苦参碱对NASH大鼠氧化应激的影响以及NASH患者氧化应激相关指标的检测及意义
摘要
非酒精性脂肪性肝病(NAFLD)是一种与胰岛素抵抗(IR)和遗传易感密切相关的代谢应激性肝脏损伤,疾病谱包括非酒精性单纯性脂肪肝(NAFL)、非酒精性脂肪性肝炎(NASH)及其相关肝硬化和肝细胞癌。NAFLD发病机制复杂,目前多数学者认同“二次打击”学说：胰岛素抵抗(IR)作为初次打击造成游离脂肪酸的增加,肝内脂肪蓄积形成脂肪肝;氧化应激及脂质过氧化损伤作为第二次打击导致脂肪变的肝脏发生炎症、坏死和纤维化。氧化应激在NASH的发生发展中起了关键作用。因此,抑制氧化应激、脂质过氧化可阻止NASH进程,对于NAFLD的预防和治疗具有重要意义。
目前对NAFLD的治疗多采用多烯磷脂酰胆碱、还原型谷胱甘肽、维生素E、熊去氧胆酸、水飞蓟素等细胞膜稳定剂和抗氧化剂,但治疗效果并不十分理想。因此,选择新型的抗氧化应激药物治疗对NAFLD有着非常重要的临床价值。日前,中医中药在抗炎抗氧化方面的疗效日益受到重视。目前研究发现生物碱,黄酮类,酚类等中药成分具有较明确的抗氧化作用,中药单体具有疗效确实,多靶点多环节起效,毒副作用小等独特优势。其中的佼佼者苦参碱(MT),是生物碱类的中药活性成分,其抗炎、抗氧化、抗纤维化等作用显著。
环氧合酶(COX)是一种膜结合蛋白,为前列腺素(PG)合成过程中的一个重要的限速酶,在慢性炎症刺激时可促进TNF-α等炎症介质大量释放,诱导肝脏炎症细胞浸润。诱导型一氧化氮合酶(iNOS)在炎症刺激下,可大量表达和激活,持续催化产生大量一氧化氮(N0),对肝细胞产生毒性作用。已有研究表明,肝脏发生炎症和坏死的同时,COX-2、 iNOS均表达增高,且与肝脏炎症呈正相关。本研究旨在通过建立动物脂肪肝模型观察苦参碱对脂肪肝大鼠的疗效,并探讨其对肝脏环氧化物酶(COX-2)、诱导型一氧化氮合酶(iNOS)表达的影响。方法：选用4周龄Wistar大鼠30只,体重为113-138g,平均125.6±7.0g。随机分为3组：正常对照组(C组,n=10)、高脂模型组(M组,n=10)、苦参碱治疗组(Ma组,n=10),雌雄各半。正常对照组投喂普通颗粒饲料,其它组以高脂饲料替代普通饲料投喂。动物造模3周后,C组和M组给生理盐水,Ma组苦参碱36mg/kg/d灌胃治疗,共30天。所有实验动物末次给药后麻醉,腹主动脉采血,分离血清,取肝脏。测定肝指数,肝中甘油三酯(TG)、总胆固醇(TC)的含量,血清TG、TC、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)含量,HE组织病理学分析,荧光定量PCR和免疫组化检测肝脏COX-2、iNOS mRNA转录和蛋白表达水平。
结果：高脂饮食能够引起大鼠脂肪代谢紊乱,肝指数升高,肝组织中TG、TC和血清中TG、TC、HDL-C、LDL-C升高(P<0.05),肝细胞变性坏死和肝组织炎症损伤(P<0.05),肝脏COX-2、iNOS mRNA转录和蛋白表达量增高(P<0.01)；与模型组比较,苦参碱能够降低肝指数,肝组织中TG、TC和血清中TG、TC、HDL-C、LDL-C含量(P<0.05),阻止肝细胞变性坏死,抑制炎症损伤(P<0.01),降低肝脏COX-2、iNOS mRNA转录和蛋白表达水平(P<0.01)。
结论：苦参碱对高脂-脂肪肝大鼠疗效明显,其作用机制可能与抑制COX-2、iNOS mRNA转录和蛋白表达,阻止炎症发生和抗氧化有关。
非酒精性脂肪性肝炎(NASH)为非酒精性脂肪性肝病较严重的病理类型,目前理论认为“二次打击”学说是其重要发病机制之一。“二次打击”主要是多种原因引起的氧化应激或脂质过氧化损伤。肿瘤坏死因子-α(TNF-α)是导致胰岛素抵抗的主要炎症因子之一,肝型脂肪酸结合蛋白(liver type fatty acid binding protein, L-FABP)是一种脂肪酸转运蛋白,其作为有效的内源性抗氧化物,有减轻氧化应激损伤的功能,本研究通过检测NASH患者血清中L-FABP、NF-α的水平,探讨二者在NASH发生发展中的相关性及意义。
方法：收集肝功能异常(ALT在40-200IU/L)的NASH患者50例,对照组健康人群32例。所有受试者经B超检查符合弥漫性脂肪肝的诊断标准,测量身高、体重、腰围及臀围,并计算BMI和WHR,晨起空腹取血检测L-FABP和TNF-α及相关临床指标。
结果：NASH组患者的ALT、AST、CH0、LDL-C、TG、BMI、WHR、hs-CRP、L-FABP和TNF-α水平均显著高于对照组人群(P<0.05)。Spearman相关分析提示,NASH组血清L-FABP水平与TNF-α、CHO、LDL-C、ALT、UA、hs-CRP显著正相关(P<0.05), TNF-α水平与ALT、UA、hs-CRP显著正相关(P<0.05)。
结论：L-FABP和TNF-α可能在NASH患者肝功能损伤与炎症反应中发挥重要作用。
Non-alcoholic fatty liver disease (NAFLD), which is considered to be the hepatic injury related to insulin resisitance and hereditary susceptibility. It encompasses a spectrum of disorders ranging from simple steatosis to inflammatory steatohepatitis (NASH) and cirrhosis. Although the mechanisms are complicated, a large amount of information on the key mechanism is "Two Hits Theory". The first hit of steatosis, giving rise to the first lesions is caused by excess free fatty acids (FFA) in the liver, which are sterified to triglycerides (TG). These initial lesions make the liver vulnerable to aggressive factors of the second hit, which is caused by the oxidative stress and lipid peroxidation. This leads to the occurrence of lesions in the hepatocytes, inflammation and fibrosis, and consequently the evolution of hepatic steatosis to steatohepatitits. Oxidative stress, along with the insulin resistance, plays one of the essential roles in NAFLD pathogenesis. Therefore, treatment with different antioxidants (vitamin E, vitamin C, betaine, etc) has been used in prevent the process of NASH. However, there are no optimal drugs for NASH treatment so far. Some monomers extracted from Chinese herbs have the property of antioxidative stress, such as alkaloid, flavonoid, phenols. Matrine (MT), is an active ingredients of alkaloids, shows an remarkable effect in anti-inflammatory, antioxidant, anti fibrosis aspects.
Cyclo-oxgenase2(COX-2) is a kind of membrane-binding proteins involved in prostaglandin synthesis, it can promote the inflammatory mediator release such as TNF-awith a chronic inflammatory stimulate, induce the liver inflammation cell infiltration. iNos also has high expression and activation with inflammatory stimulate, continuous catalyze and generate a lot of NO, produce toxic effects on liver cells. This study aim to observe the therapeutic effects of Matrine on the expression of COX-2and iNOS in rats with non-alcoholic fatty liver disease
METHODS:30Wistar rats (4-weeks,113～138g weight),were randomly divided into3groups, including the control (C, n=10), high fatty diet model (M, n=10), and matrine treatment groups (Ma, n=10). The groups of M and Ma were fed with a high-lipid diet for3weeks to induce non-alcoholic fatty liver model. After3weeks, the Ma group was administrated with Matrine36mg/kg/d for30days, and the control and model groups were administrated with normal saline. At the last day, rats were sacrificed. Then, the liver index, content of TC, TG in the liver, and the concentrations of TC, TG, HDL-C, LDL-C in serum were examined. In addition, histopathology analysis and NAS Score were performed. Furthermore, the expression of COX-2and iNOS were measured by real-time fluorescent PCR and the immunohistochemistry methods.
