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肝细胞应激防御剂,Nrf1和Nrf2,对MASLD进展的保护作用

May G Akl¹, Lei Li¹, Scott B Widenmaier¹

¹Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada.

International journal of molecular sciences

|August 10, 2024

概括

核因素红色素2相关因子-1 (Nrf1) 延迟了代谢功能障碍相关的脂肪炎肝病 (MASLD) 的进展,而Nrf2诱导缓解了脂肪肝炎 (MASH). 联合增强提供了对肝脏脂肪的协同保护,并有助于修复.

科学领域:

肝病学和分子生物学.
肝脏疾病研究肝脏疾病研究
转录因子函数的功能.

背景情况:

代谢功能障碍相关的脂肪炎肝病 (MASLD) 可以发展为脂肪肝炎 (MASH),其特征是脂质诱导的炎症,纤维化和潜在的进展到肝硬化和肝细胞癌.
核因子红色素2相关因子-1 (Nrf1) 和-2 (Nrf2) 是转录因子,之前已经证明它们可以调节对肝脂应激的协调防御.

研究的目的:

研究肝细胞特异性Nrf1和Nrf2对MASH相关肝纤维化和瘤发生的保护作用.
评估Nrf1和Nrf2诱导对肝纤维化和MASH进展的影响.

主要方法:

具有Nrf1 (Nfe2l1),Nrf2 (Nfe2l2) 或两者的合基因的小鼠在24-52周内接受了MASH诱导饮食 (高脂肪,果糖,胆固醇) 或控制饮食.
使用腺相关病毒 (AAV) -Cre诱导肝细胞特异性基因缺陷,并评估对MASH,纤维化,增殖和瘤发生的影响.
在C57bl/6J小鼠中进一步研究了肝纤维化,这些小鼠接受了四化碳和HFFC饮食治疗,干预措施包括Nrf2激活 (bardoxolone) 和Nrf1过度表达 (hNRF1).

主要成果:

诱导MASH的饮食增加了身体和肝脏的体重,肥胖症,炎症和肝细胞的增殖.
肝细胞 Nrf1 缺乏会增加肥胖症和炎症,而联合缺乏会增加炎症和肝损伤标志物.
肝细胞 Nrf1 缺乏,但不是综合缺乏,导致 52 周食 HFFC 饮食的雄性小鼠出现更多的肝瘤.
在饮食诱导和毒素诱导的肝损伤模型中,使用bardoxolone诱导nrf2可降低脂肪酸,炎症,纤维化和增殖.
肝Nrf1诱导增强了bardoxolone对肥胖症的影响,并且可能刺激了肝脏前代细胞.

结论:

生理Nrf1活动延迟了MASLD的进展.
Nrf2诱导可以缓解MASH.
联合增强Nrf1和Nrf2可以协同保护免受肥胖症,并可能促进肝脏的修复.

关键词:

在HCC中,HCC是HCC,HCC是HCC.马什 (MASH) 是一个非常重要的产品.马斯尔德马斯尔德是什么意思第1章没有了 Nrf2 没有任何问题.肝脏纤维化肝脏纤维化

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