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.

脂毒性在非酒精性脂肪肝疾病（NAFLD）的发病机理中起有害作用。红景天苷（Sal）是一种从玫瑰红景天提取的苯丙糖苷，对高脂饮食诱导的肝损伤具有抵抗力。但是，其潜在机制仍不清楚。这项研究旨在调查Sal抑制脂毒性，并阐明其潜在的机制。我们的研究表明，Sal以剂量依赖性方式显着逆转了棕榈酸诱导的AML-12小鼠肝细胞损伤，同时改善了氧化应激和线粒体损伤。机理分析表明，Sal通过逆转TLR4 / MAPKs（包括JNK，p38和ERk1 / 2）和p53激活来保护肝脂毒性，而与自噬，AMPK和Akt途径无关。而且，TLR4抑制也有助于红景天苷减少脂质的沉积。总而言之，这项研究清楚地证明了Sal对脂毒性诱导的肝细胞死亡的保护作用，这是由肝细胞中TLR4 / MAPKs通路的下调介导的。我们得出的结论是，Sal是治疗NAFLD的潜在候选人。