RESULTS:High-lipid diet increased the content of TC, TG in liver, the concentrations of TC, TG, HDL-C and LDL-C in serum (P<0.05) and increased the expression of the COX-2and iNOS (P<0.01). Matrine decreased the liver index and the content of TC, TG in liver and the concentration of TC, TG, HDL-C and LDL-C in serum (P<0.05), arrest hepatic cell adipose degeneration, inhibit inflammation and hepatic cell ballooning degeneration (P<0.01), and decreased COX-2and iNOS significantly (P<0.01).
CONCLUTION:Matrine is an effective therapeutic in treating rat non-alcoholic fatty liver disease through synergistical inhibition of COX-2and iNOS, resulting in preventing inflammation and oxidation.
Objective:To investigate the serum level of liver-type fatty acid binding protein (L-FABP) and tumor necrosis factor-α (TNF-α) and their relationship with the function and inflammation of the liver in non-alcoholic steatohepatitis(NASH).
Methods:50cases of NASH patients and32cases of healthy person as control group were included. B ultrasonic inspection has been performed to confirm the diagnosis of diffuse fatty liver. The height, weight, waist, and hipline of all subjects were measured, BMI and WHR were calculated. The level of serum L-FABP, TNF-a and related biochemical indexes were measured.
Results:Compared with the control group, the serum level of ALT, AST, CHO, LDL-C, TG, BMI, WHR, hs-CRP, L-FABP and TNF-α in the NASH group was significantly increased (P<0.05). Spearman correlation analysis revealed that the level of L-FABP is positively correlated with TNF-α, CHO, LDL-C, ALT, UA, and hs-CRP (P<0.05), and the level of TNF-α is positively correlated with ALT, UA, and hs-CRP. Conclusion:L-FABP and TNF-α may play important role in the impaired function and inflammation in the liver of NASH.
目前对NAFLD的治疗多采用多烯磷脂酰胆碱、还原型谷胱甘肽、维生素E、熊去氧胆酸、水飞蓟素等细胞膜稳定剂和抗氧化剂,但治疗效果并不十分理想。因此,选择新型的抗氧化应激药物治疗对NAFLD有着非常重要的临床价值。日前,中医中药在抗炎抗氧化方面的疗效日益受到重视。目前研究发现生物碱,黄酮类,酚类等中药成分具有较明确的抗氧化作用,中药单体具有疗效确实,多靶点多环节起效,毒副作用小等独特优势。其中的佼佼者苦参碱(MT),是生物碱类的中药活性成分,其抗炎、抗氧化、抗纤维化等作用显著。
环氧合酶(COX)是一种膜结合蛋白,为前列腺素(PG)合成过程中的一个重要的限速酶,在慢性炎症刺激时可促进TNF-α等炎症介质大量释放,诱导肝脏炎症细胞浸润。诱导型一氧化氮合酶(iNOS)在炎症刺激下,可大量表达和激活,持续催化产生大量一氧化氮(N0),对肝细胞产生毒性作用。已有研究表明,肝脏发生炎症和坏死的同时,COX-2、 iNOS均表达增高,且与肝脏炎症呈正相关。本研究旨在通过建立动物脂肪肝模型观察苦参碱对脂肪肝大鼠的疗效,并探讨其对肝脏环氧化物酶(COX-2)、诱导型一氧化氮合酶(iNOS)表达的影响。方法：选用4周龄Wistar大鼠30只,体重为113-138g,平均125.6±7.0g。随机分为3组：正常对照组(C组,n=10)、高脂模型组(M组,n=10)、苦参碱治疗组(Ma组,n=10),雌雄各半。正常对照组投喂普通颗粒饲料,其它组以高脂饲料替代普通饲料投喂。动物造模3周后,C组和M组给生理盐水,Ma组苦参碱36mg/kg/d灌胃治疗,共30天。所有实验动物末次给药后麻醉,腹主动脉采血,分离血清,取肝脏。测定肝指数,肝中甘油三酯(TG)、总胆固醇(TC)的含量,血清TG、TC、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)含量,HE组织病理学分析,荧光定量PCR和免疫组化检测肝脏COX-2、iNOS mRNA转录和蛋白表达水平。
结果：高脂饮食能够引起大鼠脂肪代谢紊乱,肝指数升高,肝组织中TG、TC和血清中TG、TC、HDL-C、LDL-C升高(P<0.05),肝细胞变性坏死和肝组织炎症损伤(P<0.05),肝脏COX-2、iNOS mRNA转录和蛋白表达量增高(P<0.01)；与模型组比较,苦参碱能够降低肝指数,肝组织中TG、TC和血清中TG、TC、HDL-C、LDL-C含量(P<0.05),阻止肝细胞变性坏死,抑制炎症损伤(P<0.01),降低肝脏COX-2、iNOS mRNA转录和蛋白表达水平(P<0.01)。
结论：苦参碱对高脂-脂肪肝大鼠疗效明显,其作用机制可能与抑制COX-2、iNOS mRNA转录和蛋白表达,阻止炎症发生和抗氧化有关。
非酒精性脂肪性肝炎(NASH)为非酒精性脂肪性肝病较严重的病理类型,目前理论认为“二次打击”学说是其重要发病机制之一。“二次打击”主要是多种原因引起的氧化应激或脂质过氧化损伤。肿瘤坏死因子-α(TNF-α)是导致胰岛素抵抗的主要炎症因子之一,肝型脂肪酸结合蛋白(liver type fatty acid binding protein, L-FABP)是一种脂肪酸转运蛋白,其作为有效的内源性抗氧化物,有减轻氧化应激损伤的功能,本研究通过检测NASH患者血清中L-FABP、NF-α的水平,探讨二者在NASH发生发展中的相关性及意义。
方法：收集肝功能异常(ALT在40-200IU/L)的NASH患者50例,对照组健康人群32例。所有受试者经B超检查符合弥漫性脂肪肝的诊断标准,测量身高、体重、腰围及臀围,并计算BMI和WHR,晨起空腹取血检测L-FABP和TNF-α及相关临床指标。
结果：NASH组患者的ALT、AST、CH0、LDL-C、TG、BMI、WHR、hs-CRP、L-FABP和TNF-α水平均显著高于对照组人群(P<0.05)。Spearman相关分析提示,NASH组血清L-FABP水平与TNF-α、CHO、LDL-C、ALT、UA、hs-CRP显著正相关(P<0.05), TNF-α水平与ALT、UA、hs-CRP显著正相关(P<0.05)。
结论：L-FABP和TNF-α可能在NASH患者肝功能损伤与炎症反应中发挥重要作用。
Non-alcoholic fatty liver disease (NAFLD), which is considered to be the hepatic injury related to insulin resisitance and hereditary susceptibility. It encompasses a spectrum of disorders ranging from simple steatosis to inflammatory steatohepatitis (NASH) and cirrhosis. Although the mechanisms are complicated, a large amount of information on the key mechanism is "Two Hits Theory". The first hit of steatosis, giving rise to the first lesions is caused by excess free fatty acids (FFA) in the liver, which are sterified to triglycerides (TG). These initial lesions make the liver vulnerable to aggressive factors of the second hit, which is caused by the oxidative stress and lipid peroxidation. This leads to the occurrence of lesions in the hepatocytes, inflammation and fibrosis, and consequently the evolution of hepatic steatosis to steatohepatitits. Oxidative stress, along with the insulin resistance, plays one of the essential roles in NAFLD pathogenesis. Therefore, treatment with different antioxidants (vitamin E, vitamin C, betaine, etc) has been used in prevent the process of NASH. However, there are no optimal drugs for NASH treatment so far. Some monomers extracted from Chinese herbs have the property of antioxidative stress, such as alkaloid, flavonoid, phenols. Matrine (MT), is an active ingredients of alkaloids, shows an remarkable effect in anti-inflammatory, antioxidant, anti fibrosis aspects.
