脂肪细胞因子在肝纤维化进展中的作用及机制
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摘要
肝纤维化是肝硬化发生发展过程的必经阶段,不加控制的肝纤维化最终可导致肝硬化和(或)肝细胞癌。肝纤维化是一个动态过程,受多种因素调控。越来越多的证据表明,脂肪因子在肝脏中传递动态功能,并参与调节肝纤维化。就目前国内外学者对参与肝纤维化的脂联素、瘦素等一些主要脂肪细胞因子的研究,以及这些脂肪细胞因子在肝纤维化中作用机制的最新进展进行了综述。
Liver fibrosis is an essential stage in the development and progression of liver cirrhosis,and uncontrolled liver fibrosis may even-tually lead to liver cirrhosis and/or hepatocellular carcinoma. Liver fibrosis is a dynamic process regulated by many factors. An increasingnumber of evidence has shown that adipokines transmit dynamic functions in the liver and are involved in the regulation of liver fibrosis. Thisarticle reviews the research on major adipocytokines( adiponectin and leptin) involved in liver fibrosis and the recent advances in the mecha-nism of action of these adipocytokines in liver fibrosis.
Liver fibrosis is an essential stage in the development and progression of liver cirrhosis,and uncontrolled liver fibrosis may even-tually lead to liver cirrhosis and/or hepatocellular carcinoma. Liver fibrosis is a dynamic process regulated by many factors. An increasingnumber of evidence has shown that adipokines transmit dynamic functions in the liver and are involved in the regulation of liver fibrosis. Thisarticle reviews the research on major adipocytokines( adiponectin and leptin) involved in liver fibrosis and the recent advances in the mecha-nism of action of these adipocytokines in liver fibrosis.
引文
[1] PARK PH,SANZ-GARCIA C,NAGY LE. Adiponectin as ananti-fibrotic and anti-inflammatory adipokine in the liver[J].Curr Pathobiol Rep,2015,3(4):243-252.
[2] DUVAL F,MORENO-CUEVAS JE,GONZLEZ-GANZA MT,etal. Liver fibrosis and protection mechanisms action of medicinalplants targeting apoptosis of hepatocytes and hepatic stellatecells[J]. Adv Pharmacol Sci,2014,2014:373295.
[3] SAXENA NK,ANANIA FA. Adipocytokines and hepatic fibrosis[J]. Trends Endocrinol Metab,2015,26(3):153-161.
[4] ABENAVOLI L,PETA V. Role of adipokines and cytokines innon-alcoholic fatty liver disease[J]. Rev Recent Clin Trials,2014,9(3):134-140.
[5] SILVA TE,COLOMBO G,SCHIAVON LL. Adiponectin:A mul-titasking player in the field of liver diseases[J]. DiabetesMetab,2014,40(2):95-107.
[6] HU E,LIANG P,SPIEGELMAN BM. AdipoQ is a novel adi-pose-specific gene dysregulated in obesity[J]. J BiolChem,1996,271(18):10697-10703.
[7] BOUTARI C,PERAKAKIS N,MANTZOROS CS. Association ofadipokines with development and progression of nonalcoholicfatty liver disease[J]. Endocrinol Metab(Seoul),2018,33(1):33-43.
[8] GAMBERI T,MAGHERINI F,MODESTI A,et al. Adiponectinsignaling pathways in liver diseases[J]. Biomedicines,2018,6(2):e52.
[9] LIM JY,OH MA,KIM WH,et al. AMP-activated protein ki-nase inhibits TGF-β-induced fibrogenic responses of hepat-ic stellate cells by targeting transcriptional coactivator p300[J]. J Cell Physiol,2012,227(3):1081-1089.
[10] SHAFIEI MS,SHETTY S,SCHERER PE,et al. Adiponectinregulation of stellate cell activation via PPARγ-dependentand-independent mechanisms[J]. Am J Pathol,2011,178(6):2690-2699.
[11] XIN X,YAN HZ,LI WQ,et al. Studies on PPARαandγpar-ticipating in progression of liver fibrosis by regulating ASCL1[J]. J Clin Hepatol,2014,30(8):833-835.(in Chinese)辛萱,颜红柱,李维卿,等.过氧化物酶体增殖物激活受体α、γ调控长链酰基辅酶A合成酶1对肝纤维化进程的影响[J].临床肝胆病杂志,2014,30(8):833-835.
[12] RM M,WANG J,HO V,et al. Adiponectin reduces hepaticstellate cell migration by promoting tissue inhibitor of metallo-proteinase-1(TIMP-1)secretion[J]. J Biol Chem,2015,290(9):5533-5542.
