摘要
非酒精性脂肪性肝病是一种临床病理综合症,其特征在于无过量饮酒史情况下肝实质发生脂肪变性和脂肪储存。线粒体功能障碍是非酒精性脂肪性肝病发生发展的关键病机,主要包括肝细胞线粒体形态学改变、线粒体DNA损伤、能量代谢异常、氧化应激与脂质过氧化、线粒体主导的肝细胞凋亡、脂肪酸代谢紊乱、线粒体自噬异常。尽管目前尚缺乏治疗非酒精性脂肪性肝病的特效药物,但很多中药可通过调节线粒体功能而加以缓解,并具有副作用低、疗效稳定、多途径作用、作用温和持久等优势。本文就线粒体与非酒精性脂肪性肝病关系,以及中药对其缓解作用进行概述,并对未来研究方向进行展望。
引文
[1]Bedogni G,Miglioli L,Masutti F,et al.Prevalence of and risk factors for nonalcoholic fatty liver disease:the dionysos nutrition and liver study[J].Hepatology,2005,42(1):44-52.
[2]谷玲霞.脂肝方对非酒精性脂肪肝大鼠线粒体的影响[D].广州:广州中医药大学,2010.
[3]Sunny N E,Bril F,Cusi K.Mitochondrial adaptation in nonalcoholic fatty liver disease:novel mechanisms and treatment strategies[J].Trends Endocrinol Metab,2017,28(4):250-260.
[4]Grattagliano I,de Bari O,Bernardo T C,et al.Role of mitochondria in nonalcoholic fatty liver disease from origin to propagation[J].Clin Biochem,2012,45(9):610-618.
[5]Liu X X,Zhang J,Ming Y,et al.The aggravation of mitochondrial dysfunction in nonalcoholic fatty liver disease accompanied with type 2 diabetes mellitus[J].Scand J Gastroenterol,2015,50(9):1152-1159.
[6]Begriche K,Massart J,Robin M A,et al.Mitochondrial adaptations and dysfunctions in nonalcoholic fatty liver disease[J].Hepatology,2013,58(4):1497-1507.
[7]王爽,黄晓峰,尹文,等.非酒精性脂肪肝病肝组织超微结构特点[J].现代生物医学进展,2012,12(14):2703-2705.
[8]李兆翌,田静,施军平,等.复方楂金颗粒(CZJG)对非酒精性脂肪肝大鼠脂质代谢及肝细胞超微结构的影响[J].中华中医药学刊,2016,34(5):1176-1179.
[9]Kamfar S,Alavian S M,Houshmand M,et al.Liver mitochondrial DNA copy number and deletion levels may contribute to nonalcoholic fatty liver disease susceptibility[J].Hepat Mon,2016,16(12):e40774.
[10]Andreux P A,Houtkooper R H,Auwerx J.Pharmacological approaches to restore mitochondrial function[J].Nat Rev Drug Discov,2013,12(6):465-483.
[11]Sanyal A J,Campbell-Sargent C,Mirshahi F,et al.Nonalcoholic steatohepatitis:association of insulin resistance and mitochondrial abnormalities[J].Gastroenterology,2001,120(5):1183-1192.
[12]康敏,钟德君,李鹏,等.线粒体损伤对NAFL大鼠肝细胞凋亡的影响[J].山东医药,2010,50(17):22-24.
[13]Caldwell S H,Hespenheide E E,Redick J A,et al.A pilot study of a thiazolidinedione,troglitazone,in nonalcoholic steatohepatitis[J].Am J Gastroenterol,2001,96(2):519-525.
[14]Perez-Carreras M,Del Hoyo P,Martin M A,et al.Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis[J].Hepatology,2003,38(4):999-1007.
[15]殷杰,李万平.非酒精性脂肪肝的发病机制研究进展[J].四川生理科学杂志,2012,34(3):126-130.
[16]马文科,戴舒惠,罗鹏,等.线粒体自噬的研究进展[J].现代生物医学进展,2017,17(6):1176-1179.
[17]刘洹洹,王志舒,谭晓荣.线粒体自噬与人类疾病[J].中国生物化学与分子生物学报,2015,31(5):466-472.
[18]Williams J A,Ding W X.A mechanistic review of mitophagy and its role in protection against alcoholic liver disease[J].Biomolecules,2015,5(4):2619-2642.
[19]Eid N,Ito Y,Otsuki Y.Triggering of parkin mitochondrial translocation in mitophagy:implications for liver diseases[J].Front Pharmacol,2016,7:100.
[20]王超臣,张培建.线粒体自噬在肝相关疾病中的作用[J].中华普通外科学文献(电子版),2013,7(5):397-399.