Cyclo-oxgenase2(COX-2) is a kind of membrane-binding proteins involved in prostaglandin synthesis, it can promote the inflammatory mediator release such as TNF-awith a chronic inflammatory stimulate, induce the liver inflammation cell infiltration. iNos also has high expression and activation with inflammatory stimulate, continuous catalyze and generate a lot of NO, produce toxic effects on liver cells. This study aim to observe the therapeutic effects of Matrine on the expression of COX-2and iNOS in rats with non-alcoholic fatty liver disease
METHODS:30Wistar rats (4-weeks,113～138g weight),were randomly divided into3groups, including the control (C, n=10), high fatty diet model (M, n=10), and matrine treatment groups (Ma, n=10). The groups of M and Ma were fed with a high-lipid diet for3weeks to induce non-alcoholic fatty liver model. After3weeks, the Ma group was administrated with Matrine36mg/kg/d for30days, and the control and model groups were administrated with normal saline. At the last day, rats were sacrificed. Then, the liver index, content of TC, TG in the liver, and the concentrations of TC, TG, HDL-C, LDL-C in serum were examined. In addition, histopathology analysis and NAS Score were performed. Furthermore, the expression of COX-2and iNOS were measured by real-time fluorescent PCR and the immunohistochemistry methods.
RESULTS:High-lipid diet increased the content of TC, TG in liver, the concentrations of TC, TG, HDL-C and LDL-C in serum (P<0.05) and increased the expression of the COX-2and iNOS (P<0.01). Matrine decreased the liver index and the content of TC, TG in liver and the concentration of TC, TG, HDL-C and LDL-C in serum (P<0.05), arrest hepatic cell adipose degeneration, inhibit inflammation and hepatic cell ballooning degeneration (P<0.01), and decreased COX-2and iNOS significantly (P<0.01).
CONCLUTION:Matrine is an effective therapeutic in treating rat non-alcoholic fatty liver disease through synergistical inhibition of COX-2and iNOS, resulting in preventing inflammation and oxidation.
Objective:To investigate the serum level of liver-type fatty acid binding protein (L-FABP) and tumor necrosis factor-α (TNF-α) and their relationship with the function and inflammation of the liver in non-alcoholic steatohepatitis(NASH).
Methods:50cases of NASH patients and32cases of healthy person as control group were included. B ultrasonic inspection has been performed to confirm the diagnosis of diffuse fatty liver. The height, weight, waist, and hipline of all subjects were measured, BMI and WHR were calculated. The level of serum L-FABP, TNF-a and related biochemical indexes were measured.
Results:Compared with the control group, the serum level of ALT, AST, CHO, LDL-C, TG, BMI, WHR, hs-CRP, L-FABP and TNF-α in the NASH group was significantly increased (P<0.05). Spearman correlation analysis revealed that the level of L-FABP is positively correlated with TNF-α, CHO, LDL-C, ALT, UA, and hs-CRP (P<0.05), and the level of TNF-α is positively correlated with ALT, UA, and hs-CRP. Conclusion:L-FABP and TNF-α may play important role in the impaired function and inflammation in the liver of NASH.
引文
[1]中华医学会肝病学分会脂肪肝和酒精性肝病学组.非酒精性脂肪性肝病诊疗指南(2010年修订版)[J].中华肝脏病杂志,2010；18(3)：163-166.
[2]Farrell GC, Laner CZ. Nonalcoholic fatty liver discase:from steatosis to cirrhosis[J]. Hepatology,2006;43(2 Suppl 1):S99-S112.
[3]de Alwis NM, DayCP. Non-alcoholic fatty liver disease:the mist gradually clears[J]. J Hepatol,2008;48 Suppl 1:S104-S112.
[4]Kopec KL, Burns D, et al. Nonalcoholic fatty liver disease:a review of the spectrum of disease, diagnosis, and therapy[J]. Nutr Clin Pract,2011; 26(5):565-576.
[5]Rolo AP, Teodoro JS, Palmeira CM, et al. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis[J]. Free Radic Biol Med,2012; 52(1):59-69.
[6]Abenavoli L, Milic N, Capasso F, et al. Anti-oxidant therapy in non-alcoholic fatty liver disease:the role of silymarin[J]. Endocrine,2012;42(3):754-5.
[7]Haedrich M, Dufour JF. UDCA for NASH:end of the story?[J]. J Hepatol,2011; 54(5):856-858.
[8]Wang T, Choi RC, Li J, et al. Trillin, A steroidal saponin isolated from the rhizomes of Dioscorea nipponica, exerts protective effects against hyperlipidemia and oxidative stress[J]. J Ethnopharmacol,2012;139(1):214-220.
[9]Hu W, Han W, Huang C, et al. Protective effect of the methanolic extract from Duchesnea indica against oxidative stress in vitro and in vivo[J]. Environ Toxicol Pharmacol,2011; 31(1):42-50.
[10]Szeto YT, Wong SC, Wong JW, et al. In vitro antioxidation activity and genoprotective effect of selected Chinese medicinal herbs[J]. Am J Chin Med,2011; 39(4):827-838.
[11]Ai ZL, Zhang WS, Yao SK, et al. Effect of baicalin on liver fatty acid binding protein in oxidative stress model in vitro[J]. Zhonghua Gan Zang Bing Za Zhi,2011; 19(12):927-931.
[12]Lim HA, Lee EK, Kim JM, et al. PPARgamma activation by baicalin suppresses NF-kappaB-mediated inflammation in aged rat kidney[J]. Biogerontology,2012; 13(2):133-145.
[13]Zhang B, Liu ZY, Li YY, et al. Antiinflammatory effects of matrine in LPS-induced acute lung injury in mice[J]. Eur J Pharm Sci,2011; 44(5):573-579.
[14]Cheng F, Wang Y, Li J, et al. Berberine improves endothelial function by reducing endothelial microparticles-mediated oxidative stress in humans[J]. Int J Cardiol,2012 [Epub ahead of print].
[15]Domitrovic R, Jakovac H, Blagojevic G. Hepatoprotective activity of berberine is mediated by inhibition of TNF-alpha, COX-2, and iNOS expression in CC1(4)-intoxicated mice[J]. Toxicology,2011; 280(1-2):33-43.
[16]Xiao J, Ho CT, Liong EC, et al. Epigallocatechin gallate attenuates fibrosis, oxidative stress, and inflammation in non-alcoholic fatty liver disease t model through TGF/SMAD, PI3 K/Akt/FoxO1, and NF-kappa B pathways[J]. Eur J Nutr.2013 Mar 21. [Epub ahead of print]
[17]Zhao J, Zheng H, Liu Y, et al. Anti-inflammatory effects of total alkaloids from Rubus aleaefolius Poir. on non-alcoholic fatty liver disease through regulation of the NF-κB pathway[J]. Int J Mol Med.2013; 31(4):931-7.
[18]Wang W, Zhou W, Wang B, et al. Antioxidant effect of apolipoprotein A-I on high-fat diet-induced non-alcoholic fatty liver disease in rabbits[J]. Acta Biochim Biophys Sin (Shanghai).2013; 45(2):95-103.
[19]Soardo G, Donnini D, Domenis L. Oxidative stress is activated by free fatty acids in cultured human hepatocytes[J]. Metab Syndr Relat Disord.2011; 9(5):397-401.
[20]Saito Y, Mori H, Takasu C,et al. Beneficial effects of green tea catechin on massive hepatectomy model in rats[J]. J Gastroenterol.2013 Mar 30. [Epub ahead of print]
[21]Fan JG, Farrell GC. Epidemiology of non-alcoholic fatty liver disease in China[J]. J HepatOl.2009;50:204-10.
[22]Farrell GC. Laner CZ. Nonalcoholic fatty liver discase:from steatosis to cirrhosis[J]. Hepatology.2006; 43(2 Suppl 1):S99-S112.
[23]de Alwis NM. DayCP. Non-alcoholic fatty liver disease:the mist gradually clears[J]. J Hepatol,2008; 48 Suppl 1:S104-S112.
