柠檬苦素抑制凋亡、促进自噬并通过PPARα促进脂肪酸氧化代谢改善非酒精性脂肪性肝病  

Limonin inhibits apoptosis,promotes autophagy and improves non-alcoholic fatty liver disease by promoting oxidative metabolism of fatty acids through PPARα

作　　者：查杨 张丰 周洁 张爽 段亚君 ZHA Yang;ZHANG Feng;ZHOU Jie;ZHANG Shuang;DUAN Ya-jun(School of Food and Biological Engineering,Hefei University of Technology,Hefei 230601,China;The First Affiliated Hospital of USTC(Anhui Provincial Hospital),Hefei 230022,China)

机构地区：[1]合肥工业大学食品与生物工程学院,安徽合肥230601 [2]中国科学技术大学第一附属医院(安徽省立医院),安徽合肥230022

出　　处：《药学学报》2023年第8期2402-2414,共13页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(8217130156);中央高校基本科研业务费专项资金(JZ2023HGTB0288).

摘　　要：非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)是临床上十分常见的慢性肝病,严重的还会进一步发展成肝纤维化、肝硬化甚至肝细胞癌、肝衰竭。柠檬苦素(limonin)是一种天然含呋喃环的三萜类化合物,既往研究发现柠檬苦素具有良好的抗炎镇痛、保护肝脏的功能,然而柠檬苦素对于NAFLD的作用机制尚未明确。基于此,本文采用高脂食物(high fat diet,HFD)喂食C57BL/6J雄性小鼠构建NAFLD模型(实验获得合肥工业大学动物伦理委员会批准,批准号为HFUT20220429001),并添加柠檬苦素以灌胃(i.g.)的给药形式进行治疗。实验结果显示,HFD可以诱导典型的NAFLD表型,包括小鼠肝脏功能受损,脂肪积累增加,血清中天门冬氨酸氨基转移酶(AST)、谷丙转氨酶(ALT)和碱性磷酸酶(ALP)水平上升;给予造模小鼠柠檬苦素(50和100 mg·kg^(-1))10周进行治疗,发现柠檬苦素可以恢复血脂异常并改善小鼠肝细胞内脂肪过度堆积。此外,本研究利用人肝癌细胞系HepG2细胞进行体外实验,发现柠檬苦素能够促进HepG2细胞氧化代谢和自噬相关基因的表达并抑制凋亡;机制上,柠檬苦素通过过氧化物酶体增殖物激活受体α(PPARα)促进氧化代谢基因过氧化物酶体增殖物激活受体γ(PPARγ)的转录辅助活化因子(PGC1α)和肉毒碱棕榈酰基转移酶1α(CPT1α)的表达来改善HFD诱导的NAFLD。以上结果显示,柠檬苦素可以抑制凋亡、促进自噬并通过PPARα促进脂肪酸氧化代谢来改善NAFLD。Non-alcoholic fatty liver disease(NAFLD)is a very common chronic liver disease in clinic,which can further develop into liver fibrosis,cirrhosis,eventually hepatocellular carcinoma and liver failure.Limonin is a natural triterpenoid compound containing furan rings.Previous studies have found that limonin has good antiinflammatory,analgesic and liver protective functions.However,the mechanism of action of limonin on NAFLD has not been clarified.Based on the background,C57BL/6J male mice were fed with high fat diet(HFD)to establish NAFLD model(the experiment was approved by the Animal Ethics Committee of Hefei University of Technology,the approval number is HFUT20220429001),and limonin was added to the mice for administration by intragastric administration(i.g.).The results showed that HFD can induce typical NAFLD phenotypes,including impaired liver function,increased fat accumulation,and increased serum aspartate amino transferase(AST),alanine transaminase(ALT)and alkaline phosphatase(ALP)levels in mice.Mice were treated with limonin(50 and 100 mg·kg^(-1))for 10 weeks,and it was found that limonin could restore dyslipidemia and improve fat accumulation in liver cells of mice.In addition,we conducted in vitro experiments with human hepatoma cell line HepG2 cells,and found that limonin can promote the expression of oxidative metabolism and autophagy related genes and inhibit apoptosis in HepG2 cells.Mechanistically,limonin improves high-fat food-induced NAFLD by promoting the expression of oxidative metabolism genes transcriptional coactivator of peroxisome proliferator activating receptorγ(PPARγ)(PGC1α)and carnitine palmitoyl transferase 1 alpha(CPT1α)through peroxisome proliferator activates receptor alpha(PPARα).These results indicate that limonin can inhibit apoptosis,promote autophagy and improve NAFLD by promoting oxidative metabolism of fatty acids through PPARα.

关 键 词：非酒精性脂肪性肝病 柠檬苦素 过氧化物酶体增殖物激活受体Α 氧化代谢 凋亡 自噬 

分 类 号：R966[医药卫生—药理学]