Kupffer细胞在非酒精性脂肪肝病中的作用
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摘要
非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)是一种无过量饮酒史、以肝细胞脂肪变性和脂肪贮积为特征的临床病理综合征。Kupffer细胞是位于肝脏中的特殊巨噬细胞,是先天免疫中的重要组成部分,在肝脏疾病中起关键作用。多项研究表明,Kupffer细胞在NAFLD的发生发展过程中起重要作用。本文总结了Kuffer细胞在NAFLD疾病发生发展中的多重作用,旨在为NAFLD的治疗提供一个有效的靶点。
Non-alcoholic fatty liver disease(NAFLD) is a clinical pathological syndrome characterized by no history of excessive drinking, hepatic steatosis and fat accumulation. Kupffer cells, special macrophages located in the liver, are an important component of innate immunity and play a key role in liver disease. In recent years, several studies have shown that Kupffer cells play an important role in the development of NAFLD.This review summarizes the multiple roles of Kuffer cells in the development of NAFLD, aiming to provide an effective target for the treatment of NAFLD.
Non-alcoholic fatty liver disease(NAFLD) is a clinical pathological syndrome characterized by no history of excessive drinking, hepatic steatosis and fat accumulation. Kupffer cells, special macrophages located in the liver, are an important component of innate immunity and play a key role in liver disease. In recent years, several studies have shown that Kupffer cells play an important role in the development of NAFLD.This review summarizes the multiple roles of Kuffer cells in the development of NAFLD, aiming to provide an effective target for the treatment of NAFLD.
引文
[1]Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes.Hepatology, 2016, 64(1):73-84
[2]EstesC,RazaviH.Modelingtheepidemicofnonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology, 2018, 67(1):123-133
[3]HaasJT,FrancqueS,StaelsB.Pathophysiologyand mechanismsofnonalcoholicfattyliverdisease. Annu Rev Physiol, 2016, 78:181-205
[4]Adams LA, Anstee QM, Tilg H, et al. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut, 2017, 66(6):1138-1153
[5]Schuster S, Cabrera D, Arrese M, et al. Triggering and resolution of inflammation in NASH. Nat Rev Gastroenterol Hepatol, 2018, 15(6):349-364
[6]JamesOF,DayCP.Non-alcoholicsteatohepatitis(NASH):a disease of emerging identity and importance.J Hepatol, 1998, 29(3):495-501
[7]Machado MV, Diehl AM. Pathogenesis of nonalcoholic steatohepatitis.Gastroenterology,2016,150(8):1769-1777
[8]Friedman SL, Neuschwander-Tetri BA, Rinella M, et al.MechanismsofNAFLDdevelopmentandtherapeutic strategies. Nat Med, 2018, 24(7):908-922
[9]Rotman Y, Sanyal AJ. Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease. Gut, 2017,66(1):180-190
[10]Krenkel O, Tacke F. Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol, 2017, 17(5):306-321
[11]ScottCL,ZhengF,DeBaetselierP,etal.Bonemarrow-derivedmonocytesgiverisetoself-renewingand fully differentiated Kupffer cells. Nat Commun, 2016, 7:10321
[12]Liddiard K, Rosas M, Davies LC, et al. Macrophage heterogeneity and acute inflammation. Eur J Immunol, 2011,41(9):2503-2508
[13]BleriotC,Dupuis T,JouvionG,etal.Liver-resident macrophage necroptosis orchestrates type 1 microbicidal inflammationandtype-2-mediatedtissuerepairduring bacterial infection. Immunity, 2015, 42(1):145-158
[14]Bartneck M, Fech V, Ehling J, et al. Histidine-rich glycoproteinpromotesmacrophageactivationandinflammation in chronic liver disease. Hepatology, 2016, 63(4):1310-1324
[15]Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature, 2013,496(7446):445-455
[16]Eckert C, Klein N, Kornek M, et al. The complex myeloid network of the liver with diverse functional capacity at steady state and in inflammation. Front Immunol,2015, 6:179
