减少LONP1表达会通过高酸水平加剧MASH诱导的肝纤维化
Dengqiu Xu1, Zehua Zhang2, Ziqi Zhu3
1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230001, China; Innovative Institute of Tumor Immunity and Medicine (ITIM), Hefei, Anhui, China; Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, Anhui, China; Anhui Provincial Innovation Institute for Pharmaceutical Basic Research, Hefei, Anhui, 230001, China; School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui 230032, China.
线粒体蛋白酶LONP1调节酸代谢,以对抗代谢功能障碍相关的脂肪肝炎 (MASH) 中的肝纤维化. 准LONP1或耳酸显示MASH诱导的肝纤维化治疗潜力.
科学领域:
- 线粒体生物学 线粒体生物学
- 代谢途径 代谢途径
- 肝病的发病因子 肝病的发病因子
背景情况:
- 代谢功能障碍相关的脂肪肝炎 (MASH) 涉及肝纤维化,但潜在的代谢驱动因素尚不清楚.
- 线粒体蛋白酶LONP1 (Lon peptidase 1) 对于线粒体质量控制至关重要.
- 了解LONP1在MASH代谢重新连接中的作用是治疗开发的关键.
研究的目的:
- 为了研究LONP1如何影响MASH诱导的肝纤维化中的线粒体代谢.
- 阐明将LONP1与代谢失调和纤维化有关的分子机制.
主要方法:
- 利用肝纤维化和肝细胞特异性Lonp1淘汰小鼠的小鼠模型.
- 分析了MASH患者的肝脏活检.
- 使用转录组学,蛋白组学和代谢组学来识别促进纤维化的代谢物.
主要成果:
- 在MASH患者和小鼠中观察到LONP1表达的减少.
- 由于LONP1缺乏,导致二基酸脱酶 (DHODH) 积累,耳酸升高,纤维化恶化.
- LONP1降解了DHODH,降低了耳酸,并通过ATF3.3抑制了肝星细胞激活.
- 血中耳酸水平与MASH患者的肝脏LONP1相反相关,与纤维化相对正相关.
结论:
- 在MASH中,LONP1-DHODH相互作用是耳酸代谢的关键调节者.
- 这一途径可以缓解MASH诱导的肝纤维化.
- 向肝细胞LONP1或耳酸是MASH的潜在治疗策略.
更多相关视频
10:42Development of an Ethanol-induced Fibrotic Liver Model in Zebrafish to Study Progenitor Cell-mediated Hepatocyte Regeneration
Published on: May 13, 2016
07:03Author Spotlight: Establishing MASLD Cell Models for Investigating Disease Mechanisms and the Lipid-Lowering Effects of Koumiss
Published on: July 19, 2024