[24]Angulo P. GI epidemiology:nonalcoholic fatty liver disease[J]. Aliment Pharmacol Ther,2007; 25:883-889.
[25]Fan JG. Saibara T'Chitturi S. What are tIle risk factors and settings of non. alcoholic fatty liver disease in Asia-Pacific[J]? J Gastroenterol Hepatol,2007; 22:794-800.
[26]Day CP, James OF. Steatohepatitis:a tale of two"hits" [J]? Gastroenterology 1998; 114:842-845.
[27]Fan JG. Strengthen the management ofchronic viral hepatitis patients with fatty liver[J]. Zhonghua Ganzangbing Zazhi,2009;17:801-803.
[28]Torres DM, Harrison SA. Diagnosis and therapy of nonalcoholic steatohepatitis[J]. Gastroenterology,2008; 134:1682-1698.
[29]Fan JG. Impact of nOB—alcoholic fatty liver disease on accelerated metabolic complications[J]. J Dig Dis,2008;9:63-67.
[30]Bugianesi E. Nonalcoholic fatty liver disease(NAFLD)and cardiac lipotoxicity: another piece ofthe puzzle[J]. Hepatology,2008; 47:2-4.
[31]Loomba R, Sirlin CB, Schwimmer JB, et al. Advances in pediatric nonalcoholic fatty liver disease[J]. Hepatology,2009; 50:1282-1293.
[32]Gorg B, Schliess F, Haussinger D. Osmotic and Oxidative/Nitrosative Stress in Ammonia Toxicity and Hepatic Encephalopathy[J]. Arch Biochem Biophys.2013 Apr 5. [Epub ahead of print]
[33]Xiao J, Guo R, Fung ML, et al. Therapeutic approaches to non-alcoholic fatty liver disease:past achievements and future challenges[J]. Hepatobiliary Pancreat Dis Int.2013; 12(2):125-35.
[34]Zhang HF, Shi LJ, Song GY, et al. Protective effects of matrine against progression of high-fructose diet-induced steatohepatitis by enhancing antioxidant and anti-inflammatory defences involving Nrf2 translocation[J]. Food Chem Toxicol.2013; 55:70-7.
[35]Sun M, Cao H, Sun L, et al. Antitumor activities of kushen:literature review[J]. Evid Based Complement Alternat Med.2012;2012:373219.
[36]Chen J, Liu D, Bai Q, et al. Celecoxib attenuates liver steatosis and inflammation in non-alcoholic steatohepatitis induced by high-fat diet in rats[J]. Mol Med Rep.2011, 4(5):811-6.
[37]Cao MB, Yang YX, Dong L. Relationship between single nucleotide polymorphisms in the promoter of COX-2 gene and hereditariness to NAFLD[J]. Zhonghua Gan Zang Bing Za Zhi.2010;18(10):773-7.
[38]Li N, Sood S, Wang S, et al. Overexpression of 5-lipoxygenase and cyclooxygenase-2 in hamster and human nral cancer and chemopreventive effects of zileuton and celecoxib[J]. Clin Cancer Res,2005; 11 (5):2089-2096.
[39]Chakraborti AK, Garg SK, Kumar R, et al. Progress in COX-2 inhibitors:a journey so far[J]. Curr Med Chem,2010;17(15):1563-1593.
[40]Esposito E, lacono A, Bianco G, et al. Probiotics reduce the inflammatory response induced by a high-fat diet in the liver of young rats[J]. J Nutr.2009; 139(5):905-11.
[41]Yokoyama Y, Xu H, Kresge N, et al. Role of thromboxane A2 in early BDL-induced portal hypertension[J]. Am J Physiol Gastrointest Liver Physiol,2003; 284(3):G453-460.
[42]Yin XY, Jiang JM, Liu J Y, et al. Effects of endogenous nit ric oxide induced by 5-fluorouracil and L-Arg on liver carcinoma in nude mice [J]. World J Gastroenterology, 2007;13 (46):6249-6253.
[43]LIU MY, CHENG YJ, CHEN CK, et al. Cocxposure of leadand lipopolysaceharide-induced fiver injury in rats:involvement of nitric oxide-initiated oxidative stress and TNF-alpha[J]. Shock,2005; 23(4):360-364.
[44]Tipoe GL, Ho CT, Liong EC, et al. Voluntary oral feeding of rats not requiring a very high fat diet is a clinically relevant animal model of non-alcoholic fatty liver disease (NAFLD) [J]. Histol Histopathol.2009;24(9):1161-9.
[45]Sanchez-Miranda E, Lemus-Bautista J, Perez S, et al. Effect of kramecyne on the inflammatory response in lipopolysaccharide-stimulated peritoneal macrophages[J]. Evid Based Complement Alternat Med.2013; 2013:762020.
[46]Vuppalanchi R, Chalasani N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis:selected practical issues in their evaluation and management[J]. Hepatology.2009 Jan; 49(1):306-17.
[47]Day CP, James OF. Steatohepatitis:a tale of two"hits" [J]? Gastroenterology 1998; 114:842-845.
[48]李兰芳等。肿瘤坏死因子α诱导肝细胞胰岛素抵抗的机制[J]。中国糖尿病杂志2012；20(1)：58-60.
[49]Wang G, Gong Y, Anderson J, et al. Antioxidative function of L-FABP in L-FABP stably transfected.Chang liver cells[J]. Hepatology,2005; 42(4):871-879.
[50]Liu W, Baker SS, Baker RD, et al. Upregulation of hemoglobin expression by oxidative stress in hepatocytes and its implication in nonalcoholic steatohepatitis [J]. PLoS One,2011; 6(9):e24363.
[51]Leamy AK, Egnatchik RA, Young JD. Molecular mechanisms and the role of saturated fatty acids in the progression of non-alcoholic fatty liver disease [J].Prog Lipid Res,2013; 52(1):165-74.
[52]Arias IM. Liver function from Y to Z[J]. J Clin Invest,2012 Aug 1; 122(8):2763-4. Review.
[53]Lancaster JR Jr, Laster SM, Gooding LR. Inhibition of target cell mitochondrial electron transfer by tumor necrosis factor[J]. FEBS Lett,1989; 248:169-174.
[54]Chitturi S, George J. Hepatotoxicity of commonly used drugs:nonsteroidal anti-inflammatory drugs, antihypertensives, antidiabetic agents, anticonvulsants, lipid-lowering agents, psychotropic drugs[J]. Sermin Liver Dis,2002; 22:169-183.
[55]Wang J, Wei Y, Wang D, et al. Proteomic study of the effects of complex environmental stresses in the livers of goldfish(Carassius auratus)that inhabit Gaobeidian Lake in Beijing, China[J]. Ecotoxicology,2008;17:213-220.
[56]Pagliassotti MJ. Endoplasmic reticulum stress in nonalcoholic fatty liver disease[J]. Annu Rev Nutr.2012;21;(32):17-33.Review.
[57]Rolo AP, Teodoro JS, Palmeira CM. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis[J]. Free Radic Biol Med,2012; 52(1):59-69.
[1]V. Ratziu, S. Bellentani, H. Cortez-Pinto, et al. A position statement on NAFLD/NASH based on the EASL 2009 special conference. Journal of Hepatology, 2010;53(2):372-384.
[2]L. S. Szczepaniak, P. Nurenberg, D. Leonard et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content:prevalence of hepatic steatosis in the general population. American Journal of Physiology,2005;288(2):E462-E468.
[3]G. Marchesini, M. Brizi, A. M. Morselli-Labate, et al. Association of nonalcoholic fatty liver disease with insulin resistance. American Journal of Medicine, 1999;107(5):450-455.
[4]P. Marceau, S. Biron, F. S. Hould et al. Liver pathology and the metabolic syndrome X in severe obesity. Journal of Clinical Endocrinology and Metabolism,1999;84(5): 1513-1517.
[5]G.Marchesini, M. Brizi, G. Blanchi et al. Nonalcoholic fatty liver disease:a feature of the metabolic syndrome. Diabetes,2001;50,(8):1844-1850.
