氧化应激与核因子E2相关因子2在非酒精性脂肪性肝病中的作用

陆孝良; 蒋元烨; 曹勤

doi:10.3969/j.issn.1001-5256.2020.04.048

氧化应激与核因子E2相关因子2在非酒精性脂肪性肝病中的作用

DOI: 10.3969/j.issn.1001-5256.2020.04.048

上海中医药大学附属普陀医院

基金项目:

国家自然科学基金青年项目(81703879)；上海市卫计委临床研究专项面上项目(201840377)；上海市普陀区中心医院人才培养项目(2016212B)；上海中医药大学预算内项目(18LK022)；上海市普陀区中心医院院级重点专科项目(2016103A)；

详细信息

中图分类号: R575.5
计量
- 文章访问数: 801
- HTML全文浏览量: 17
- PDF下载量: 184
- 被引次数: 0
出版历程
- 出版日期: 2020-04-20

The role of oxidative stress and nuclear factor erythroid 2-related factor 2 in nonalcoholic fatty liver disease

Putuo Hospital, Shanghai University of Traditional Chinese Medicine

Research funding:

摘要

摘要: 非酒精性脂肪肝病(NAFLD)是全球最流行的慢性肝病,发病率逐年上升。氧化应激是非酒精性脂肪肝病经典"二次打击"发病机制的第二次打击,是目前公认的NAFLD发病机制之一。核因子E2相关因子2(Nrf2)是保护肝细胞免受氧化应激的一组正向调节因子,是细胞抗氧化应激的关键因子,也是拮抗肝脏氧化应激的关键转录因子,在NAFLD发生发展中起重要作用,Nrf2可能是改善NAFLD的潜在治疗靶点。对氧化应激及Nrf2通路在NAFLD中的发病机制进行了综述。
- 非酒精性脂肪性肝病 /
- 氧化性应激 /
- NF-E2相关因子2
Abstract: Nonalcoholic fatty liver disease( NAFLD) is the most prevalent chronic liver disease around the world,and its incidence rate is increasing year by year. Oxidative stress is the second hit in the classic“two-hit”pathogenesis of NAFLD,which is currently recognized as one of the pathogeneses of NAFLD. Nuclear factor erythroid 2-related factor 2( Nrf2) is a group of positive regulators that protect hepatocytes against oxidative stress. It is a key factor for cellular anti-oxidative stress and a key transcription factor that antagonizes liver oxidative stress. It plays an important role in the development and progression of NAFLD and may be a potential treatment target for improving NAFLD. This article reviews the role of oxidative stress and the Nrf2 pathway in the pathogenesis of NAFLD.
- nonalcoholic fatty liver /
- oxidant stress /
- NF-E2-related factor 2

HTML全文

参考文献(45)

[1] YU X,WANG WJ,JIN JY,et al. Linggui Zhugan decoction combined with probiotics in the treatment of nonalcoholic fatty liver disease[J]. J Changchun Univ Chin Med,2019,35(5):891-894.(in Chinese)喻晓，王雯婕，金嘉悦，等．苓桂术甘汤联合益生菌治疗非酒精性脂肪肝[J]．长春中医药大学学报，2019,35(5):891-894.

[2] EKSTEDT M,FRANZEN LE,MATHIESEN UL,et al. Longterm follow-up of patients with NAFLD and elevated liver enzymes.[J]. Hepatology,2006,44(4):865-873.

[3] ARAU'JO AR,ROSSO N,BEDOGNI G,et al. Global epidemiology of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis:What we need in the future[J]. Liver Int,2018,38(Suppl 1):47-51.

[4] YOUNOSSI ZM,KOENIG AB,ABDELATIF D,et al. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes[J]. Hepatology,2016,64(1):73-84.

[5] LI J. Epidemiology characteristics of nonalcoholic fatty liver disease in Asia[J]. J Clin Hepatol,2018,34(12):34-38.(in Chinese)李婕．亚洲地区非酒精性脂肪性肝病的流行病学特点[J]．临床肝胆病杂志，2018,34(12):34-38.

[6] MARCHESINI G,BRIZI M,BIANCHI G,et al. Metformin in nonalcoholic steatohepatitis[J]. Lancet,2001,358(9285):893-894.

[7] LEBEAUPIN C,VALLEE D,HAZARI Y,et al. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease[J]. J Hepatol,2018,69(4):927-947.

[8] AKAZAWA Y,NAKAO K. To die or not to die:Death signaling in nonalcoholic fatty liver disease[J]. J Gastroenterol,2018,53(8):893-906.