[21]王毓洁.保和丸及保和丸加虎杖对大鼠非酒精性脂肪性肝炎的防治作用及部分机制[D].合肥:安徽医科大学,2010.
[22]罗闳丹.四逆散对小鼠非酒精性脂肪性肝炎的防治作用及机制的研究[D].长沙:湖南中医药大学,2014.
[23]石磊,杨鹏,郭舜,等.二陈汤对非酒精性脂肪肝CYP2E1及线粒体能量代谢的影响[J].中国药师,2017,20(2):205-207,224.
[24]曾兰,盛国光,王平,等.疏肝健脾、化痰活血方对非酒精性脂肪性肝病体外细胞模型线粒体脂质过氧化的影响[J].湖北中医杂志,2011,33(4):7-8.
[25]赵文霞.化痰祛湿活血方治疗非酒精性脂肪性肝炎的临床研究及作用机制探讨[D].南京:南京中医药大学,2012.
[26]杨成志,狄灵,聂丹丽,等.肝舒汤对非酒精性脂肪肝大鼠脂质过氧化的影响[J].西安交通大学学报(医学版),2008,29(3):336-339.
[27]洪素兰,崔姗姗,张惠娟,等.肝舒乐片对非酒精性脂肪肝大鼠肝细胞线粒体能量代谢的影响[J].世界中西医结合杂志,2010,5(2):111-113,116.
[28]贾学平.肝脂康胶囊防治非酒精性脂肪肝的实验研究[D].武汉:湖北中医学院,2003.
[29]张传涛,周道杰,杨鸿,等.加味楂曲饮对实验性非酒精性脂肪性肝病大鼠FATP4、UCP2、COXⅠ的影响[J].时珍国医国药,2014,25(6):1505-1507.
[30]娄永强.健脾疏肝降脂方对非酒精性脂肪肝小鼠血脂及肝组织病理学的影响[D].郑州:河南中医学院,2015.
[31]张玲燕,李民,邵建国,等.清脂护肝方对非酒精性脂肪肝大鼠肝组织病理及纤维化指标的影响[J].上海中医药杂志,2013,47(8):78-81.
[32]农朝雷,陈威.调肝祛脂方介导PI3K/Akt-m TOR通路干预非酒精性脂肪肝的实验研究[J].中国中医药科技,2013,20(2):119-121,104.
[33]魏翠萍.消瘀化痰饮对非酒精性脂肪肝大鼠肝组织UCP2表达的影响[D].石家庄:河北医科大学,2008.
[34]姬爱冬,李立,余轶群,等.益肾调肝方对非酒精性脂肪性肝炎大鼠线粒体的调控作用研究[J].中国实验方剂学杂志,2009,15(9):61-63.
[35]张渐轩,陈雁,李柳梅,等.脂肝方对NASH肝细胞自噬、线粒体及其能量代谢的影响[J].广西中医药大学学报,2017,20(2):1-4.
[36]党中勤,崔瑛,赵会茹,等.十味肝脂康胶囊对脂肪肝大鼠肝组织生化学及超微结构影响[J].中华中医药学刊,2007,25(11):2354-2356.
[37]程聪.葱白提取物对非酒精性脂肪性肝病脂质过氧化影响的临床观察和实验研究[D].武汉:湖北中医药大学,2013.
[38]赵旦博.蓝莓对非酒精性脂肪性肝病大鼠Nqo1、GCLC、UPC-2表达的影响[D].贵阳:贵州医科大学,2016.
[39]卢岩松,田青山,王晶宇,等.柳茶提取物对非酒精性脂肪肝大鼠脂质代谢的影响[J].中药新药与临床药理,2011,22(1):40-43.
[40]林献威,林贯川,马文丽,等.石榴皮对非酒精性脂肪肝病的基因表达调控数据分析[J].中药材,2017,40(1):171-176.
[41]Xu J Y,Zhang L,Li Z P,et al.Natural products on nonalcoholic fatty liver disease[J].Curr Drug Targets,2015,16(12):1347-1355.
[42]潘磊.中药蛤蚧对非酒精性脂肪肝内质网应激的影响分析[J].解放军医药杂志,2016,28(3):85-87,116.
[43]谢慧臣,刘芬,罗丽华,等.延龄草提取物抗非酒精性脂肪肝作用及对肝细胞超微结构的影响[J].中成药,2017,39(4):817-821.
[44]Müller C,Gardemann A,Keilhoff G,et al.Prevention of free fatty acid-induced lipid accumulation,oxidative stress,and cell death in primary hepatocyte cultures by a Gynostemma pentaphyllum extract[J].Phytomedicine,2012,19(5):395-401.