[17]Wenfeng Z, Yakun W, Di M, et al. Kupffer cells:increasingly significant role in nonalcoholic fatty liver disease.Ann Hepatol, 2014, 13(5):489-495
[18]Liu W, Baker SS, Baker RD, et al. Antioxidant mechanisms in nonalcoholic fatty liver disease. Curr Drug Targets, 2015, 16(12):1301-1314
[19]Satapati S, Kucejova B, Duarte JA, et al. Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver. J Clin Invest, 2015, 125(12):4447-4462
[20]AshrafNU,Sheikh TA.Endoplasmicreticulumstress and oxidative stress in the pathogenesis of non-alcoholic fatty liver disease. Free Radic Res, 2015, 49(12):1405-1418
[21]vanGalenP,Kreso A,MbongN,etal. Theunfolded protein response governs integrity of the haematopoietic stem-cellpoolduringstress.Nature,2014,510(7504):268-272
[22]KimSY,JeongJM,KimSJ,etal.Pro-inflammatory hepaticmacrophagesgenerateROSthroughNADPH oxidase2viaendocytosisofmonomeric TLR4-MD2complex. Nat Commun 2017, 8(1):2247
[23]SethRK,DasS,DattaroyD,etal. TRPV4activation of endothelial nitric oxide synthase resists nonalcoholic fatty liver disease by blocking CYP2E1-mediated redox toxicity. Free Radic Biol Med, 2017, 102:260-273
[24]Reiniers MJ, van Golen RF, van Gulik TM, et al. Reactive oxygen and nitrogen species in steatotic hepatocytes:a molecular perspective on the pathophysiology of ischemia-reperfusion injury in the fatty liver. Antioxid Redox Signal, 2014, 21(7):1119-1142
[25]Usami M, Miyoshi M, Yamashita H. Gut microbiota and host metabolism in liver cirrhosis. World J Gastroenterol,2015, 21(41):11597-11608
[26]Li P, He K, Li J, et al. The role of Kupffer cells in hepatic diseases. Mol Immunol, 2017, 85:222-229
[27]Leroux A, Ferrere G, Godie V, et al. Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis. J Hepatol,2012, 57(1):141-149
[28]Frasinariu OE, Ceccarelli S, Alisi A, et al. Gut-liver axis and fibrosis in nonalcoholic fatty liver disease:an input for novel therapies. Dig Liver Dis, 2013, 45(7):543-551
[29]CaiC,ZhuX,LiP,etal.NLRP3deletioninhibitsthe non-alcoholic steatohepatitis development and inflammation in Kupffer cells induced by palmitic acid. Inflammation, 2017, 40(6):1875-1883
[30]Nishio T, Taura K, Iwaisako K, et al. Hepatic vagus nerve regulatesKupffercellactivationviaalpha7nicotinic acetylcholine receptor in nonalcoholic steatohepatitis. J Gastroenterol, 2017, 52(8):965-976
[31]Ercin CN, Dogru T, Genc H, et al. Insulin Resistance but not visceral adiposity index is associated with liver fibrosis in nondiabetic subjects with nonalcoholic fatty liver disease. Metab Syndr Relat Disord, 2015, 13(7):319-325
[32]ZaitoneSA,BarakatBM,BilasySE,etal.Protective effectofboswellicacidsversuspioglitazoneinarat model of diet-induced non-alcoholic fatty liver disease:influence on insulin resistance and energy expenditure.Naunyn Schmiedebergs Arch Pharmacol, 2015, 388(6):587-600
[33]Celebi G, Genc H, Gurel H, et al. The relationship of circulating fetuin-a with liver histology and biomarkers of systemic inflammation in nondiabetic subjects with nonalcoholic fatty liver disease. Saudi J Gastroenterol, 2015,21(3):139-145
[34]Mortezaee K. Nicotinamide adenine dinucleotide phosphate(NADPH)oxidase(NOX)and liver fibrosis:a review. Cell Biochem Funct, 2018:
[35]Bao Y.[The progress of studying the mechanisms of immune cells in the regulation of non-alcoholic fatty liver diseases]. Zhonghua Gan Zang Bing Za Zhi, 2017, 25(7):553-556
[36]BiJ,SunK, WuH,etal.PPARgammaalleviatedhepatocyte steatosis through reducing SOCS3 by inhibiting JAK2/STAT3 pathway. Biochem Biophys Res Commun,2018, 498(4):1037-1044
[37]Dembek A, Laggai S, Kessler SM, et al. Hepatic interleukin-6productionismaintainedduringendotoxintolerance and facilitates lipid accumulation. Immunobiology,2017, 222(6):786-796
