升降散通过抑制大鼠Akt/mTOR/S6信号通路激活改善高脂饮食诱导的非酒精性脂肪性肝病
Sheng-Jiang Powder Ameliorates High Fat Diet Induced Nonalcoholic Fatty Liver Disease via Inhibiting Activation of Akt/mTOR/S6 Pathway in Rats.
作者信息
Li Juan, Zhu Lv, Zhang Yu-Mei, Chen Huan, Miao Yi-Fan, Kang Hong-Xin, Ren Hong-Yu, Wan Mei-Hua, Long Dan, Tang Wen-Fu
机构信息
Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China.
Key Laboratory of Transplant Engineering and Immunology, Sichuan University, Chengdu 610041, Sichuan Province, China.
出版信息
Evid Based Complement Alternat Med. 2018 Oct 4;2018:6190254. doi: 10.1155/2018/6190254. eCollection 2018.
BACKGROUND AND AIMS
Nonalcoholic fatty liver disease (NAFLD) is an alarming public health problem that directly contributes to increased prevalence of liver cirrhosis and hepatic cell cancer, but without any specific pharmacological option. Sheng-jiang powder (SJP), an empirical Chinese medicine formula to treat NAFLD, showed great efficacy but the specific mechanisms have never been reported. Therefore, we performed this study to explore the effect of SJP on NAFLD and the potential mechanism.
METHODS
NAFLD was induced by high fat diet (HFD) feeding. Rats were treated with SJP/normal saline daily for 10 weeks and all rats were euthanized after 12 weeks' feeding. Liver tissue samples were obtained for biochemistry test and pathological evaluation. Additionally, oleic acid induced LO2 cells were employed to simulate a cell model of NAFLD. Cells were subjected to western blotting for Akt, mTOR, S6, SREBP1-c, and FASN detection after coincubated with SJP, LY294002 (a selective PI3K inhibitor), or the combination for 24h.
RESULTS
HFD significantly induced hepatic steatosis. Plenty of lipid droplets were observed under transmission electron microscope. The ultrastructure of liver cells showed distinct changes with obvious endoplasmic reticulum expansion, mitochondrial contraction, and cell matrix solidification. Although no difference was detected in serum hepatic enzymes and tissue proinflammatory cytokines, the tissue level of SOD and GSH-px was much lower and the pathologic injuries were much severe in HFD feeding rats. However, SJP treatment significantly attenuated the ultrastructure changes and protected rat liver against inflammatory injury. Abundant of lipid droplets and high expression of pAkt, pmTOR, pS6, and FASN were observed in oleic acid treated LO2 cells, while these changes were restored by SJP treatment.
CONCLUSIONS
SJP is efficient in attenuating HFD induced NAFLD in rats and this effect might be partly related to the inhibition of Akt/mTOR/S6 pathway.
背景与目的
非酒精性脂肪性肝病（NAFLD）是一个令人担忧的公共卫生问题，它直接导致肝硬化和肝细胞癌的患病率增加，但目前尚无任何特效药物治疗方案。升降散（SJP）是一种用于治疗NAFLD的经验性中药方剂，已显示出显著疗效，但具体机制尚未见报道。因此，我们开展本研究以探讨SJP对NAFLD的影响及其潜在机制。
方法
通过高脂饮食（HFD）诱导建立NAFLD模型。大鼠每日给予SJP/生理盐水，连续给药10周，喂养12周后全部处死。取肝脏组织样本进行生化检测和病理评估。此外，采用油酸诱导LO2细胞建立NAFLD细胞模型。细胞与SJP、LY294002（一种选择性PI3K抑制剂）或二者联合孵育24小时后，进行蛋白质免疫印迹法检测Akt、mTOR、S6、SREBP1-c和FASN的表达。
结果
HFD显著诱导肝脏脂肪变性。透射电镜下可见大量脂滴。肝细胞超微结构显示出明显变化，内质网明显扩张、线粒体收缩、细胞基质凝固。尽管血清肝酶和组织促炎细胞因子水平未检测到差异，但HFD喂养大鼠的组织超氧化物歧化酶（SOD）和谷胱甘肽过氧化物酶（GSH-px）水平明显降低，病理损伤更严重。然而，SJP治疗显著减轻了超微结构变化，保护大鼠肝脏免受炎症损伤。油酸处理的LO2细胞中观察到大量脂滴以及pAkt、pmTOR、pS6和FASN的高表达，而SJP处理可使其恢复。
结论
SJP可有效减轻HFD诱导的大鼠NAFLD，其作用机制可能部分与抑制Akt/mTOR/S6信号通路有关。
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