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辛纳巴林酸通过激活依赖于酸碳化合物受体的AMPK信号传导来防止与代谢功能障碍相关的脂肪肝炎
Nikhil Y Patil1, Iulia Rus1, Felix Ampadu1
1Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States.
概括
辛纳巴林酸 (CA) 通过激活肝细胞中的酸碳水化合物受体 (AhR) 来防止与代谢功能障碍相关的脂肪肝炎 (MASH). 这一途径对于减少MASH中的肝脂肪,炎症和纤维化至关重要.
科学领域:
- 肝病学和代谢疾病
- 分子生物学和信号通路
- 药理学和治疗学 药理学和治疗学
背景情况:
- 代谢功能障碍相关的脂肪肝炎 (MASH) 是一种严重的肝脏疾病,其特点是脂肪积累,炎症和纤维化.
- 在MASH的发病和治疗中,肝脏的阿里碳化合物受体 (AhR) 信号的作用仍然不完全理解.
研究的目的:
- 调查肝脏AhR信号传递在巴氨酸 (CA) 介导的MASH防护中的重要性.
- 阐明CA在MASH中的治疗效果背后的分子机制.
主要方法:
- 使用肝细胞特异性AhR淘汰赛小鼠 (AhR-hKO) 养高脂肪,高果糖,高胆固醇饮食.
- 给药的青酸 (CA),以评估其对AhR-hKO和对照小鼠MASH特征的影响.
- 采用了体外人类肝细胞模型来证实CA对脂毒性的保护作用.
主要成果:
- 缺少肝脏AhR加剧MASH,包括肥胖症,炎症和纤维化.
- 在AhR-floxed小鼠中,CA治疗显著减弱了MASH特征,但在AhR-hKO小鼠中没有,这证实了AhR依赖性.
- 由CA激活的AhR信号调节AMPK和PGC1α,同时降低SREBP1,从而改善肝脂代谢.
结论:
- 肝脏AhR信号传递对于CA介导的MASH防护至关重要.
- CA的治疗作用包括通过AhR-AMPK-PGC1α-SREBP1轴调节脂质代谢.
- 用选择性激动剂向肝脏AhR代表了对MASH和MASLD的有希望的治疗策略.
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