[9] SAFARI Z,GERARD P. The links between the gut microbiome and non-alcoholic fatty liver disease(NAFLD)[J]. Cell Mol Life Sci,2019,76(8):1541-1558.

[10] MUSSO G,CASSADER M,GAMBINO R. Non-alcoholic steatohepatitis:Emerging molecular targets and therapeutic strategies[J]. Nat Rev Drug Discov,2016,15(4):249-274.

[11] AKIYAMA K,WARABI E,OKADA K,et al. Deletion of both p62 and Nrf2 spontaneously results in the development of nonalcoholic steatohepatitis[J]. Exp Anim,2018,67(2):201-218.

[12] DAY CP,JAMES OF. Steatohepatitis:A tale of two “hits”?[J]. Gastroenterology,1998,114(4):842-845.

[13] SCHUSTER S,CABRERA D,ARRESE M,et al. Triggering and resolution of inflammation in NASH[J]. Nat Rev Gastroenterol Hepatol,2018,15(6):349-364.

[14] BOLAND ML,OLDHAM S,BOLAND BB,et al. Nonalcoholic steatohepatitis severity is defined by a failure in compensatory antioxidant capacity in the setting of mitochondrial dysfunction[J]. World J Gastroenterol,2018,24(16):1748-1765.

[15] VALENZUELA R,RINCON-CERVERA MA，ECHEVERRA F,et al. Iron-induced pro-oxidant and pro-lipogenic responses in relation to impaired synthesis and accretion of longchain polyunsaturated fatty acids in rat hepatic and extrahepatic tissues[J]. Nutrition,2018,45:49-58.

[16] JONES RM,NEISH AS. Redox signaling mediated by the gut microbiota[J]. Free Radic Biol Med,2017,105:41-47.

[17] IPSEN DH,LYKKESFELDT J,TVEDEN-NYBORG P. Molecular mechanisms of hepatic lipid accumulation in non-alcoholic fatty liver disease[J]. Cel Mol Life Sci,2018,75(18):3313-3327.

[18] BUZZETTI E,PINZANI M,TSOCHATZIS EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease(NAFLD)[J]. Metab Clin Exp,2016,65(8):1038-1048.

[19] BELLANTI F,VILLANI R,FACCIORUSSO A,et al. Lipid oxidation products in the pathogenesis of non-alcoholic steatohepatitis[J]. Free Radic Biol Med,2017,111:173-185.

[20] PFANNER N,WARSCHEID B,WIEDEMANN N. Mitochondrial proteins:From biogenesis to functional networks[J]. Nat Rev Mol Cell Biolm,2019,20(5):267-284.

[21] LEBEAUPIN C,VALLEE D,HAZARI Y,et al. Endoplasmic reticulum stress signalling and the pathogenesis of non-alcoholic fatty liver disease[J]. J Hepatol,2018,69(4):927-947.

[22] HENKEL A,GREEN RM. The unfolded protein response in fatty liver disease[J]. Semin Liver Dis,2013,33(4):321-329.

[23] HAN CY,RHO HYUN S,KIM A,et al. FXR inhibits endoplasmic reticulum stress-induced NLRP3 inflammasome in hepatocytes and ameliorates liver injury[J]. Cell Rep,2018,24(11):2985-2999.

[24] AROSIO P,ELIA L,POLI MF. Ferritin,cellular iron storage and regulation[J]. IUBMB Life,2017,69(6):414-422.

[25] DATZ C,MULLER E,AIGNER E. Iron overload and non-alcoholic fatty liver disease[J]. Minerva Endocrinol,2017,42(2):173-183.

[26] HANDA P,MORGAN-STEVENSON V,MALIKEN BD,et al.Iron overload results in hepatic oxidative stress,immune cell activation,and hepatocellular ballooning injury, leading to nonalcoholic steatohepatitis in genetically obese mice[J]. Am J Physiol Gastrointest Liver Physiol,2016,310(2):g117-g127.

[27] ATARASHI M,IZAWA T,MIYAGI R,et al. Dietary iron supplementation alters hepatic inflammation in a rat model of nonalcoholic steatohepatitis[J]. Nutrients,2018,10(2):175.

[28] TAN TC,CRAWFORD DH,JASKOWSKI LA,et al. Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse model of alcohol and high-fat diet-induced liver injury[J]. Lab Invest,2013,93(12):1295-1312.