[38]Borrelli A,BonelliP, TuccilloFM,etal.Roleofgut microbiotaandoxidativestressintheprogressionof non-alcoholicfattyliverdiseasetohepatocarcinoma:Currentandinnovativetherapeuticapproaches.Redox Biol, 2018, 15:467-479
[39]AntyRandLemoineM.Liverfibrogenesisandmetabolic factors. Clin Res Hepatol Gastroenterol, 2011, 35Suppl 1:S10-20
[40]ChenXM,LiFQ, YanS,etal.[Nicotinealleviates theliverinflammationofnon-alcoholicsteatohepatitis induced by high-fat and high-fructose in mice]. Beijing Da Xue Xue Bao Yi Xue Ban, 2016, 48(5):777-782
[41]Kessoku T,ImajoK,Honda Y,etal.Resveratrolameliorates fibrosis and inflammation in a mouse model of nonalcoholic steatohepatitis. Sci Rep, 2016, 6:22251
[42]Zhan YT and An W. Roles of liver innate immune cells in nonalcoholic fatty liver disease. World J Gastroenterol,2010, 16(37):4652-4660
[43]MeliR,MattaceRasoG,Calignano A.Roleofinnate immuneresponseinnon-alcoholicFattyliverdisease:metabolic complications and therapeutic tools. Front Immunol, 2014, 5:177
[44]Byun JS and Yi HS. Hepatic immune microenvironment in alcoholic and nonalcoholic liver disease. Biomed Res Int, 2017, 2017:6862439
[45]Tang T, Sui Y, Lian M, et al. Pro-inflammatory activated KupffercellsbylipidsinducehepaticNKTcellsdeficiency through activation-induced cell death. PLoS One,2013, 8(12):e81949
[46]Mouralidarane A,SoedaJ, Visconti-PugmireC,etal.Maternal obesity programs offspring nonalcoholic fatty liverdiseasebyinnateimmunedysfunctioninmice.Hepatology, 2013, 58(1):128-138
[47]Gonzalez-Rodriguez A, ValdecantosMP,RadaP,etal.Dual role of protein tyrosine phosphatase 1B in the progression and reversion of non-alcoholic steatohepatitis.Mol Metab, 2018, 7:132-146
[48]KiagiadakiF,KampaM, Voumvouraki A,etal. Activin-A causes hepatic stellate cell activation via the induction of TNFalpha and TGFbeta in Kupffer cells. Biochim Biophys Acta, 2018, 1864(3):891-899
[49]Ghazwani M, Zhang Y, Gao X, et al. Anti-fibrotic effect ofthymoquinoneonhepaticstellatecells.Phytomedicine, 2014, 21(3):254-260
[50]Li W, Li N, Wang R, et al. Interferon gamma, interleukin-6,and-17alevelswerecorrelatedwithminimal hepaticencephalopathyinHBVpatients.HepatolInt,2015, 9(2):218-223
[51]Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesisofnon-alcoholicfattyliverdisease(NAFLD). Metabolism, 2016, 65(8):1038-1048
[52]PetersonKR,CottamMA,Kennedy AJ,etal.Macrophage-TargetedTherapeuticsforMetabolicDisease.Trends Pharmacol Sci, 2018, 39(6):536-546
[53]Tacke F. Targeting hepatic macrophages to treat liver diseases. J Hepatol, 2017, 66(6):1300-1312
[2]EstesC,RazaviH.Modelingtheepidemicofnonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology, 2018, 67(1):123-133
[3]HaasJT,FrancqueS,StaelsB.Pathophysiologyand mechanismsofnonalcoholicfattyliverdisease. Annu Rev Physiol, 2016, 78:181-205
[4]Adams LA, Anstee QM, Tilg H, et al. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut, 2017, 66(6):1138-1153
[5]Schuster S, Cabrera D, Arrese M, et al. Triggering and resolution of inflammation in NASH. Nat Rev Gastroenterol Hepatol, 2018, 15(6):349-364
[6]JamesOF,DayCP.Non-alcoholicsteatohepatitis(NASH):a disease of emerging identity and importance.J Hepatol, 1998, 29(3):495-501
[7]Machado MV, Diehl AM. Pathogenesis of nonalcoholic steatohepatitis.Gastroenterology,2016,150(8):1769-1777
[8]Friedman SL, Neuschwander-Tetri BA, Rinella M, et al.MechanismsofNAFLDdevelopmentandtherapeutic strategies. Nat Med, 2018, 24(7):908-922
[9]Rotman Y, Sanyal AJ. Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease. Gut, 2017,66(1):180-190
