Atractylenolide III ameliorates Non-Alcoholic Fatty Liver Disease by activating Hepatic Adiponectin Receptor 1-Mediated AMPK Pathway.
Atractylenolide III ameliorates Non-Alcoholic Fatty Liver Disease by activating Hepatic Adiponectin Receptor 1-Mediated AMPK Pathway.
复制标题
阿曲肽III通过激活肝脂联素受体1介导的AMPK通路改善非酒精性脂肪肝。
DOI：
10.7150/ijbs.68873
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发表时间：
2022
影响因子：
9.2
通讯作者：
Li M
中科院分区：
文献类型：
--
作者：
Li Q;Tan JX;He Y;Bai F;Li SW;Hou YW;Ji LS;Gao YT;Zhang X;Zhou ZH;Yu Z;Fang M;Gao YQ;Li M
背景：非酒精性脂肪肝（NAFLD）是全球慢性肝脏疾病最常见的原因。目前，除了生活方式干预介导的体重减轻外，没有有效的药物治疗NAFLD。青蒿素III（ATL III）是在马兜铃中发现的主要生物活性成分，已被证明具有抗氧化、抗肿瘤、抗过敏反应、抗菌作用和认知保护作用。在这里，我们研究ATL III治疗NAFLD的治疗潜力和潜在机制。方法：雄性C57 BL/6 J小鼠喂食高脂饮食（HFD）并用ATL III处理。通过油红O染色分析肝组织和游离脂肪酸（FFA）处理的肝细胞中的脂质蓄积。AMP活化蛋白（AMPK）和沉默调节蛋白1（SIRT 1）信号通路分别在体外被化合物C和EX 527抑制。采用小干扰RNA（siRNA）技术，抑制HepG 2细胞脂联素受体1（AdipoR 1）的表达。结果如下：ATL III治疗改善了HFD诱导的NAFLD小鼠模型中的肝损伤和肝脂质积累，如通过ATL III施用显著降低丙氨酸转氨酶、谷草转氨酶、甘油三酯、总胆固醇和低密度脂蛋白的血清水平所证明的。此外，用ATL III治疗减轻了HFD喂养模型中的肝氧化应激、炎症和纤维化。为了研究潜在的机制，我们进行了计算机辅助设计分析，发现开放型AdipoR 1和脂联素受体2是ATL III靶向的潜在受体。有趣的是，HFD喂养或FFA治疗仅降低肝脏AdipoR 1表达，而ATL III给药消除了这种降低。此外，在体外用ATL III处理激活AdipoR 1下游AMPK /SIRT 1信号通路，并减少HepG 2细胞中的脂质沉积，这通过沉默AdipoR 1而减少。最后，抑制AMPK或SIRT 1，AdipoR 1下游信号，消除ATL III对FFAs处理的HepG 2细胞中脂质沉积和氧化应激的保护作用。结论：我们的研究结果表明ATL III是一种治疗NAFLD的药物，这种保护作用是通过激活肝脏AdipoR 1介导的AMPK/SIRT 1信号通路介导的。
Background: Nonalcoholic fatty liver disease (NAFLD) is the most frequent cause of chronic liver diseases worldwide. At present, there are no effective pharmacological therapies for NAFLD except lifestyle intervention-mediated weight loss. Atractylenolide III (ATL III), the major bioactive component found in Atractylode smacrocephala Koidz, has been shown to exert anti-oxidant, anti-tumor, anti-allergic response, anti-bacterial effects and cognitive protection. Here we investigate the therapeutic potential and underlying mechanisms of ATL III for the treatment of NAFLD. Methods: Male C57BL/6J mice were fed a high-fat diet (HFD) and treated with ATL III. Lipid accumulation was analyzed by Oil Red O staining in liver tissues and free fatty acids (FFAs)-treated hepatocytes. AMP-activated protein (AMPK) and sirtuin 1(SIRT1) signaling pathways were inhibited by Compound C and EX527 in vitro, respectively. Small-interfering RNA (siRNA) was used to knockdown adiponectin receptor 1 (AdipoR1) expression in HepG2 cells. Results: ATL III treatment ameliorated liver injury and hepatic lipid accumulation in the HFD-induced NAFLD mouse model as demonstrated by that ATL III administration significantly reduced serum levels of alanine aminotransferase, glutamic oxaloacetic transaminase, triglycerides, total cholesterol and low-density lipoprotein. Furthermore, treatment with ATL III alleviated hepatic oxidative stress, inflammation and fibrosis in the HFD feeding model. To study the underlying mechanisms, we performed Computer Aided Design assay and found that open-formed AdipoR1 and adiponectin receptor 2 were the potential receptors targeted by ATL III. Interestingly, HFD feeding or FFAs treatment only reduced hepatic AdipoR1 expression, while such reduction was abolished by ATL III administration. In addition, in vitro treatment with ATL III activated the AdipoR1 downstream AMPK /SIRT1 signaling pathway and reduced lipid deposition in HepG2 cells, which was diminished by silencing AdipoR1. Finally, inhibition of AMPK or SIRT1, the AdipoR1 downstream signaling, abolished the protective effects of ATL III on lipid deposition and oxidative stress in FFAs-treated HepG2 cells. Conclusion: Our findings suggest that ATL III is a therapeutic drug for the treatment of NAFLD and such protective effect is mediated by activating hepatic AdipoR1-mediated AMPK/SIRT1 signaling pathway.
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影响因子：
14.9
作者：
Kim S;Thiessen PA;Bolton EE;Chen J;Fu G;Gindulyte A;Han L;He J;He S;Shoemaker BA;Wang J;Yu B;Zhang J;Bryant SH
通讯作者：
Bryant SH
影响因子：
5.7
作者：
Liao, Jung-Chun;Chang, Wen-Te;Peng, Wen-Huang
通讯作者：
Peng, Wen-Huang
影响因子：
3
作者：
Hajighasem, Amir;Farzanegi, Parvin;Mazaheri, Zohreh
通讯作者：
Mazaheri, Zohreh
影响因子：
6.5
作者：
Gaidhu, Mandeep P.;Fediuc, Sergiu;Ceddia, Rolando B.
通讯作者：
Ceddia, Rolando B.
影响因子：
29.4
作者：
Imamura, M;Ogawa, T;Ueno, H
通讯作者：
Ueno, H