[6]Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel Ⅲ) final report. Circulation,2002; 106(25):3143-3421.
[7]A. I. Shulman and D. J. Mangelsdorf. Retinoid X receptor heterodimers in the metabolic syndrome. The New England Journal of Medicine,2005;353(6):604-615.
[8]J. R. Lewis and S. R. Mohanty. Nonalcoholic fatty liver disease:a review and update. Digestive Diseases and Sciences,2010; 55(3):560-578.
[9]A. Wieckowska and A. E. Feldstein. Diagnosis of nonalcoholic fatty liver disease: invasive versus noninvasive. Seminars in Liver Disease,2008; 28(4):386-395.
[10]B. W. Smith and L. A. Adams. Nonalcoholic fatty liver disease and diabetes mellitus:pathogenesis and treatment. Nature Reviews Endocrinology,2011; 7(8):456-465.
[11]J. D. Browning, L. S. Szczepaniak, R. Dobbins et al. Prevalence of hepatic steatosis in an urban population in the United States:impact of ethnicity. Hepatology,2004; 40(6):1387-1395.
[12]P.Mofrad, M. J. Contos, M. Haque, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology,2003; 37 (6):1286-1292.
[13]D. S. Pratt and M. M. Kaplan. Evaluation of abnormal liverenzyme results in asymptomatic patients. The New England Journal of Medicine,2000; 342(17): 1266-1271.
[14]P. Angulo, J. C. Keach, K. P. Batts, et al. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology,1999; 30(6):1356-1362.
[15]R. Haring, H. Wallaschofski, M. Nauck, et al. Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum gamma-glutamyl transpeptidase levels. Hepatology,2009; 50(5):1403-1411.
[16]C. E. Ruhl, J. E. Everhart. Elevated serum alanine aminotransferase and gamma-glutamyltransferase and mortality in the United States population. Gastroenterology; 2009; 136 (2):477-485.
[17]Y. Sumida, T. Yoshikawa, T. Okanoue. Role of hepatic iron in non-alcoholic steatohepatitis.Hepatology Research,2009; 39(3):213-222.
[18]A. M. Diehl. Nonalcoholic fatty liver disease:implications for alcoholic liver disease pathogenesis. Alcoholism,2001; 25 (5):8S-14S.
[19]S. Abiru, K. Migita, Y. Maeda, et al. Serum cytokineand soluble cytokine receptor levels in patients with nonalcoholic steatohepatitis. Liver International,2006; 26(1): 39-45.
[20]M. Shimada, H. Kawahara, K. Ozaki, et al. Usefulnessof a combined evaluation of the serum adiponectin level,HOMA-IR, and serum type IV collagen 7S level to predict the early stage of nonalcoholic steatohepatitis. American Journal of Gastroenterology, 2007; 102(9):1931-1938.
[21]M. Argentou, D. G. Tiniakos, M. Karanikolas, et al. Adipokine serum levels are related to liver histology inseverely obese patients undergoing bariatric surgery. ObesitySurgery,2009; 19(9):1313-1323.
[22]M. Yoneda, H. Mawatari, K. Fujita, et al. High-sensitivity C-reactive protein is an independent clinical feature of nonalcoholic steatohepatitis (NASH) and also of the severity of fibrosis in NASH.Journal of Gastroenterology,2007; 42(7):573-582.
[23]M. Lemoine, V. Ratziu, M. Kim, et al. Serum adipokine levels predictive of liver injury in non-alcoholic fatty liver disease. Liver International,2009; 29(9):1431-1438.
[24]N. Chalasani, D. W. Crabb, O. W. Cummings, et al. Does leptin play a role in the pathogenesis of human nonalcoholic steatohepatitis? American Journal of Gastroenterology,2003;98(12):2771-2776.
[25]S. Chitturi, G. Farrell, L. Frost, et al. Serum leptin in NASH correlates with hepatic steatosis but not fibrosis:a manifestation of lipotoxicity? Hepatology,2002; 36(2):403-409.
[26]H. Sakugawa, T. Nakayoshi, K. Kobashigawa, et al. Clinical usefulness of biochemical markers of liver fibrosis in patients with nonalcoholic fatty liver disease. World Journal of Gastroenterology,2005; 11(2):255-259.
[27]M. Yoneda, H.Mawatari, K. Fujita, et al. Type IV collagen 7s domain is an independent clinical marker of the severity of fibrosis in patients with nonalcoholic steatohepatitis before the cirrhotic stage. Journal of Gastroenterology,2007; 42(5): 375-381.
[28]C. P. M. S. Oliveira, L. C. Da Costa Gayotto, C. Tatai, et al. Oxidative stress in the pathogenesis of nonalcoholic fatty liver disease, in rats fed with a choline-deficient diet. Journal of Cellular andMolecularMedicine,2002; 6(3):399-406.
[29]A. Wieckowska, A. J. McCullough, A. E. Feldstein. Noninvasive diagnosis and monitoring of nonalcoholic steatohepatitis:present and future. Hepatology,2007; 46 (2):582-589.
[30]A. E. Feldstein, A. Canbay, P. Angulo, et al. Hepatocyte apoptosis and Fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology,2003; 125(2):437-443.
[31]A. Wieckowska, N. N. Zein, L. M. Yerian, et al. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease.Hepatology,2006; 44(1):27-33.
[32]. A. E. Feldstein, A.Wieckowska, A. R. Lopez, et al. Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis:amulticenter validation study. Hepatology,2009; 50(4):1072-1078.
[33]D. L. Diab, L. Yerian, P. Schauer, et al. Cytokeratin 18 fragment levels as a noninvasive biomarker for nonalcoholic steatohepatitis in bariatric surgery patients. Clinical Gastroenterology and Hepatology,2008; 6 (11):1249-1254.
[34]J. K. Dowman, J. W. Tomlinson, P. N. Newsome. Systematic review:the diagnosis and staging of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Alimentary Pharmacology and Therapeutics,2011; 33(5):525-540.
[35]G. Bedogni, S. Bellentani, L. Miglioli, et al. The fatty liver index:a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterology, 2006; 6:33.
[36]G. Bedogni, H. S. Kahn, S. Bellentani, and C. Tiribelli. A simple index of lipid overaccumulation is a good marker of liver steatosis. BMC Gastroenterology,2010; 10:98.
[37]S. Petta, M. Amato, D. Cabibi, et al. Visceral adiposity index is associated with histological findings and high viral load in patients with chronic hepatitis C due to genotype 1. Hepatology,2010; 52(5):1543-1552.
[38]J. B. Dixon, P. S. Bhathal, P. E. O'Brien. Nonalcoholic fatty liver disease:predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology, 2001; 121(1):91-100.
[39]N. A. Palekar, R. Naus, S. P. Larson, et al. Clinical model for distinguishing nonalcoholic steatohepatitis from simple steatosis in patients with nonalcoholic fatty liver disease. Liver International,2006;26 (2):151-156.
[40]T. Poynard, V. Ratziu, F. Charlotte, et al. Diagnostic value of biochemical markers (Nash Test) for the prediction of non alcoholo steato hepatitis in patients with non-alcoholic fatty liver disease. BMC Gastroenterology,2006; 6:34.
[41]V. Ratziu, J. Massard, F. Charlotte, et al. Diagnostic value of biochemical markers (Fibro Test-FibroSURE) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease. BMC Gastroenterology,2006; 6:6.
[42]P. Angulo, J. M. Hui, G. Marchesini, et al. The NAFLD fibrosis score:a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology, 2007; 45(4):846-854.
[43]G. Musso, R. Gambino, M. Cassader, et al. Metaanalysis:natural history of non-alcoholic fatty liver disease and diagnostic accuracy of non-invasive tests for liver disease severity. Annals of Medicine, In press.
[44]W. M. C. Rosenberg, M. Voelker, R. Thiel, et al. Serum markers detect the presence of liver fibrosis:a cohort study. Gastroenterology,2004; 127 (6):1704-1713.
