饮食,并使用AAV8-CMV-Cre进行基因淘汰.
- 诺奇抑制剂avagacestat被用于评估其在纤维化中的作用.
主要成果:
- KDM5B/KDM5C淘汰赛加剧了酒精诱导的肝病;淋巴切除术扭转了这种影响.
- 男性性激素在KDM5缺乏的小鼠中促进了肝纤维化,但在其他情况下是保护性的.
- KDM5B水平调节了雄激素受体在纤维化中的作用,由KDM5-依赖的Notch抑制介导.
结论:
- 男性性激素对肝纤维化的信号效应取决于KDM5的表观遗传状态.
- KDM5脱甲基酶通过Notch信号调节丸激素对肝星细胞激活的影响.
- 准痕信号可能为具有特定表观遗传特征的ALD提供治疗策略.
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