[13] HANDY JA,SAXENA NP,LIN S,et al. Adiponectin activationof AMPK disrupts leptin-mediated hepatic fibrosis via sup-pressors of cytokine signaling(SOCS-3)[J]. J Cell Bio-chem,2010,112(2):1195-1207.
[14] KUMAR P,SMITH T,RAHMAN K,et al. Adiponectin modu-lates focal adhesion disassembly in activated hepatic stellatecells:Implication for reversing hepatic fibrosis[J]. FASEB J,2014,28(12):5172-5183.
[15] KAMADA Y,TAMURA S,KISO S,et al. Enhanced carbon tet-rachloride-induced liver fibrosis in mice lacking adiponectin[J]. Gastroenterology,2003,125(6):1796-1807.
[16] ASANO T,WATANABE K,KUBOTA N,et al. Adiponectinknockout mice on high fat diet develop fibrosing steatohepati-tis[J]. J Gastroenterol Hepatol,2009,24(10):1669-1676.
[17] KUMAR P,SMITH T,RAHMAN K,et al. Adiponectin agonistADP355 attenuates CCl4-induced liver fibrosis in mice[J].PLo S One,2014,9(10):e110405.
[18] ZHANG W,WU R,ZHANG F,et al. Thiazolidinediones im-prove hepatic fibrosis in rats with non-alcoholic steatohepati-tis by activating the adenosine monophosphate-activatedprotein kinase signalling pathway[J]. Clin Exp PharmacolPhysiol,2012,39(12):1026-1033.
[19] DA ST,COSTA-SILVA M,CORREA CG,et al. Clinical signif-icance of serum adiponectin and resistin levels in liver cirrhosis[J]. Ann Hepatol,2018,17(2):286-299.
[20] TRIANTAFYLLOU GA,PASCHOU SA,MANTZOROS CS. Lep-tin and hormones:Energy homeostasis[J]. Endocrinol MetabClin North Am,2016,45(3):633-645.
[21] MEEK TH,MORTON GJ. The role of leptin in diabetes:Meta-bolic effects[J]. Diabetologia,2016,59(5):928-932.
[22] ZHAO ZB,LI JF,HUANG SS,et al. The advances of profi-brogenic research of leptin and its signaling pathways in he-patic fibrosis[J]. J Clin Hepatol,2011,27(10):1106-1108.(in Chinese)赵正斌,李俊峰,黄双盛,等.瘦素及其信号通路促肝纤维化机制研究进展[J].临床肝胆病杂志,2011,27(10):1106-1108.
[23] POLYZOS SA,KOUNTOURAS J,MANTZOROS CS. Leptin innonalcoholic fatty liver disease:A narrative review[J]. Metab-olism,2015,64(1):60-78.
[24] MUNZBERG H,MORRISON CD. Structure,production andsignaling of leptin[J]. Metabolism,2015,64(1):13-23.
[25] GE HY,ZHANG SH. Research advances in association be-tween matrix metalloproteinases and liver fibrosis[J]. J ClinHepatol,2017,33(3):563-566.(in Chinese)戈宏焱,张仕华.基质金属蛋白酶与肝纤维化关系的研究进展[J].临床肝胆病杂志,2017,33(3):563-566.
[26] GUI X,SUN L,GU L,et al. Leptin promotes pulmonary fibro-sis development by inhibiting autophagy via PI3K/Akt/m TORpathway[J]. Biochem Biophys Res Commun,2018,498(3):660-666.
[27] ZHOU Q,GUAN W,QIAO H,et al. GATA binding protein 2mediates leptin inhibition of PPARγ1 expression in hepatic stel-late cells and contributes to hepatic stellate cell activation[J].Biochim Biophys Acta,2014,1842(12):2367-2377.
[28] HANDY JA,FU PP,KUMAR P,et al. Adiponectin inhibits lep-tin signalling via multiple mechanisms to exert protectiveeffects against hepatic fibrosis[J]. Biochem J,2011,440(3):385-395.
[29] BUECHLER C,HABERL EM,REINFISCHBOECK L,et al. Adi-pokines in liver cirrhosis[J]. Int J Mol Sci,2017,18(7):1392.
[30] KASZTELANSZCZERBINSKA B,SURDACKA A,SLOMKA M,et al. Association of serum adiponectin,leptin,and resistinconcentrations with the severity of liver dysfunction and thedisease complications in alcoholic liver disease[J]. MediatorsInflamm,2013,2013(3):148526.
