Salidroside alleviates lipotoxicity-induced cell death through inhibition of TLR4/MAPKs pathway, and independently of AMPK and autophagy in AML-12 mouse hepatocytes
Salidroside alleviates lipotoxicity-induced cell death through inhibition of TLR4/MAPKs pathway, and independently of AMPK and autophagy in AML-12 mouse hepatocytes
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Salidroside 通过抑制 TLR4/MAPKs 通路，独立于 AMPK 和 AML-12 小鼠肝细胞自噬，减轻脂毒性诱导的细胞死亡
DOI：
10.1016/j.jff.2019.103691
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发表时间：
2020-02-01
影响因子：
5.6
通讯作者：
Li, Songtao
中科院分区：
文献类型：
--
作者：
Dou, Xiaobing;Ding, Qinchao;Li, Songtao
脂毒性在非酒精性脂肪性肝病（NAFLD）的发病机制中起着有害的作用。红景天苷（Salidroside，Sal）是从红景天中提取的一种苯丙素苷，具有抗高脂饮食诱导的肝损伤的作用。然而，其潜在机制仍不清楚。本研究旨在探讨盐抑制脂毒性的作用机制。我们的研究表明，Sal以剂量依赖性方式显著逆转棕榈酸诱导的AML-12小鼠肝细胞损伤，并伴有氧化应激和线粒体损伤的改善。机制分析表明，Sal通过逆转TLR 4/MAPK（包括JNK，p38和ERK 1/2）和p53激活来保护肝脏脂毒性，独立于自噬，AMPK和Akt途径。此外，TLR 4抑制也有助于红景天苷减少脂质沉积。总之，该研究清楚地证明了Sal对脂毒性诱导的肝细胞死亡的保护作用，其通过下调肝细胞中的TLR 4/MAPKs途径介导。我们得出结论，Sal是治疗NAFLD的潜在候选者。
Lipotoxicity plays a detrimental role in the pathogenesis of non-alcoholic fatty liver diseases (NAFLD). Salidroside (Sal), a phenylpropanoid glycoside extracted from Rhodiola rosea L, conferred resistance to high-fat diet-induced liver injury. However, the underlying mechanisms are still unclear. This study aimed at investigating Sal-inhibited lipotoxicity and clarify its potential mechanisms. Our study indicated that Sal significantly reversed palmitic acids-induced injury in dose-dependent manner in AML-12 mouse hepatocytes, accompanied with improvement of oxidative stress and mitochondrial damage. Mechanistic analysis revealed that Sal protected hepatic lipotoxicity via reversing TLR4/MAPKs (including JNK, p38, and ERk1/2) and p53 activation, independent from autophagy, AMPK, and Akt pathways. Moreover, TLR4 inhibition also contributed to salidroside-reduced lipids deposition. In sum, this research clearly demonstrated the protective effects of Sal against lipotoxicity-induced hepatic cell death, which was mediated by downregulation of TLR4/MAPKs pathways in hepatocytes. We conclude that Sal is a potential candidate for the treatment of NAFLD.