[10]Krenkel O, Tacke F. Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol, 2017, 17(5):306-321
[11]ScottCL,ZhengF,DeBaetselierP,etal.Bonemarrow-derivedmonocytesgiverisetoself-renewingand fully differentiated Kupffer cells. Nat Commun, 2016, 7:10321
[12]Liddiard K, Rosas M, Davies LC, et al. Macrophage heterogeneity and acute inflammation. Eur J Immunol, 2011,41(9):2503-2508
[13]BleriotC,Dupuis T,JouvionG,etal.Liver-resident macrophage necroptosis orchestrates type 1 microbicidal inflammationandtype-2-mediatedtissuerepairduring bacterial infection. Immunity, 2015, 42(1):145-158
[14]Bartneck M, Fech V, Ehling J, et al. Histidine-rich glycoproteinpromotesmacrophageactivationandinflammation in chronic liver disease. Hepatology, 2016, 63(4):1310-1324
[15]Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature, 2013,496(7446):445-455
[16]Eckert C, Klein N, Kornek M, et al. The complex myeloid network of the liver with diverse functional capacity at steady state and in inflammation. Front Immunol,2015, 6:179
[17]Wenfeng Z, Yakun W, Di M, et al. Kupffer cells:increasingly significant role in nonalcoholic fatty liver disease.Ann Hepatol, 2014, 13(5):489-495
[18]Liu W, Baker SS, Baker RD, et al. Antioxidant mechanisms in nonalcoholic fatty liver disease. Curr Drug Targets, 2015, 16(12):1301-1314
[19]Satapati S, Kucejova B, Duarte JA, et al. Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver. J Clin Invest, 2015, 125(12):4447-4462
[20]AshrafNU,Sheikh TA.Endoplasmicreticulumstress and oxidative stress in the pathogenesis of non-alcoholic fatty liver disease. Free Radic Res, 2015, 49(12):1405-1418
[21]vanGalenP,Kreso A,MbongN,etal. Theunfolded protein response governs integrity of the haematopoietic stem-cellpoolduringstress.Nature,2014,510(7504):268-272
[22]KimSY,JeongJM,KimSJ,etal.Pro-inflammatory hepaticmacrophagesgenerateROSthroughNADPH oxidase2viaendocytosisofmonomeric TLR4-MD2complex. Nat Commun 2017, 8(1):2247
[23]SethRK,DasS,DattaroyD,etal. TRPV4activation of endothelial nitric oxide synthase resists nonalcoholic fatty liver disease by blocking CYP2E1-mediated redox toxicity. Free Radic Biol Med, 2017, 102:260-273
[24]Reiniers MJ, van Golen RF, van Gulik TM, et al. Reactive oxygen and nitrogen species in steatotic hepatocytes:a molecular perspective on the pathophysiology of ischemia-reperfusion injury in the fatty liver. Antioxid Redox Signal, 2014, 21(7):1119-1142
[25]Usami M, Miyoshi M, Yamashita H. Gut microbiota and host metabolism in liver cirrhosis. World J Gastroenterol,2015, 21(41):11597-11608
[26]Li P, He K, Li J, et al. The role of Kupffer cells in hepatic diseases. Mol Immunol, 2017, 85:222-229
[27]Leroux A, Ferrere G, Godie V, et al. Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis. J Hepatol,2012, 57(1):141-149
[28]Frasinariu OE, Ceccarelli S, Alisi A, et al. Gut-liver axis and fibrosis in nonalcoholic fatty liver disease:an input for novel therapies. Dig Liver Dis, 2013, 45(7):543-551
[29]CaiC,ZhuX,LiP,etal.NLRP3deletioninhibitsthe non-alcoholic steatohepatitis development and inflammation in Kupffer cells induced by palmitic acid. Inflammation, 2017, 40(6):1875-1883
[30]Nishio T, Taura K, Iwaisako K, et al. Hepatic vagus nerve regulatesKupffercellactivationviaalpha7nicotinic acetylcholine receptor in nonalcoholic steatohepatitis. J Gastroenterol, 2017, 52(8):965-976
[31]Ercin CN, Dogru T, Genc H, et al. Insulin Resistance but not visceral adiposity index is associated with liver fibrosis in nondiabetic subjects with nonalcoholic fatty liver disease. Metab Syndr Relat Disord, 2015, 13(7):319-325