[45]I. N. Guha, J. Parkes, P. Roderick et al. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease:validating the European liver fibrosis panel and exploring simple markers. Hepatology,2008; 47(2):455-460.
[46]S. A. Harrison, D. Oliver, H. L. Arnold, et al. Development and validation of a simpleNAFLD clinical scoring system for identifying patients without advanced disease. Gut,2008; 57(10):1441-1447.
[47]G. Ruffillo, E. Fassio, E. Alvarez, et al. Comparison of NAFLD fibrosis score and BARD score in predicting fibrosis in nonalcoholic fatty liver disease. Journal of Hepatology,2011; 54(1):160-163.
[48]C. T. Wai, J. K. Greenson, R. J. Fontana, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology,2003; 38(2):518-526.
[49]B. A. Neuschwander-Tetri, J. M. Clark, N. M. Bass et al. Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease. Hepatology,2010; 52(3):913-924.
[50]P. CaTes, F. Oberti, S. Michalak, et al. A novel panel of blood markers to assess the degree of liver fibrosis. Hepatology,2005;42(6):1373-1381.
[51]Mehta SR, Thomas EL, Bell JD, et al. Non-invasive means of mcasuring hepatic fat content. World J Gastroenterology,2008;14:3476-3483.
[52]J. Piekarski, H. I. Goldberg, S. A. Royal. Difference between liver and spleen CT numbers in the normal adult:its usefulness in predicting the presence of diffuse liver disease. Radiology,1980; 137(3):727-729.
[53]S.G.H"ubscher. Histological assessment of non-alcoholic fatty liver disease. Histopathology,2006; 49(5):450-465.
[2]Farrell GC, Laner CZ. Nonalcoholic fatty liver discase:from steatosis to cirrhosis[J]. Hepatology,2006;43(2 Suppl 1):S99-S112.
[3]de Alwis NM, DayCP. Non-alcoholic fatty liver disease:the mist gradually clears[J]. J Hepatol,2008;48 Suppl 1:S104-S112.
[4]Kopec KL, Burns D, et al. Nonalcoholic fatty liver disease:a review of the spectrum of disease, diagnosis, and therapy[J]. Nutr Clin Pract,2011; 26(5):565-576.
[5]Rolo AP, Teodoro JS, Palmeira CM, et al. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis[J]. Free Radic Biol Med,2012; 52(1):59-69.
[6]Abenavoli L, Milic N, Capasso F, et al. Anti-oxidant therapy in non-alcoholic fatty liver disease:the role of silymarin[J]. Endocrine,2012;42(3):754-5.
[7]Haedrich M, Dufour JF. UDCA for NASH:end of the story?[J]. J Hepatol,2011; 54(5):856-858.
[8]Wang T, Choi RC, Li J, et al. Trillin, A steroidal saponin isolated from the rhizomes of Dioscorea nipponica, exerts protective effects against hyperlipidemia and oxidative stress[J]. J Ethnopharmacol,2012;139(1):214-220.
[9]Hu W, Han W, Huang C, et al. Protective effect of the methanolic extract from Duchesnea indica against oxidative stress in vitro and in vivo[J]. Environ Toxicol Pharmacol,2011; 31(1):42-50.
[10]Szeto YT, Wong SC, Wong JW, et al. In vitro antioxidation activity and genoprotective effect of selected Chinese medicinal herbs[J]. Am J Chin Med,2011; 39(4):827-838.
[11]Ai ZL, Zhang WS, Yao SK, et al. Effect of baicalin on liver fatty acid binding protein in oxidative stress model in vitro[J]. Zhonghua Gan Zang Bing Za Zhi,2011; 19(12):927-931.
[12]Lim HA, Lee EK, Kim JM, et al. PPARgamma activation by baicalin suppresses NF-kappaB-mediated inflammation in aged rat kidney[J]. Biogerontology,2012; 13(2):133-145.
[13]Zhang B, Liu ZY, Li YY, et al. Antiinflammatory effects of matrine in LPS-induced acute lung injury in mice[J]. Eur J Pharm Sci,2011; 44(5):573-579.
[14]Cheng F, Wang Y, Li J, et al. Berberine improves endothelial function by reducing endothelial microparticles-mediated oxidative stress in humans[J]. Int J Cardiol,2012 [Epub ahead of print].
[15]Domitrovic R, Jakovac H, Blagojevic G. Hepatoprotective activity of berberine is mediated by inhibition of TNF-alpha, COX-2, and iNOS expression in CC1(4)-intoxicated mice[J]. Toxicology,2011; 280(1-2):33-43.
[16]Xiao J, Ho CT, Liong EC, et al. Epigallocatechin gallate attenuates fibrosis, oxidative stress, and inflammation in non-alcoholic fatty liver disease t model through TGF/SMAD, PI3 K/Akt/FoxO1, and NF-kappa B pathways[J]. Eur J Nutr.2013 Mar 21. [Epub ahead of print]
[17]Zhao J, Zheng H, Liu Y, et al. Anti-inflammatory effects of total alkaloids from Rubus aleaefolius Poir. on non-alcoholic fatty liver disease through regulation of the NF-κB pathway[J]. Int J Mol Med.2013; 31(4):931-7.
[18]Wang W, Zhou W, Wang B, et al. Antioxidant effect of apolipoprotein A-I on high-fat diet-induced non-alcoholic fatty liver disease in rabbits[J]. Acta Biochim Biophys Sin (Shanghai).2013; 45(2):95-103.
[19]Soardo G, Donnini D, Domenis L. Oxidative stress is activated by free fatty acids in cultured human hepatocytes[J]. Metab Syndr Relat Disord.2011; 9(5):397-401.
[20]Saito Y, Mori H, Takasu C,et al. Beneficial effects of green tea catechin on massive hepatectomy model in rats[J]. J Gastroenterol.2013 Mar 30. [Epub ahead of print]
[21]Fan JG, Farrell GC. Epidemiology of non-alcoholic fatty liver disease in China[J]. J HepatOl.2009;50:204-10.
[22]Farrell GC. Laner CZ. Nonalcoholic fatty liver discase:from steatosis to cirrhosis[J]. Hepatology.2006; 43(2 Suppl 1):S99-S112.
[23]de Alwis NM. DayCP. Non-alcoholic fatty liver disease:the mist gradually clears[J]. J Hepatol,2008; 48 Suppl 1:S104-S112.
[24]Angulo P. GI epidemiology:nonalcoholic fatty liver disease[J]. Aliment Pharmacol Ther,2007; 25:883-889.
[25]Fan JG. Saibara T'Chitturi S. What are tIle risk factors and settings of non. alcoholic fatty liver disease in Asia-Pacific[J]? J Gastroenterol Hepatol,2007; 22:794-800.
[26]Day CP, James OF. Steatohepatitis:a tale of two"hits" [J]? Gastroenterology 1998; 114:842-845.
[27]Fan JG. Strengthen the management ofchronic viral hepatitis patients with fatty liver[J]. Zhonghua Ganzangbing Zazhi,2009;17:801-803.
[28]Torres DM, Harrison SA. Diagnosis and therapy of nonalcoholic steatohepatitis[J]. Gastroenterology,2008; 134:1682-1698.
[29]Fan JG. Impact of nOB—alcoholic fatty liver disease on accelerated metabolic complications[J]. J Dig Dis,2008;9:63-67.
[30]Bugianesi E. Nonalcoholic fatty liver disease(NAFLD)and cardiac lipotoxicity: another piece ofthe puzzle[J]. Hepatology,2008; 47:2-4.
[31]Loomba R, Sirlin CB, Schwimmer JB, et al. Advances in pediatric nonalcoholic fatty liver disease[J]. Hepatology,2009; 50:1282-1293.
[32]Gorg B, Schliess F, Haussinger D. Osmotic and Oxidative/Nitrosative Stress in Ammonia Toxicity and Hepatic Encephalopathy[J]. Arch Biochem Biophys.2013 Apr 5. [Epub ahead of print]
[33]Xiao J, Guo R, Fung ML, et al. Therapeutic approaches to non-alcoholic fatty liver disease:past achievements and future challenges[J]. Hepatobiliary Pancreat Dis Int.2013; 12(2):125-35.