[31] SADIK NA,AHMED A,AHMED S. The significance of serumlevels of adiponectin,leptin,and hyaluronic acid in hepatocel-lular carcinoma of cirrhotic and noncirrhotic patients[J]. HumExp Toxicol,2012,31(4):311-321.
[32] VIKRANT R,BORHANI AA,DUNN MA,et al. Serum leptin isa biomarker of malnutrition in decompensated cirrhosis[J].PLo S One,2016,11(9):e0159142.
[33] BEIER JI,ARTEEL GE. Alcoholic liver disease and the poten-tial role of plasminogen activator inhibitor-1 and fibrin metabo-lism[J]. Exp Biol Mde,2012,237(1):1-9.
[34] GHOSH AK,VAUGHAN DE. PAI-1 in tissue fibrosis[J]. J CellPhysiol,2012,227(2):493-507.
[35] BAECK C,WEI X,BARTNECK M,et al. Pharmacological inhi-bition of the chemokine C-C motif chemokine ligand 2(mon-ocyte chemoattractant protein 1)accelerates liver fibrosis re-gression by suppressing Ly-6C+macrophage infiltration inmice[J]. Hepatology,2014,59(3):1060-1072.
[36] LI Y,DING L,HASSAN W,et al. Adipokines and hepatic in-sulin resistance[J]. J Diabetes Res,2013,2013:170532.
[37] NOBILI V,CARPINO G,ALISI A,et al. Hepatic progenitorcells activation,fibrosis,and adipokines production in pediat-ric nonalcoholic fatty liver disease[J]. Hepatology,2012,56(6):2142-2153.
[38] DONG ZX,SU L,BRYMORA J,et al. Resistin mediates thehepatic stellate cell phenotype[J]. World J Gastroenterol,2013,19(28):4475-4485.
[39] KRIST J,WIEDER K,KLOTING N,et al. Effects of weight lossand exercise on apelin serum concentrations and adipose tis-sue expression in human obesity[J]. Obesity Facts,2013,6(1):57-69.
[40] NAN YM,KONG LB,REN WG,et al. Activation of peroxisomeproliferator activated receptor alpha ameliorates ethanol medi-ated liver fibrosis in mice[J]. Lipids Health Dis,2013,12(1):11.
[41] REN RZ,ZHANG X,XU J,et al. Chronic ethanol consumptionincreases the levels of chemerin in the serum and adipose tis-sue of humans and rats[J]. Acta Pharmacol Sin,2012,33(5):652-659.
[42] WU MS,NING CL,LIU KZ. The research progress of Chemerin[J]. Med Recap,2016,22(11):2102-2106.(in Chinese)吴孟水,宁翠利,刘宽芝. Chemerin的研究进展[J].医学综述,2016,22(11):2102-2106.
[43] DOCKE S,LOCK JF,BIRKENFELD AL,et al. Elevated hepat-ic chemerin mRNA expression in human non-alcoholic fattyliver disease[J]. Eur J Endocrinol,2013,169(5):547-557.
[44] EISINGER K,KRAUTBAUER S,WIEST R,et al. Portal veinomentin is increased in patients with liver cirrhosis but is notassociated with complications of portal hypertension[J]. Eur JClin Invest,2013,43(9):926-932.
[2] DUVAL F,MORENO-CUEVAS JE,GONZLEZ-GANZA MT,etal. Liver fibrosis and protection mechanisms action of medicinalplants targeting apoptosis of hepatocytes and hepatic stellatecells[J]. Adv Pharmacol Sci,2014,2014:373295.
[3] SAXENA NK,ANANIA FA. Adipocytokines and hepatic fibrosis[J]. Trends Endocrinol Metab,2015,26(3):153-161.
[4] ABENAVOLI L,PETA V. Role of adipokines and cytokines innon-alcoholic fatty liver disease[J]. Rev Recent Clin Trials,2014,9(3):134-140.
[5] SILVA TE,COLOMBO G,SCHIAVON LL. Adiponectin:A mul-titasking player in the field of liver diseases[J]. DiabetesMetab,2014,40(2):95-107.
[6] HU E,LIANG P,SPIEGELMAN BM. AdipoQ is a novel adi-pose-specific gene dysregulated in obesity[J]. J BiolChem,1996,271(18):10697-10703.
[7] BOUTARI C,PERAKAKIS N,MANTZOROS CS. Association ofadipokines with development and progression of nonalcoholicfatty liver disease[J]. Endocrinol Metab(Seoul),2018,33(1):33-43.