[45]鲁超.虫草多糖对非酒精性脂肪性肝炎的预防作用及部分机制研究[D].合肥:安徽医科大学,2005.
[46]邹宇宏.豹皮樟总黄酮对非酒精性脂肪性肝炎预防作用及部分机制[D].合肥:安徽医科大学,2006.
[47]王焱.橙皮苷对大鼠非酒精性脂肪肝脂质代谢和炎症反应的影响及部分机制的研究[D].合肥:安徽医科大学,2010.
[48]曾祥龙,杨济宁,易龙,等.二氢杨梅素通过调控SIRT3通路调节线粒体功能改善非酒精性脂肪肝[C]//中国营养学会第十三届全国营养科学大会暨全球华人营养科学家大会论文汇编.北京:中国营养学会,2017:496.
[49]杨子平,包怡敏.三七总皂苷对线粒体调控作用的研究进展[J].中国中药杂志,2017,42(5):870-874.
[50]陆新烈,袁建芬,徐建立,等.大黄酸对非酒精性脂肪性肝病大鼠肝脏病理组织学及超微结构变化的影响[J].中国中医药科技,2013,20(5):477-478.
[51]张霖.虎杖苷对非酒精性脂肪肝保护作用及机制研究[D].广州:南方医科大学,2010.
[52]宋春艳.槐果碱对非酒精性脂肪性肝炎防治作用的实验研究[D].上海:第二军医大学,2009.
[53]常珊珊,王爽,吴锋,等.灵芝多糖对非酒精性脂肪肝大鼠PPARγ和环氧合酶-2表达的影响[J].交通医学,2013,27(1):9-13.
[54]Tsai S Y,Chung P C,Owaga E E,et al.Alpha-mangostin from mangosteen(Garcinia mangostana Linn.)pericarp extract reduces high fat-diet induced hepatic steatosis in rats by regulating mitochondria function and apoptosis[J].Nutr Metab(Lond),2016,13:88-98.
[55]Wang L,Lv Y,Yao H,et al.Curcumin prevents the non-alcoholic fatty hepatitis via mitochondria protection and apoptosis reduction[J].Int J Clin Exp Pathol,2015,8(9):11503-11509.
[56]Wang Y C,Kong W Z,Jin Q M,et al.Effects of salvianolic acid B on liver mitochondria of rats with nonalcoholic steatohepatitis[J].World J Gastroenterol,2015,21(35):10104-10112.
[57]Zou X,Yan C,Shi Y,et al.Mitochondrial dysfunction in obesity-associated nonalcoholic fatty liver disease:the protective effects of pomegranate with its active component punicalagin[J].Antioxid Redox Signal,2014,21(11):1557-1570.
[58]Poulsen M M,Larsen J,Hamilton-Dutoit S,et al.Resveratrol up-regulates hepatic uncoupling protein 2 and prevents development of nonalcoholic fatty liver disease in rats fed a highfat diet[J].Nutr Res,2012,32(9):701-708.
[59]Xin H G,Zhang B B,Wu Z Q,et al.Treatment with baicalein attenuates methionine-choline deficient diet-induced non-alcoholic steatohepatitis in rats[J].Eur J Pharmacol,2014,738:310-318.
[60]Chen Q,Wang T T,Li J,et al.Effects of natural products on fructose-induced nonalcoholic fatty liver disease(NAFLD)[J].Nutrients,2017,9(96):1-12.
[61]Yang X X,Xu F,Wang D,et al.Development of a mitochondria-based centrifugal ultrafiltration/liquid chromatography/mass spectrometry method for screening 10 mitochondria-targeted bioactive constituents from complex matrixes:Herbal medicines as a case study[J].J Chromatogr A,2015,1413:33-46.
[62]杨兴鑫,徐风,俞捷,等.中药对线粒体功能的影响及其药理作用研究进展[J].生命科学仪器,2017,15(4):15-21.
[63]许静怡,陈超翔,韩锦艳,等.线粒体蛋白质组学研究进展[J].分析化学,2015,43(9):1257-1264.
[64]Go Y M,Uppal K,Walker D I,et al.Mitochondrial metabolomics using high-resolution Fourier-transform mass spectrometry[J].Methods Mol Biol,2014,1198:43-73.
[65]Li Q,Qiao P,Chen X,et al.Affinity chromatographic methodologies based on immobilized voltage dependent anion channel isoform 1 and application in protein-ligand interaction analysis and bioactive compounds screening from traditional medicine[J].J Chromatogr A,2017,1495:31-45.
[66]Yang X X,Gu W,Liang L,et al.Screening for the bioactive constituents of traditional Chinese medicines—progress and challenges[J].RSC Adv,2017,7(6):3089-3100.