[32]ZaitoneSA,BarakatBM,BilasySE,etal.Protective effectofboswellicacidsversuspioglitazoneinarat model of diet-induced non-alcoholic fatty liver disease:influence on insulin resistance and energy expenditure.Naunyn Schmiedebergs Arch Pharmacol, 2015, 388(6):587-600
[33]Celebi G, Genc H, Gurel H, et al. The relationship of circulating fetuin-a with liver histology and biomarkers of systemic inflammation in nondiabetic subjects with nonalcoholic fatty liver disease. Saudi J Gastroenterol, 2015,21(3):139-145
[34]Mortezaee K. Nicotinamide adenine dinucleotide phosphate(NADPH)oxidase(NOX)and liver fibrosis:a review. Cell Biochem Funct, 2018:
[35]Bao Y.[The progress of studying the mechanisms of immune cells in the regulation of non-alcoholic fatty liver diseases]. Zhonghua Gan Zang Bing Za Zhi, 2017, 25(7):553-556
[36]BiJ,SunK, WuH,etal.PPARgammaalleviatedhepatocyte steatosis through reducing SOCS3 by inhibiting JAK2/STAT3 pathway. Biochem Biophys Res Commun,2018, 498(4):1037-1044
[37]Dembek A, Laggai S, Kessler SM, et al. Hepatic interleukin-6productionismaintainedduringendotoxintolerance and facilitates lipid accumulation. Immunobiology,2017, 222(6):786-796
[38]Borrelli A,BonelliP, TuccilloFM,etal.Roleofgut microbiotaandoxidativestressintheprogressionof non-alcoholicfattyliverdiseasetohepatocarcinoma:Currentandinnovativetherapeuticapproaches.Redox Biol, 2018, 15:467-479
[39]AntyRandLemoineM.Liverfibrogenesisandmetabolic factors. Clin Res Hepatol Gastroenterol, 2011, 35Suppl 1:S10-20
[40]ChenXM,LiFQ, YanS,etal.[Nicotinealleviates theliverinflammationofnon-alcoholicsteatohepatitis induced by high-fat and high-fructose in mice]. Beijing Da Xue Xue Bao Yi Xue Ban, 2016, 48(5):777-782
[41]Kessoku T,ImajoK,Honda Y,etal.Resveratrolameliorates fibrosis and inflammation in a mouse model of nonalcoholic steatohepatitis. Sci Rep, 2016, 6:22251
[42]Zhan YT and An W. Roles of liver innate immune cells in nonalcoholic fatty liver disease. World J Gastroenterol,2010, 16(37):4652-4660
[43]MeliR,MattaceRasoG,Calignano A.Roleofinnate immuneresponseinnon-alcoholicFattyliverdisease:metabolic complications and therapeutic tools. Front Immunol, 2014, 5:177
[44]Byun JS and Yi HS. Hepatic immune microenvironment in alcoholic and nonalcoholic liver disease. Biomed Res Int, 2017, 2017:6862439
[45]Tang T, Sui Y, Lian M, et al. Pro-inflammatory activated KupffercellsbylipidsinducehepaticNKTcellsdeficiency through activation-induced cell death. PLoS One,2013, 8(12):e81949
[46]Mouralidarane A,SoedaJ, Visconti-PugmireC,etal.Maternal obesity programs offspring nonalcoholic fatty liverdiseasebyinnateimmunedysfunctioninmice.Hepatology, 2013, 58(1):128-138
[47]Gonzalez-Rodriguez A, ValdecantosMP,RadaP,etal.Dual role of protein tyrosine phosphatase 1B in the progression and reversion of non-alcoholic steatohepatitis.Mol Metab, 2018, 7:132-146
[48]KiagiadakiF,KampaM, Voumvouraki A,etal. Activin-A causes hepatic stellate cell activation via the induction of TNFalpha and TGFbeta in Kupffer cells. Biochim Biophys Acta, 2018, 1864(3):891-899
[49]Ghazwani M, Zhang Y, Gao X, et al. Anti-fibrotic effect ofthymoquinoneonhepaticstellatecells.Phytomedicine, 2014, 21(3):254-260
[50]Li W, Li N, Wang R, et al. Interferon gamma, interleukin-6,and-17alevelswerecorrelatedwithminimal hepaticencephalopathyinHBVpatients.HepatolInt,2015, 9(2):218-223
[51]Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesisofnon-alcoholicfattyliverdisease(NAFLD). Metabolism, 2016, 65(8):1038-1048
[52]PetersonKR,CottamMA,Kennedy AJ,etal.Macrophage-TargetedTherapeuticsforMetabolicDisease.Trends Pharmacol Sci, 2018, 39(6):536-546
[53]Tacke F. Targeting hepatic macrophages to treat liver diseases. J Hepatol, 2017, 66(6):1300-1312