[34]Zhang HF, Shi LJ, Song GY, et al. Protective effects of matrine against progression of high-fructose diet-induced steatohepatitis by enhancing antioxidant and anti-inflammatory defences involving Nrf2 translocation[J]. Food Chem Toxicol.2013; 55:70-7.
[35]Sun M, Cao H, Sun L, et al. Antitumor activities of kushen:literature review[J]. Evid Based Complement Alternat Med.2012;2012:373219.
[36]Chen J, Liu D, Bai Q, et al. Celecoxib attenuates liver steatosis and inflammation in non-alcoholic steatohepatitis induced by high-fat diet in rats[J]. Mol Med Rep.2011, 4(5):811-6.
[37]Cao MB, Yang YX, Dong L. Relationship between single nucleotide polymorphisms in the promoter of COX-2 gene and hereditariness to NAFLD[J]. Zhonghua Gan Zang Bing Za Zhi.2010;18(10):773-7.
[38]Li N, Sood S, Wang S, et al. Overexpression of 5-lipoxygenase and cyclooxygenase-2 in hamster and human nral cancer and chemopreventive effects of zileuton and celecoxib[J]. Clin Cancer Res,2005; 11 (5):2089-2096.
[39]Chakraborti AK, Garg SK, Kumar R, et al. Progress in COX-2 inhibitors:a journey so far[J]. Curr Med Chem,2010;17(15):1563-1593.
[40]Esposito E, lacono A, Bianco G, et al. Probiotics reduce the inflammatory response induced by a high-fat diet in the liver of young rats[J]. J Nutr.2009; 139(5):905-11.
[41]Yokoyama Y, Xu H, Kresge N, et al. Role of thromboxane A2 in early BDL-induced portal hypertension[J]. Am J Physiol Gastrointest Liver Physiol,2003; 284(3):G453-460.
[42]Yin XY, Jiang JM, Liu J Y, et al. Effects of endogenous nit ric oxide induced by 5-fluorouracil and L-Arg on liver carcinoma in nude mice [J]. World J Gastroenterology, 2007;13 (46):6249-6253.
[43]LIU MY, CHENG YJ, CHEN CK, et al. Cocxposure of leadand lipopolysaceharide-induced fiver injury in rats:involvement of nitric oxide-initiated oxidative stress and TNF-alpha[J]. Shock,2005; 23(4):360-364.
[44]Tipoe GL, Ho CT, Liong EC, et al. Voluntary oral feeding of rats not requiring a very high fat diet is a clinically relevant animal model of non-alcoholic fatty liver disease (NAFLD) [J]. Histol Histopathol.2009;24(9):1161-9.
[45]Sanchez-Miranda E, Lemus-Bautista J, Perez S, et al. Effect of kramecyne on the inflammatory response in lipopolysaccharide-stimulated peritoneal macrophages[J]. Evid Based Complement Alternat Med.2013; 2013:762020.
[46]Vuppalanchi R, Chalasani N. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis:selected practical issues in their evaluation and management[J]. Hepatology.2009 Jan; 49(1):306-17.
[47]Day CP, James OF. Steatohepatitis:a tale of two"hits" [J]? Gastroenterology 1998; 114:842-845.
[48]李兰芳等。肿瘤坏死因子α诱导肝细胞胰岛素抵抗的机制[J]。中国糖尿病杂志2012；20(1)：58-60.
[49]Wang G, Gong Y, Anderson J, et al. Antioxidative function of L-FABP in L-FABP stably transfected.Chang liver cells[J]. Hepatology,2005; 42(4):871-879.
[50]Liu W, Baker SS, Baker RD, et al. Upregulation of hemoglobin expression by oxidative stress in hepatocytes and its implication in nonalcoholic steatohepatitis [J]. PLoS One,2011; 6(9):e24363.
[51]Leamy AK, Egnatchik RA, Young JD. Molecular mechanisms and the role of saturated fatty acids in the progression of non-alcoholic fatty liver disease [J].Prog Lipid Res,2013; 52(1):165-74.
[52]Arias IM. Liver function from Y to Z[J]. J Clin Invest,2012 Aug 1; 122(8):2763-4. Review.
[53]Lancaster JR Jr, Laster SM, Gooding LR. Inhibition of target cell mitochondrial electron transfer by tumor necrosis factor[J]. FEBS Lett,1989; 248:169-174.
[54]Chitturi S, George J. Hepatotoxicity of commonly used drugs:nonsteroidal anti-inflammatory drugs, antihypertensives, antidiabetic agents, anticonvulsants, lipid-lowering agents, psychotropic drugs[J]. Sermin Liver Dis,2002; 22:169-183.
[55]Wang J, Wei Y, Wang D, et al. Proteomic study of the effects of complex environmental stresses in the livers of goldfish(Carassius auratus)that inhabit Gaobeidian Lake in Beijing, China[J]. Ecotoxicology,2008;17:213-220.
[56]Pagliassotti MJ. Endoplasmic reticulum stress in nonalcoholic fatty liver disease[J]. Annu Rev Nutr.2012;21;(32):17-33.Review.
[57]Rolo AP, Teodoro JS, Palmeira CM. Role of oxidative stress in the pathogenesis of nonalcoholic steatohepatitis[J]. Free Radic Biol Med,2012; 52(1):59-69.
[1]V. Ratziu, S. Bellentani, H. Cortez-Pinto, et al. A position statement on NAFLD/NASH based on the EASL 2009 special conference. Journal of Hepatology, 2010;53(2):372-384.
[2]L. S. Szczepaniak, P. Nurenberg, D. Leonard et al. Magnetic resonance spectroscopy to measure hepatic triglyceride content:prevalence of hepatic steatosis in the general population. American Journal of Physiology,2005;288(2):E462-E468.
[3]G. Marchesini, M. Brizi, A. M. Morselli-Labate, et al. Association of nonalcoholic fatty liver disease with insulin resistance. American Journal of Medicine, 1999;107(5):450-455.
[4]P. Marceau, S. Biron, F. S. Hould et al. Liver pathology and the metabolic syndrome X in severe obesity. Journal of Clinical Endocrinology and Metabolism,1999;84(5): 1513-1517.
[5]G.Marchesini, M. Brizi, G. Blanchi et al. Nonalcoholic fatty liver disease:a feature of the metabolic syndrome. Diabetes,2001;50,(8):1844-1850.
[6]Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel Ⅲ) final report. Circulation,2002; 106(25):3143-3421.
[7]A. I. Shulman and D. J. Mangelsdorf. Retinoid X receptor heterodimers in the metabolic syndrome. The New England Journal of Medicine,2005;353(6):604-615.
[8]J. R. Lewis and S. R. Mohanty. Nonalcoholic fatty liver disease:a review and update. Digestive Diseases and Sciences,2010; 55(3):560-578.
[9]A. Wieckowska and A. E. Feldstein. Diagnosis of nonalcoholic fatty liver disease: invasive versus noninvasive. Seminars in Liver Disease,2008; 28(4):386-395.
[10]B. W. Smith and L. A. Adams. Nonalcoholic fatty liver disease and diabetes mellitus:pathogenesis and treatment. Nature Reviews Endocrinology,2011; 7(8):456-465.
[11]J. D. Browning, L. S. Szczepaniak, R. Dobbins et al. Prevalence of hepatic steatosis in an urban population in the United States:impact of ethnicity. Hepatology,2004; 40(6):1387-1395.
[12]P.Mofrad, M. J. Contos, M. Haque, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology,2003; 37 (6):1286-1292.
[13]D. S. Pratt and M. M. Kaplan. Evaluation of abnormal liverenzyme results in asymptomatic patients. The New England Journal of Medicine,2000; 342(17): 1266-1271.
[14]P. Angulo, J. C. Keach, K. P. Batts, et al. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology,1999; 30(6):1356-1362.
