Yao You-Li, Han Xin, Song Jian, Zhang Jing, Li Ya-Mei, Lian Li-Hua, Wu Yan-Ling, Nan Ji-Xing
Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
Key Laboratory for Natural Resource of Changbai Mountain & Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji 133002, Jilin Province, China.
Toxicol Lett. 2017 Nov 5;281:127-138. doi: 10.1016/j.toxlet.2017.09.020. Epub 2017 Sep 28.
The aim of this study was to investigate the effects of acanthoic acid (AA) on the regulation of inflammatory response, lipid accumulation, and fibrosis via AMPK- IRAK4 signaling against chronic alcohol consumption in mice. Ethanol-induced liver injury was induced in male mice by Lieber-DeCarli diet for 28d. And mice in AA groups were gavaged with AA (20 or 40mg/kg) for 28d. AA treatment significantly decreased serum AST and TG, hepatic TG levels, serum ethanol and LPS levels compared with chronic ethanol administration. AA ameliorated histological changes, lipid droplets, hepatic fibrosis, and inflammation induced by ethanol. AA significantly increased the expressions of p-LKB1, p-AMPK, and SIRT1 caused by chronic ethanol administration, and attenuated the increasing protein expressions of IRAK1 and IRAK4.siRNA against AMPKα1 blocked AMPKα1 and increased IRAK4 protein expressions, compared with control-siRNA-transfected group, while AA treatment significantly decreased IRAK4 expressions compared with AMPKα1-siRNA-transfected group. AMPK-siRNA also blocked the decreased effect of AA on inflammatory factors. AA decreased over-expression of IRAK4 and inflammation under ethanol plus LPS challenge. AA recruited LKB1-AMPK phosphorylation and activated SIRT1 to regulate alcoholic liver injury, especially, inhibited IRAK1/4 signaling pathway to regulate lipid metabolism, hepatic fibrosis and inflammation caused by alcohol consumption.
本研究旨在探讨刺鼠酸（AA）通过AMPK-IRAK4信号通路对慢性酒精摄入小鼠炎症反应、脂质蓄积和纤维化调节的影响。采用Lieber-DeCarli饮食诱导雄性小鼠乙醇性肝损伤28天。AA组小鼠给予AA（20或40mg/kg）灌胃28天。与慢性乙醇给药相比，AA治疗显著降低了血清AST和TG、肝TG水平、血清乙醇和LPS水平。AA改善了乙醇诱导的组织学变化、脂滴、肝纤维化和炎症。AA显著增加了慢性乙醇给药引起的p-LKB1、p-AMPK和SIRT1的表达，并减弱了IRAK1和IRAK4蛋白表达的增加。与对照-siRNA转染组相比，针对AMPKα1的siRNA阻断了AMPKα1并增加了IRAK4蛋白表达，而与AMPKα1-siRNA转染组相比，AA治疗显著降低了IRAK4表达。AMPK-siRNA也阻断了AA对炎症因子的降低作用。在乙醇加LPS刺激下，AA降低了IRAK4的过表达和炎症。AA募集LKB1-AMPK磷酸化并激活SIRT1以调节酒精性肝损伤，特别是抑制IRAK1/4信号通路以调节酒精消费引起的脂质代谢、肝纤维化和炎症。