[8] GAMBERI T,MAGHERINI F,MODESTI A,et al. Adiponectinsignaling pathways in liver diseases[J]. Biomedicines,2018,6(2):e52.
[9] LIM JY,OH MA,KIM WH,et al. AMP-activated protein ki-nase inhibits TGF-β-induced fibrogenic responses of hepat-ic stellate cells by targeting transcriptional coactivator p300[J]. J Cell Physiol,2012,227(3):1081-1089.
[10] SHAFIEI MS,SHETTY S,SCHERER PE,et al. Adiponectinregulation of stellate cell activation via PPARγ-dependentand-independent mechanisms[J]. Am J Pathol,2011,178(6):2690-2699.
[11] XIN X,YAN HZ,LI WQ,et al. Studies on PPARαandγpar-ticipating in progression of liver fibrosis by regulating ASCL1[J]. J Clin Hepatol,2014,30(8):833-835.(in Chinese)辛萱,颜红柱,李维卿,等.过氧化物酶体增殖物激活受体α、γ调控长链酰基辅酶A合成酶1对肝纤维化进程的影响[J].临床肝胆病杂志,2014,30(8):833-835.
[12] RM M,WANG J,HO V,et al. Adiponectin reduces hepaticstellate cell migration by promoting tissue inhibitor of metallo-proteinase-1(TIMP-1)secretion[J]. J Biol Chem,2015,290(9):5533-5542.
[13] HANDY JA,SAXENA NP,LIN S,et al. Adiponectin activationof AMPK disrupts leptin-mediated hepatic fibrosis via sup-pressors of cytokine signaling(SOCS-3)[J]. J Cell Bio-chem,2010,112(2):1195-1207.
[14] KUMAR P,SMITH T,RAHMAN K,et al. Adiponectin modu-lates focal adhesion disassembly in activated hepatic stellatecells:Implication for reversing hepatic fibrosis[J]. FASEB J,2014,28(12):5172-5183.
[15] KAMADA Y,TAMURA S,KISO S,et al. Enhanced carbon tet-rachloride-induced liver fibrosis in mice lacking adiponectin[J]. Gastroenterology,2003,125(6):1796-1807.
[16] ASANO T,WATANABE K,KUBOTA N,et al. Adiponectinknockout mice on high fat diet develop fibrosing steatohepati-tis[J]. J Gastroenterol Hepatol,2009,24(10):1669-1676.
[17] KUMAR P,SMITH T,RAHMAN K,et al. Adiponectin agonistADP355 attenuates CCl4-induced liver fibrosis in mice[J].PLo S One,2014,9(10):e110405.
[18] ZHANG W,WU R,ZHANG F,et al. Thiazolidinediones im-prove hepatic fibrosis in rats with non-alcoholic steatohepati-tis by activating the adenosine monophosphate-activatedprotein kinase signalling pathway[J]. Clin Exp PharmacolPhysiol,2012,39(12):1026-1033.
[19] DA ST,COSTA-SILVA M,CORREA CG,et al. Clinical signif-icance of serum adiponectin and resistin levels in liver cirrhosis[J]. Ann Hepatol,2018,17(2):286-299.
[20] TRIANTAFYLLOU GA,PASCHOU SA,MANTZOROS CS. Lep-tin and hormones:Energy homeostasis[J]. Endocrinol MetabClin North Am,2016,45(3):633-645.
[21] MEEK TH,MORTON GJ. The role of leptin in diabetes:Meta-bolic effects[J]. Diabetologia,2016,59(5):928-932.
[22] ZHAO ZB,LI JF,HUANG SS,et al. The advances of profi-brogenic research of leptin and its signaling pathways in he-patic fibrosis[J]. J Clin Hepatol,2011,27(10):1106-1108.(in Chinese)赵正斌,李俊峰,黄双盛,等.瘦素及其信号通路促肝纤维化机制研究进展[J].临床肝胆病杂志,2011,27(10):1106-1108.
[23] POLYZOS SA,KOUNTOURAS J,MANTZOROS CS. Leptin innonalcoholic fatty liver disease:A narrative review[J]. Metab-olism,2015,64(1):60-78.
[24] MUNZBERG H,MORRISON CD. Structure,production andsignaling of leptin[J]. Metabolism,2015,64(1):13-23.
[25] GE HY,ZHANG SH. Research advances in association be-tween matrix metalloproteinases and liver fibrosis[J]. J ClinHepatol,2017,33(3):563-566.(in Chinese)戈宏焱,张仕华.基质金属蛋白酶与肝纤维化关系的研究进展[J].临床肝胆病杂志,2017,33(3):563-566.
[26] GUI X,SUN L,GU L,et al. Leptin promotes pulmonary fibro-sis development by inhibiting autophagy via PI3K/Akt/m TORpathway[J]. Biochem Biophys Res Commun,2018,498(3):660-666.
[27] ZHOU Q,GUAN W,QIAO H,et al. GATA binding protein 2mediates leptin inhibition of PPARγ1 expression in hepatic stel-late cells and contributes to hepatic stellate cell activation[J].Biochim Biophys Acta,2014,1842(12):2367-2377.
[28] HANDY JA,FU PP,KUMAR P,et al. Adiponectin inhibits lep-tin signalling via multiple mechanisms to exert protectiveeffects against hepatic fibrosis[J]. Biochem J,2011,440(3):385-395.
[29] BUECHLER C,HABERL EM,REINFISCHBOECK L,et al. Adi-pokines in liver cirrhosis[J]. Int J Mol Sci,2017,18(7):1392.
[30] KASZTELANSZCZERBINSKA B,SURDACKA A,SLOMKA M,et al. Association of serum adiponectin,leptin,and resistinconcentrations with the severity of liver dysfunction and thedisease complications in alcoholic liver disease[J]. MediatorsInflamm,2013,2013(3):148526.
[31] SADIK NA,AHMED A,AHMED S. The significance of serumlevels of adiponectin,leptin,and hyaluronic acid in hepatocel-lular carcinoma of cirrhotic and noncirrhotic patients[J]. HumExp Toxicol,2012,31(4):311-321.
[32] VIKRANT R,BORHANI AA,DUNN MA,et al. Serum leptin isa biomarker of malnutrition in decompensated cirrhosis[J].PLo S One,2016,11(9):e0159142.
[33] BEIER JI,ARTEEL GE. Alcoholic liver disease and the poten-tial role of plasminogen activator inhibitor-1 and fibrin metabo-lism[J]. Exp Biol Mde,2012,237(1):1-9.
[34] GHOSH AK,VAUGHAN DE. PAI-1 in tissue fibrosis[J]. J CellPhysiol,2012,227(2):493-507.
[35] BAECK C,WEI X,BARTNECK M,et al. Pharmacological inhi-bition of the chemokine C-C motif chemokine ligand 2(mon-ocyte chemoattractant protein 1)accelerates liver fibrosis re-gression by suppressing Ly-6C+macrophage infiltration inmice[J]. Hepatology,2014,59(3):1060-1072.
[36] LI Y,DING L,HASSAN W,et al. Adipokines and hepatic in-sulin resistance[J]. J Diabetes Res,2013,2013:170532.
[37] NOBILI V,CARPINO G,ALISI A,et al. Hepatic progenitorcells activation,fibrosis,and adipokines production in pediat-ric nonalcoholic fatty liver disease[J]. Hepatology,2012,56(6):2142-2153.
[38] DONG ZX,SU L,BRYMORA J,et al. Resistin mediates thehepatic stellate cell phenotype[J]. World J Gastroenterol,2013,19(28):4475-4485.
[39] KRIST J,WIEDER K,KLOTING N,et al. Effects of weight lossand exercise on apelin serum concentrations and adipose tis-sue expression in human obesity[J]. Obesity Facts,2013,6(1):57-69.
[40] NAN YM,KONG LB,REN WG,et al. Activation of peroxisomeproliferator activated receptor alpha ameliorates ethanol medi-ated liver fibrosis in mice[J]. Lipids Health Dis,2013,12(1):11.
[41] REN RZ,ZHANG X,XU J,et al. Chronic ethanol consumptionincreases the levels of chemerin in the serum and adipose tis-sue of humans and rats[J]. Acta Pharmacol Sin,2012,33(5):652-659.
[42] WU MS,NING CL,LIU KZ. The research progress of Chemerin[J]. Med Recap,2016,22(11):2102-2106.(in Chinese)吴孟水,宁翠利,刘宽芝. Chemerin的研究进展[J].医学综述,2016,22(11):2102-2106.
[43] DOCKE S,LOCK JF,BIRKENFELD AL,et al. Elevated hepat-ic chemerin mRNA expression in human non-alcoholic fattyliver disease[J]. Eur J Endocrinol,2013,169(5):547-557.
[44] EISINGER K,KRAUTBAUER S,WIEST R,et al. Portal veinomentin is increased in patients with liver cirrhosis but is notassociated with complications of portal hypertension[J]. Eur JClin Invest,2013,43(9):926-932.