[29] FUKE N,NAGATA N,SUGANUMA H,et al. Regulation of gut microbiota and metabolic endotoxemia with dietary factors[J]. Nutrients,2019,11(10):2277.

[30] ZHU LX,BAKER RD,ZHU RX,et al. Gut microbiota produce alcohol and contribute to NAFLD[J]. Gut,2016,65(7):1232.

[31] HU YB,LIU XY,ZHAN W. Farnesoid X receptor agonist INT-767 attenuates liver steatosis and inflammation in rat model of nonalcoholic steatohepatitis[J]. Drug Des Devel Ther,2018,16(12):2213-2221.

[32] WANG YX,LI W,CHENG DY,et al. Characteristics of intestinal flora of patients with hepatitis B related decompensated cirrhosis[J/CD]. Chin J Exp Clin Infect Dis(Electronic Version),2019,13(2):110-116.(in Chinese)王艺璇，李炜，程丹颖，等．乙型肝炎失代偿期肝硬化患者肠道菌群特征[J/CD]．中华实验和临床感染病杂志(电子版)，2019,13(2):110-116.

[33] LI YC,LU Z,RU JH,et al. Saturated fatty acid combined with lipopolysaccharide stimulates a strong inflammatory response in hepatocytes in vivo and in vitro[J]. Am J Physiol Endocrinol Metab,2018,315(1):e745-e757.

[34] TONELLI C,CHIO IIC,TUVESON DA. Transcriptional regulation by Nrf2[J]. Antioxid Redox Signal,2018,29(17):1727-1745.

[35] WANG T,ROJO VM,SCHMIDLIN CJ,et al. Kelch-like ECHassociated protein 1(KEAP1)differentially regulates nuclear factor erythroid-2-related factors 1 and 2(NRF1 and NRF2)[J]. J Biol Chem,2018,293(6):2029-2040.

[36] DINKOVA-KOSTOVA AT,ABRAMOV AY. The emerging role of Nrf2 in mitochondrial function[J]. Free Radic Biol Med,2015,88(Pt B):179-188.

[37] DU J,ZHANG ML,LU JX,et al. Osteocalcin improves nonalcoholic fatty liver disease in mice through activation of Nrf2 and inhibition of JNK[J]. Endocrine,2016,53(3):701-709.

[38] SHARMA RS,HARRISON DJ,KISIELEWSKI D,et al. Experimental nonalcoholic steatohepatitis and liver fibrosis are ameliorated by pharmacologic activation of Nrf2(NF-E2 p45-Related Factor 2)[J]. Cell Mol Gastroenterol Hepatol,2017,5(3):367-398.

[39] WANG XH,LI CY,XU S,et al. NF-E2-related factor 2 deletion facilitates hepatic fatty acids metabolism disorder induced by high-fat diet via regulating related genes in mice[J].Food Chem Toxicol,2016,(94):186-196.

[40] YAMADA SJ,KIMURA M,SAITO Y,et al. Nrf2-mediated anti-oxidant effects contribute to suppression of non-alcoholic steatohepatitis-associated hepatocellular carcinoma in murine model[J]. J Clin Biochem Nutr,2018,63(2):123-128.

[41] CHAMBEL SS,SANTOS-GONCALVES A,DUARTE TL. The dual role of Nrf2 in nonalcoholic fatty liver disease:Regulation of antioxidant defenses and hepatic lipid metabolism[J]. Biomed Res Int,2015,(2015):597134.

[42] ZHANG XX,JI RP,SUN HJ,et al. Scutellarin ameliorates nonalcoholic fatty liver disease through the PPARγ/PGC-1α-Nrf2pathway[J]. Free Radic Res,2018,52(2):198-211.

[43] ZHAO MG,SHENG XP,HUANG YP,et al. Triterpenic acidsenriched fraction from cyclocarya paliurus attenuates non-alcoholic fatty liver disease via improving oxidative stress and mitochondrial dysfunction[J]. Biomed Pharmacother,2018,(104):229-239.

[44] SHEN BY,ZHAO CX,WANG Y,et al. Aucubin inhibited lipid accumulation and oxidative stress via Nrf2/HO-1 and AMPK signal ing pathways[J]. J Cell Mol Med,2019,23(6):4063-4075.

[45] GOPAL S,MIKULSKIS A,GOLD R,et al. Evidence of activation of the Nrf2 pathway in multiple sclerosis patients treated with delayed-release dimethyl fumarate in the Phase 3 DEFINE and CONFIRM studies[J]. Mult Scler,2017,23(14):1875-1883.

施引文献

资源附件(0)

访问统计