[15]R. Haring, H. Wallaschofski, M. Nauck, et al. Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum gamma-glutamyl transpeptidase levels. Hepatology,2009; 50(5):1403-1411.
[16]C. E. Ruhl, J. E. Everhart. Elevated serum alanine aminotransferase and gamma-glutamyltransferase and mortality in the United States population. Gastroenterology; 2009; 136 (2):477-485.
[17]Y. Sumida, T. Yoshikawa, T. Okanoue. Role of hepatic iron in non-alcoholic steatohepatitis.Hepatology Research,2009; 39(3):213-222.
[18]A. M. Diehl. Nonalcoholic fatty liver disease:implications for alcoholic liver disease pathogenesis. Alcoholism,2001; 25 (5):8S-14S.
[19]S. Abiru, K. Migita, Y. Maeda, et al. Serum cytokineand soluble cytokine receptor levels in patients with nonalcoholic steatohepatitis. Liver International,2006; 26(1): 39-45.
[20]M. Shimada, H. Kawahara, K. Ozaki, et al. Usefulnessof a combined evaluation of the serum adiponectin level,HOMA-IR, and serum type IV collagen 7S level to predict the early stage of nonalcoholic steatohepatitis. American Journal of Gastroenterology, 2007; 102(9):1931-1938.
[21]M. Argentou, D. G. Tiniakos, M. Karanikolas, et al. Adipokine serum levels are related to liver histology inseverely obese patients undergoing bariatric surgery. ObesitySurgery,2009; 19(9):1313-1323.
[22]M. Yoneda, H. Mawatari, K. Fujita, et al. High-sensitivity C-reactive protein is an independent clinical feature of nonalcoholic steatohepatitis (NASH) and also of the severity of fibrosis in NASH.Journal of Gastroenterology,2007; 42(7):573-582.
[23]M. Lemoine, V. Ratziu, M. Kim, et al. Serum adipokine levels predictive of liver injury in non-alcoholic fatty liver disease. Liver International,2009; 29(9):1431-1438.
[24]N. Chalasani, D. W. Crabb, O. W. Cummings, et al. Does leptin play a role in the pathogenesis of human nonalcoholic steatohepatitis? American Journal of Gastroenterology,2003;98(12):2771-2776.
[25]S. Chitturi, G. Farrell, L. Frost, et al. Serum leptin in NASH correlates with hepatic steatosis but not fibrosis:a manifestation of lipotoxicity? Hepatology,2002; 36(2):403-409.
[26]H. Sakugawa, T. Nakayoshi, K. Kobashigawa, et al. Clinical usefulness of biochemical markers of liver fibrosis in patients with nonalcoholic fatty liver disease. World Journal of Gastroenterology,2005; 11(2):255-259.
[27]M. Yoneda, H.Mawatari, K. Fujita, et al. Type IV collagen 7s domain is an independent clinical marker of the severity of fibrosis in patients with nonalcoholic steatohepatitis before the cirrhotic stage. Journal of Gastroenterology,2007; 42(5): 375-381.
[28]C. P. M. S. Oliveira, L. C. Da Costa Gayotto, C. Tatai, et al. Oxidative stress in the pathogenesis of nonalcoholic fatty liver disease, in rats fed with a choline-deficient diet. Journal of Cellular andMolecularMedicine,2002; 6(3):399-406.
[29]A. Wieckowska, A. J. McCullough, A. E. Feldstein. Noninvasive diagnosis and monitoring of nonalcoholic steatohepatitis:present and future. Hepatology,2007; 46 (2):582-589.
[30]A. E. Feldstein, A. Canbay, P. Angulo, et al. Hepatocyte apoptosis and Fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology,2003; 125(2):437-443.
[31]A. Wieckowska, N. N. Zein, L. M. Yerian, et al. In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease.Hepatology,2006; 44(1):27-33.
[32]. A. E. Feldstein, A.Wieckowska, A. R. Lopez, et al. Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis:amulticenter validation study. Hepatology,2009; 50(4):1072-1078.
[33]D. L. Diab, L. Yerian, P. Schauer, et al. Cytokeratin 18 fragment levels as a noninvasive biomarker for nonalcoholic steatohepatitis in bariatric surgery patients. Clinical Gastroenterology and Hepatology,2008; 6 (11):1249-1254.
[34]J. K. Dowman, J. W. Tomlinson, P. N. Newsome. Systematic review:the diagnosis and staging of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Alimentary Pharmacology and Therapeutics,2011; 33(5):525-540.
[35]G. Bedogni, S. Bellentani, L. Miglioli, et al. The fatty liver index:a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterology, 2006; 6:33.
[36]G. Bedogni, H. S. Kahn, S. Bellentani, and C. Tiribelli. A simple index of lipid overaccumulation is a good marker of liver steatosis. BMC Gastroenterology,2010; 10:98.
[37]S. Petta, M. Amato, D. Cabibi, et al. Visceral adiposity index is associated with histological findings and high viral load in patients with chronic hepatitis C due to genotype 1. Hepatology,2010; 52(5):1543-1552.
[38]J. B. Dixon, P. S. Bhathal, P. E. O'Brien. Nonalcoholic fatty liver disease:predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology, 2001; 121(1):91-100.
[39]N. A. Palekar, R. Naus, S. P. Larson, et al. Clinical model for distinguishing nonalcoholic steatohepatitis from simple steatosis in patients with nonalcoholic fatty liver disease. Liver International,2006;26 (2):151-156.
[40]T. Poynard, V. Ratziu, F. Charlotte, et al. Diagnostic value of biochemical markers (Nash Test) for the prediction of non alcoholo steato hepatitis in patients with non-alcoholic fatty liver disease. BMC Gastroenterology,2006; 6:34.
[41]V. Ratziu, J. Massard, F. Charlotte, et al. Diagnostic value of biochemical markers (Fibro Test-FibroSURE) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease. BMC Gastroenterology,2006; 6:6.
[42]P. Angulo, J. M. Hui, G. Marchesini, et al. The NAFLD fibrosis score:a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology, 2007; 45(4):846-854.
[43]G. Musso, R. Gambino, M. Cassader, et al. Metaanalysis:natural history of non-alcoholic fatty liver disease and diagnostic accuracy of non-invasive tests for liver disease severity. Annals of Medicine, In press.
[44]W. M. C. Rosenberg, M. Voelker, R. Thiel, et al. Serum markers detect the presence of liver fibrosis:a cohort study. Gastroenterology,2004; 127 (6):1704-1713.
[45]I. N. Guha, J. Parkes, P. Roderick et al. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease:validating the European liver fibrosis panel and exploring simple markers. Hepatology,2008; 47(2):455-460.
[46]S. A. Harrison, D. Oliver, H. L. Arnold, et al. Development and validation of a simpleNAFLD clinical scoring system for identifying patients without advanced disease. Gut,2008; 57(10):1441-1447.
[47]G. Ruffillo, E. Fassio, E. Alvarez, et al. Comparison of NAFLD fibrosis score and BARD score in predicting fibrosis in nonalcoholic fatty liver disease. Journal of Hepatology,2011; 54(1):160-163.
[48]C. T. Wai, J. K. Greenson, R. J. Fontana, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology,2003; 38(2):518-526.
[49]B. A. Neuschwander-Tetri, J. M. Clark, N. M. Bass et al. Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease. Hepatology,2010; 52(3):913-924.
[50]P. CaTes, F. Oberti, S. Michalak, et al. A novel panel of blood markers to assess the degree of liver fibrosis. Hepatology,2005;42(6):1373-1381.
[51]Mehta SR, Thomas EL, Bell JD, et al. Non-invasive means of mcasuring hepatic fat content. World J Gastroenterology,2008;14:3476-3483.
[52]J. Piekarski, H. I. Goldberg, S. A. Royal. Difference between liver and spleen CT numbers in the normal adult:its usefulness in predicting the presence of diffuse liver disease. Radiology,1980; 137(3):727-729.
[53]S.G.H"ubscher. Histological assessment of non-alcoholic fatty liver disease. Histopathology,2006; 49(5):450-465.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |