摘要
目的:高脂饲料喂养SD大鼠构建非酒精性脂肪肝病(nonalcoholic fatty liver disease, NAFLD)模型,动态观察NAFLD大鼠血清学和肝匀浆指标、IR及肝组织病理改变等指标的变化。
方法:雄性SD大鼠192只,随机分为对照组(NG)和高脂组(HG)各96只,对照组喂饲普通饲料,高脂组喂饲高脂饲料。于第1周(w)开始、第2、4、8、12、16w末随机从各组抽取16只大鼠,其中8只行正糖高胰岛素钳夹实验技术检测葡萄糖输注率(GIR),另8只测量体重、肝指数,门静脉采血予以生物化学法检测空腹血糖(FBS)、谷丙转氨酶(ALT)、谷草转氨酶(AST)、甘油三酯(TG)、总胆固醇(TC);放射免疫法检测空腹胰岛素(FIns)、肿瘤坏死因子a (TNF-a);分光光度计检测游离脂肪酸(FFAs);制备肝匀浆分光光度计测定超氧化物歧化酶(SOD)、丙二醛(MDA);大鼠肝组织行HE染色和苏丹Ⅳ染色,光镜下对肝脏脂肪变性情况进行评定。
结果:与同期NG比较:HG大鼠体重、肝指数、血清ALT、AST、TG、TC、FIns、FFAs、TNF-a及肝匀浆MDA在第8、12、16w末均明显升高,肝匀浆SOD水平则降低,差异均具有统计学意义(p值均<0.05)HG各组间两两比较:在第8、12、16w末随着高脂饲料喂养时间的延长,除肝匀浆SOD水平逐渐降低外,肝指数、血清各项指标及肝匀浆MDA水平均逐渐升高,差异均具有统计学意义(p值均<0.05)。与同期NG比较,在第4、8、12、16w末,HG大鼠的GIR水平降低;HG各组间两两比较,差异均具有统计学意义(p值均<0.05)。肝组织病理学检查显示HG大鼠第8w末形成单纯性脂肪肝,随着喂养时间的延长,HG大鼠肝细胞脂肪变性逐渐加重,第12w末形成了非酒精性脂肪性肝炎(non alcoholic steatohepatitis, NASH)。
结论:高脂饮食喂饲SD大鼠8w成功构建单纯性脂肪肝模型,12w可形成NASH模型;肝脏脂肪沉积,TNF-α、FFAs.氧化应激反应都参与了NAFLD的发生发展;IR出现在肝脏脂肪变性之前,IR可能是NAFLD发病的始动因素。
第二部分动态研究非酒精性脂肪肝病中JNK1蛋白表达及其对胰岛素信号通路的影响
目的:动态观察非酒精性脂肪肝病(non alcoholic fatty liver disease, NAFLD)中c-jun氨基末端激酶1(c-Jun N-terminal kinase-1,JNK1)蛋白表达及其对胰岛素(Insulin, INS)信号通路的影响,探讨JNK1、INS信号通路蛋白变化及其与IR和NAFLD的关系。
方法:雄性SD大鼠192只,随机分为对照组(NG)和高脂组(HG)每组各96只,对照组喂饲普通饲料,高脂组喂饲高脂饲料。于第1周(w)开始、第2、4、8、12、16w末随机从各组抽取8只大鼠,处死后取肝组织行Western blot检测JNKl、胰岛素受体底物1(insulin receptor substrate-1,IRS-1)、胰岛素受体底物1丝氨酸307磷酸化(phospho-IRS-1 Ser307,p-IRS-1Ser307)、蛋白激酶B(Protein kinase B,PKB)、蛋白激酶B丝氨酸473磷酸化(phospho-PKBSer473,p-PKBSer473)水平。
结果:第2、4、8、12、16w末,HG与同期NG比较:肝组织JNK1蛋白表达、p-IRS1Ser307水平增高,p-PKBSer473水平降低;HG各组间上述各项指标比较,从第2w末开始,随着时间的延长,除p-PKBSer473水平逐渐降低外,JNK1蛋白表达及p-IRS1Ser307水平均逐渐升高,差异均具有统计学意义(p值均<0.05)。NG各组间比较JNK1蛋白表达、p-IRS1Ser307和p-PKBSer473水平,差异均无统计学意义(p值均>0.05)。各组间两两比较IRS-1和PKB蛋白表达,差异均无统计学意义(p值均>0.05)。JNK1的蛋白表达强度与IR呈正相关(Pearson相关系数为0.931,p值<0.01)。
结论:高脂饮食可诱导肝组织JNK1蛋白表达增高,增加的JNK1结合IRS-1后可以上调p-IRS-1Ser307水平,下调p-PKBSer473水平,从而干扰INS信号传导,导致IR,引起NAFLD; TNF-α、FFAs、氧化应激反应通过促进JNK1活性增强,进一步加重IR从而参与NAFLD的发生发展过程;肝组织的R出现在全身IR和肝脏脂肪变性之前,IR可能是NAFLD发病的启动因素。
第三部分应用表达DN-JNK1的重组腺病毒治疗SD大鼠非酒精性脂肪肝病及其机制研究
目的:应用表达失活型c-jun氨基末端激酶1的重组腺病毒(recombinant adenovirus expressing adenovirus expressing dominant negative type c-Jun N-terminal kinase1, Ad-DN-JNK1)治疗SD大鼠非酒精性脂肪肝病(non alcoholic fatty liver disease, NAFLD),探讨其对NAFLD的治疗作用及作用机制。
方法:雄性SD大鼠96只,随机分为对照组(NG)32只、高脂组(HG)64只,对照组喂饲普通饲料,高脂组喂饲高脂饲料。于第8周(w)末随机从各组抽取16只大鼠,其中8只行正糖高胰岛素钳夹实验技术(钳夹技术)检测葡萄糖输注率(GIR),另8只门静脉抽血和肝组织病理切片鉴定成模后,将余下的16只对照组大鼠继续喂饲普通饲料至12w末称为12w对照组(NG12w);余下的高脂组大鼠随机分为12w高脂组(HG12w),携带绿色荧光蛋白的腺病毒(Ad-GFP)组和Ad-DN-JNK1组,各组均16只,此3组均喂饲高脂饲料至12w末。第8w末,NG12w和HG12w大鼠均从尾静脉注入1ml生理盐水作为安慰剂对照,Ad-GFP组大鼠尾静脉注入1ml2.5×1010pfu的Ad-GFP作为腺病毒对照,Ad-DN-JNK1组大鼠尾静脉注入1ml 2.5×1010pfu的Ad-DN-JNK1作为治疗组。12w末随机从各组抽取8只大鼠行钳夹技术检测胰岛素抵抗(IR)情况,各组余下8只大鼠门静脉采血生物化学法检测空腹血糖(FBS)、谷丙转氨酶(ALT)、谷草转氨酶(AST)、甘油三酯(TG)、总胆固醇(TC);放射免疫法检测空腹胰岛素(FIns)、肿瘤坏死因子-a (TNF-a),分光光度计测定游离脂肪酸(FFAs);制备肝匀浆测定TG、TC、FFAs(检测方法同上),分光光度计法检测超氧化物歧化酶(SOD)、丙二醛(MDA);另取部分肝组织行Western Blot技术检测肝组织c-jun氨基末端激酶1(c-Jun N-terminal kinase-1, JNK1)、胰岛素受体底物1(insulin receptor substrate-1,IRS-1)、蛋白激酶B(Protein kinase B,PKB)蛋白表达和胰岛素受体底物1丝氨酸307磷酸化(phospho-IRS-1 Ser307,p-IRS-1 Ser307)、蛋白激酶B丝氨酸473磷酸化(phospho-PKBSer473,p-PKBSer473)水平。部分肝组织行HE染色、苏丹Ⅳ染色,光镜下评定肝脏脂肪变性情况。
结果:第8w末高脂组大鼠已构建成单纯性脂肪肝IR模型。与NG12w大鼠比较,HG12w和Ad-GFP组的体重、肝指数、血清ALT、AST、TG、TC、FFAs、FIns、TNF-a及肝匀浆TG、TC、FFAs、MDA均明显升高,肝匀浆SOD降低;葡萄糖输注率(GIR)降低;肝组织JNK1蛋白表达、p-IRS-1Ser307水平增高,p-PKBSer473水平降低,差异均具有统计学意义(p值均<0.05)。Ad-DN-JNK1组与HG12w及Ad-GFP组大鼠分别比较上述各项指标,Ad-DN-JNK1组的体重、肝指数、血清ALT、AST、TG、TC、FFAs、FIns、TNF-a及肝匀浆TG、TC、FFAs、MDA均明显降低,肝匀浆SOD升高;GIR升高;肝组织JNK1蛋白表达、p-IRSlSer307水平降低,p-PKBSer473水平升高,差异均具有统计学意义(p值均<0.05)。Ad-DN-JNK1组与NG12w组比较,体重、肝指数、AST、FIns、GIR水平、JNK1蛋白表达、p-IRS1Ser307、p-PKBser473水平差异均无统计学意义(p值均>0.05),其余血清学及肝匀浆指标差异均具有统计学意义(p值均<0.05)。各组间两两比较IRS-1和PKB蛋白表达,差异均无统计学意义;HG12w与Ad-GFP组比较血清和肝匀浆各项指标以及JNK1、INS信号通路蛋白表达及磷酸化水平,差异均无统计学意义(p值均>0.05)。HG12w及Ad-GFP组大鼠均进展为非酒精性脂肪性肝炎(non alcoholic steatohepatitis, NASH);而Ad-DN-JNK1组大鼠肝脏脂肪变性明显改善,未出现炎症反应。
结论:腺病毒载体是安全有效的基因治疗载体,应用Ad-DN-JNK1治疗SD大鼠NAFLD,可明显改善NAFLD,其作用机制可能为:Ad-DN-JNK1抑制JNK1活性后,下调p-IRS-1Ser307水平,升高其下游p-PKBSer473水平,进而促进INS信号传导,减弱IR,并降低TNF-α、FFAs水平,减少氧化应激反应,减轻肥胖和肝脏脂肪变性,最终改善NAFLD。
Objective:To establish the model of nonalcoholic fatty liver disease(NAFLD) by feeding Sprague-Dawley (SD) rats with high-fat diet. To make dynamic observation on the change of indicators of serum, liver homogenates,IR and histopathology on the whole process of constructing the model of NAFLD in SD rats.
Methods:Male SD rats(n=192) were randomly divided into two groups;control group(NG,n=96) fed on normal diet, and high-fat diet group(HG,n=96) fed on high-fat diet. At the beginning of the 1st week(w) and at the end of the 2end,4th,8th,12th,16 th w,8 rats in each group were randomly chosen to test glucose infusion rate(GIR) by euglycemic hyperinsulinemic clamp.Meanwhile,among the rests,8 rats that been randomly selected from both groups respectively,which blood was obtained from portal vein before liver removal.The blood of rats were assayed for alanine aminotransferase(ALT),aspartate aminotransfer-ase(AST), triglyceride (TG),total cholesterol(TC) and fasting blood sugar (FBS) by biochemistry automatic analyzer.The fast insulin(FIns) and tumor necrosis factor-α(TNF-α) were determined with radioimmunoassay and Free fatty acids(FFAs) were analyzed with spectrophotometer in blood.Superoxide dismutase(SOD) and malondialdehyde(MDA) of the liver homogenates were tested by spectrophotometer.Liver tissue of all rats were stained with hematoxylin-eosin and SudanⅣ.Hepatic stetosis was observed by microscope.
Results:Compared with NQthe weight,liver index, ALT, AST,TG, TC,FIns,FFAs,TNF-a and MDA levels increased,while the SOD level decreased in HG at the end of the 8th,12th,16th(p<0.05). From the 8th to 16thw, liver index and the levels of indicators of serum and liver homogenates progressively increased,while SOD level gradually reduced in HG (p<0.05). Compared with NQGIR in HG were reduced at the end of the 4th,8th,12th,16th w.GIR gradually reduced in HG from 4th to 16thw, and it presented time-dependant manner(p<0.05).Hepatocytes fatty degeneration in HG aggravated progressively.Hepatic steatosis and nonalcoholic steatohepatitis(NASH) were obtained respectively by feeding on high-fat diet for 8 weeks and 12 weeks.
Conclusion:The models of the hepatic steatosis and NASH could be established respectively by feeding on high-fat diet for 8 weeks and 12 weeks in SD rats.Hepatic lipid accumulation,TNF-a, FFAs and oxidative stress reaction have involved in the progression of NAFLD. IR occurred before hepatic steatosis.And IR could be the initiating factor of NAFLD.
Objective:To make dynamic observation on the expression of JNK1(C-Jun N-terminal kinase-1) and its effect on insulin signal transduction pathway in nonalcoholic fatty liver disease(NAFLD).
Methods:Male SD rats(n=192) were randomly divided into two groups:control group(NG,n=96) fed on normal diet,high-fat diet group(HG,n=96) fed on high-fat diet. At the beginning of the 1st week(w) and at the end of the 2nd,4th,8th,12th,16th w,8 rats taken randomly from each group were sacrificed and liver samples were taken.The expression of JNK1 protein,insulin receptor substrate-1 (IRS-1) protein,Protein kinase B(PKB),phospho-IRS-1 Ser307(p-IRS-1Ser307)and phospho-PKBSer473 (p-PKBSer473) in liver tissue were detected by Western blot.
Results:The expression of JNK1 protein and p-IRS-1Ser307 in liver tissue increased,while expression of p-PKBSer473 decreased at the end of the 2nd,4th,8th,12th,16thw in HG compared with NG.The expression of JNK1 protein and p-IRS-1 Ser307 in liver tissue progressively increased while expression of p-PKBSer473 gradually reduced in HG from the 2nd to the 16thw,and the levels presented time-dependant manner(p<0.05). No differences were observed in IRS-1Ser307 and PKBSer473 phosphorylation in NG at different periods.(p>0.05).No differences were observed concerning the expression of IRS-1 and PKB in multiple comparison in each group(p>0.05). A positive correlation was found between the expression intensity of JNK1 and Insulin resistance(IR) (Pearson correlation:0.931,p<0.01).
Conclusion:The high-fat diet could increase the expression of JNK1. Increased JNK1 promoted p-IRS-1 Ser307 up-regulated and p-PKBSer473 down-regulated,and these changes disturbed the insulin signal transduction.Finally,it led to IR,so NAFLD ensued.Furthermore, tumor necrosis factor-a,free fatty acids and oxidative stress reaction mediated IR through JNK1 activation.IR of liver occurred before systemic IR and liver steatosis.And IR could be the initiating factor of NAFLD.
Objective:To investigate the therapeutic effect and mechanism of recombinant adenovirus expressing dominant-negative type c-Jun N-terminal kinase1(Ad-DN-JNK1) on NAFLD in SD rats.
Methods:Male SD rats (n=96) were randomly divided into two groups:control group(NG,n=32) fed on normal diet,and high-fat diet group(HG,n=64) fed on high-fat diet.After 8 weeks treatment,8 Rats that been chosen randomly from each group were tested glucose infusion rate(GIR) by euglycemic hyperinsulinemic clamp.Meanwhile,among the rests,8 rats that been randomly selected from both groups respectively, which blood was obtained from portal vein before liver removal.The rats liver samples were harvested for identifying model.The rest 16 rats in NG were named control group 12w(NG12w).And the rest 48 rats in HG were divided randomly into three groups with 16 rats in each group:HG12w,adenovirus vector carrying green fluorescence protein (Ad-GFP) group and Ad-DN-JNK1 group.The NG12w fed on normal diet, while the other three groups fed on high-fat diet.Rats from NG12w and HG12w groups were injected with 1ml normal saline as control;rats from Ad-GFP group were injected with lml 2.5×1010pfu Ad-GFP as adenovirus control, and rats from Ad-DN-JNK1 group were injected with 1ml 2.5×1010pfu Ad-DN-JNK1 as treatment group at the end of the 8thw.All rats were injected from caudal vein. At the end of the 12thw,8 rats that been randomly selected from each group were tested GIR by euglycemic hyperinsulinemic clamp.And blood samples were obtained from portal vein before liver removal of the rest rats in each group.Rats blood were tested for alanine aminotransferase (ALT),aspartate aminotr-ansferase(AST),triglyceride(TG),total cholesterol(TC) and fasting blood sugar(FBS) by biochemistry automatic analyzer.The fast insulin(FIns) and tumor necrosis factor-a(TNF-a) were determined with radioimmunoassay and Free fatty acids(FFAs) were analyzed with spectrophotometer in blood. Superoxide dismutase(SOD) and malondialdehyde(MDA) of liver homogenates were tested by spectrophotometer.TG,TC and FFAs of liver homogenates were analyzed with the technique as previously described.The expression of c-Jun N-terminal kinase-1(JNK1)protein, insulin receptor substrate-1 (IRS-1) protein,Protein kinase B(PKB),phospho-IRS-1Ser307(p-IRS-1Ser307)and phospho-PKBSer473(p-PKBSer473) in the liver tissue were detected by Western blot.The liver tissue of all rats were stained with hematoxylin-eosin and Sudan IV.The hepatic stetosis was observed by microscope.
Results:The model of hepatic stetosis with insulin resistance(IR) in SD rats were established in HG at the end of the 8thw.Compared with NG12w,the weight,liver index, ALT,AST,TG,TC,FIns,FFAs and TNF-a levels in blood and the levels of TG,TC,FFAs and MDA of the liver homogenates increased while SOD level of liver homogenates and GIR decreased in HG12w and Ad-GFP group(p<0.05).Compared with NG12w,increases in JNK1 and p-IRS1Ser307 and decrease in p-PKBSer473 were observed in HG12w and Ad-GFP group (p<0.05). Compared with HG12w and Ad-GFP group,all the index in serum and liver homogenates decreased except SOD in liver homogenates and GIR increased,and the expression of JNK1 and p-IRS1Ser307 decreased while p-PKBSer473 increased in Ad-DN-JNK1 group (p<0.05).No significant differences were observed in the weight,liver index, and levels of AST,FIns,GIR and the expression of JNK1,p-PKBSer473 and p-IRSlSer307 (p>0.05) except the rest indicators of serum and liver homogenates in Ad-DN-JNK1 group compared with NG12w (p<0.05).There were no obvious difference on the expression of IRS-1 and PKB in multiple comparison in each group(p>0.05).No difference were observed about all indicators in HG12w compared with Ad-GFP group.The model of NASH was established in HG12w and Ad-GFP group.Hepatic steatosis has been improved and no inflammation was observed in Ad-DN-JNK1 group.
Conclusion:Adenovirus vector was a safe and effective gene vector.NAFLD could be improved by using Ad-DN-JNK1.The mechanism is possibly that Ad-DN-JNK1 inhibit the activation of JNK1,thereby reducing the phosphorylation of IRS-1Ser307 and enhancing the phosphorylation of PKBSer473,and then accelerating the insulin signal transduction pathway,so IR decreased.Furthermore,TNF-a,FFAs and oxidative stress reaction reduced; Obesity and hepatic steatosis alleviated.Finally NAFLD has been improved.
引文
[1]Farrell GC, Larter CZ. Nonalcoholic fatty liver disease:from steatosis to cirrhosis. Hepatology.2006.43(2 Suppl 1):S99-S112.
[2]Preiss D, Sattar N. Non-alcoholic fatty liver disease:an overview of prevalence, diagnosis, pathogenesis and treatment considerations. Clin Sci (Lond).2008.115(5):141-50.
[3]Bedogni G, Miglioli L, Masutti F, Tiribelli C, Marchesini G, Bellentani S. Prevalence of and risk factors for nonalcoholic fatty liver disease:the Dionysos nutrition and liver study. Hepatology.2005.42(1):44-52.
[4]Clouston AD, Jonsson JR, Powell EE. Steatosis as a cofactor in other liver diseases:hepatitis C virus, alcohol, hemochromatosis, and others. Clin Liver Dis.2007.11(1):173-89, x.
[5]Fan JG, Farrell GC. Epidemiology of non-alcoholic fatty liver disease in China. J Hepatol.2009.50(1):204-10.
[6]Sung KC, Ryan MC, Kim BS, Cho YK, Kim BI, Reaven GM. Relationships between estimates of adiposity, insulin resistance, and nonalcoholic fatty liver disease in a large group of nondiabetic Korean adults. Diabetes Care.2007. 30(8):2113-8.
[7]Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology.2003.37(4):917-23.
[8]Hamaguchi M, Kojima T, Takeda N, et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med.2005.143(10): 722-8.
[9]Almeda-Valdes P, Cuevas-Ramos D, Aguilar-Salinas CA. Metabolic syndrome and non-alcoholic fatty liver disease. Ann Hepatol.2009.8 Suppl 1:S18-24.
[10]Adams LA, Lymp JF, St SJ, et al. The natural history of nonalcoholic fatty liver disease:a population-based cohort study. Gastroenterology.2005.129(1): 113-21.
[11]Gupte P, Amarapurkar D, Agal S, et al. Non-alcoholic steatohepatitis in type 2 diabetes mellitus. J Gastroenterol Hepatol.2004.19(8):854-8.
[12]Dixon JB, Bhathal PS, O'Brien PE. Nonalcoholic fatty liver disease:predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology.2001.121(1):91-100.
[13]Hamaguchi M, Kojima T, Takeda N, et al. Nonalcoholic fatty liver disease is a novel predictor of cardiovascular disease. World J Gastroenterol.2007.13(10): 1579-84.
[14]Day CP, James OF. Steatohepatitis:a tale of two "hits". Gastroenterology. 1998.114(4):842-5.
[15]Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance:a metabolic pathway to chronic liver disease. Hepatology.2005.42(5):987-1000.
[16]Svegliati-Baroni G, Candelaresi C, Saccomanno S, et al. A model of insulin resistance and nonalcoholic steatohepatitis in rats:role of peroxisome proliferator-activated receptor-alpha and n-3 polyunsaturated fatty acid treatment on liver injury. Am J Pathol.2006.169(3):846-60.
[17]Paschos P, Paletas K. Non alcoholic fatty liver disease and metabolic syndrome. Hippokratia.2009.13(1):9-19.
[18]London RM, George J. Pathogenesis of NASH:animal models. Clin Liver Dis. 2007.11(1):55-74, viii.
[19]Kraegen EW, James DE, Bennett SP, Chisholm DJ. In vivo insulin sensitivity in the rat determined by euglycemic clamp. Am J Physiol.1983.245(1):E1-7.
[20]中华医学会肝脏病学分会脂肪肝和酒精性肝病学组,Association FLaALDSGotCLD.非酒精性脂肪性肝病诊疗指南.中华肝脏病杂志.2006.14(3):161-163.
[21]王泰龄,刘霞,周元平.慢性肝炎炎症活动度及纤维化程度计分方案.中华肝脏病杂志.1998.6(4):195.
[22]Unger RH. Leptin physiology:a second look. Regul Pept.2000.92(1-3): 87-95.
[23]Yin HQ, Kim M, Kim JH, et al. Hepatic gene expression profiling and lipid homeostasis in mice exposed to steatogenic drug, tetracycline. Toxicol Sci. 2006.94(1):206-16.
[24]Chung H, Hong DP, Kim HJ, et al. Differential gene expression profiles in the steatosis/fibrosis model of rat liver by chronic administration of carbon tetrachloride. Toxicol Appl Pharmacol.2005.208(3):242-54.
[25]Xu ZJ, Fan JG, Ding XD, Qiao L, Wang GL. Characterization of High-Fat, Diet-Induced, Non-alcoholic Steatohepatitis with Fibrosis in Rats. Dig Dis Sci. 2009.
[26]Lieber CS, Leo MA, Mak KM, et al. Model of nonalcoholic steatohepatitis. Am J Clin Nutr.2004.79(3):502-9.
[27]Ahmed U, Redgrave TG, Oates PS. Effect of dietary fat to produce non-alcoholic fatty liver in the rat. J Gastroenterol Hepatol.2009.24(8): 1463-71.
[28]Safwat GM, Pisano S, D'Amore E, et al. Induction of non-alcoholic fatty liver disease and insulin resistance by feeding a high-fat diet in rats:does coenzyme Q monomethyl ether have a modulatory effect. Nutrition.2009.25(11-12): 1157-68.
[29]Nanji AA. Animal models of nonalcoholic fatty liver disease and steatohepatitis. Clin Liver Dis.2004.8(3):559-74, ix.
[30]Toshimitsu K, Matsuura B, Ohkubo I, et al. Dietary habits and nutrient intake in non-alcoholic steatohepatitis. Nutrition.2007.23(1):46-52.
[31]Cha MC, Chou CJ, Boozer CN. High-fat diet feeding reduces the diurnal variation of plasma leptin concentration in rats. Metabolism.2000.49(4): 503-7.
[32]陈世清,刘杞,孙航,张桂灵,石小枫.脂肪肝胰岛素抵抗大鼠模型的建立.中华肝脏病杂志.2005.13(2):105-108.
[33]钟岚,范建高,王国良,李为真,吴伟清,姜军梅.非酒精性脂肪性肝炎发病机制的实验研究.中华消化杂志.2001.21(8):484-484.
[34]钟岚,王国良,史祺.肥胖、高脂血症性脂肪性肝炎模型的建立.实验动物 科学与管理.2000.(02):16-20.
[35]Angulo P. Nonalcoholic fatty liver disease. N Engl J Med.2002.346(16): 1221-31.
[36]Bellentani S, Saccoccio G, Masutti F, et al. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med.2000.132(2):112-7.
[37]Kim HJ, Kim HJ, Lee KE, et al. Metabolic significance of nonalcoholic fatty liver disease in nonobese, nondiabetic adults. Arch Intern Med.2004.164(19): 2169-75.
[38]Machado M, Marques-Vidal P, Cortez-Pinto H. Hepatic histology in obese patients undergoing bariatric surgery. J Hepatol.2006.45(4):600-6.
[39]Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance:a metabolic pathway to chronic liver disease. Hepatology.2005.42(5):987-1000.
[40]Monzillo LU, Hamdy O. Evaluation of insulin sensitivity in clinical practice and in research settings. Nutr Rev.2003.61(12):397-412.
[41]Ferrannini E, Mari A. How to measure insulin sensitivity. J Hypertens.1998. 16(7):895-906.
[42]Zhande R, Mitchell JJ, Wu J, Sun XJ. Molecular mechanism of insulin-induced degradation of insulin receptor substrate 1. Mol Cell Biol. 2002.22(4):1016-26.
[43]Feldstein AE, Canbay A, Guicciardi ME, Higuchi H, Bronk SF, Gores GJ. Diet associated hepatic steatosis sensitizes to Fas mediated liver injury in mice. J Hepatol.2003.39(6):978-83.
[44]Feldstein AE, Canbay A, Angulo P, et al. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology.2003.125(2):437-43.
[45]Crespo J, Cayon A, Fernandez-Gil P, et al. Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology.2001.34(6):1158-63.
[46]Tilg H, Moschen AR. Inflammatory mechanisms in the regulation of insulin resistance. Mol Med.2008.14(3-4):222-31.
[47]Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature.2006.440(7086):944-8.
[48]Marra F, Gastaldelli A, Svegliati BG, Tell G, Tiribelli C. Molecular basis and mechanisms of progression of non-alcoholic steatohepatitis. Trends Mol Med. 2008.14(2):72-81.
[1]Kodama Y, Brenner DA. c-Jun N-terminal kinase signaling in the pathogenesis of nonalcoholic fatty liver disease:Multiple roles in multiple steps. Hepatology.2009.49(1):6-8.
[2]Bennett BL, Satoh Y, Lewis AJ. JNK:a new therapeutic target for diabetes. Curr Opin Pharmacol.2003.3(4):420-5.
[3]Barr RK, Bogoyevitch MA. The c-Jun N-terminal protein kinase family of mitogen-activated protein kinases (JNK MAPKs). Int J Biochem Cell Biol. 2001.33(11):1047-63.
[4]Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol.2006.7(2):85-96.
[5]Chen YR, Tan TH. The c-Jun N-terminal kinase pathway and apoptotic signaling (review). Int J Oncol 2000.16:651-662
[6]Dhanasekaran DN, Reddy EP. JNK signaling in apoptosis. Oncogene.2008. 27(48):6245-51.
[7]Samuel VT, Liu ZX, Qu X, et al Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem.2004.30;279:32345-53.
[8]Schattenberg JM, Singh R, Wang Y, et al JNK1 but not JNK2 promotes the development of steatohepatitis in mice. Hepatology.2006.43(1):163-72.
[9]Kodama Y, Brenner DA. c-Jun N-terminal kinase signaling in the pathogenesis of nonalcoholic fatty liver disease:Multiple roles in multiple steps. Hepatology.2009.49(1):6-8.
[10]Singh R, Wang Y, Xiang Y, Tanaka KE, Gaarde WA, Czaja MJ. Differential e ffects of JNK1 and JNK2 inhibition on murine steatohepatitis and insulin resistance. Hepatology.2009.49(1):87-96.
[11]Fletcher B, Lamendola C. Insulin resistance syndrome. J Cardiovasc Nurs. 2004.19(5):339-45.
[12]Nguyen MT, Satoh H, Favelyukis S, et al. JNK and tumor necrosis factor-alpha mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes. J Biol Chem 2005.280:35361-35371.
[13]Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006.444: 860-867.
[14]Herbert Tilg, Gokhan S, Hotamisligil. Nonalcoholic Fatty Liver Disease: Cytokine-Adipokine Interplay and Regulation of Insulin Resistance. Gastroenterology 2006.131:934-945
[15]Marchesini G, Forlani G. NASH:from liver diseases to metabolic disorders and back to clinical hepatology. Hepatology.2002.35(2):497-9.
[16]Bugianesi E, Zannoni C, Vanni E, et al.Non-alcoholic fatty liver and insulin resistance:a cause-effect relationship? Dig Liver Dis.2004.36:165-73.
[17]Tilg H, Moschen AR. Insulin resistance, inflammation, and non-alcoholic fatty liver disease. Trends Endocrinol Metab.2008.19(10):371-9.
[18]Sabio G, Das M, Mora A, et al. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 2008.322:1539-1543
[19]Jensen M, De Meyts P. Molecular mechanisms of differential intracellular signaling from the insulin receptor. Vitam Horm.2009.80:51-75
[20]Leclercq, I.A. et al.Insulin resistance in hepatocytes and sinusoidal liver cells: mechanisms and consequences. J. Hepatol.2007.47:142-156
[21]Schreuder TC, Verwer BJ, van NCM, Mulder CJ. Nonalcoholic fatty liver disease:an overview of current insights in pathogenesis, diagnosis and treatment. World J Gastroenterol.2008.14(16):2474-86.
[22]Saltiel AR and Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 2001.414:799-806
[23]Fritsche L, Weigert C, Haring HU, Lehmann R. How insulin receptor substrate proteins regulate the metabolic capacity of the liver-implications for health and disease. Curr Med Chem.2008.15(13):1316-29
[24]Gual P, Le Marchand-Brustel Y and Tanti JF. Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie 2005.87: 99-109.
[25]Kim T, Wayne LJ, Adochio R, et al. Knockdown of JNK rescues 3T3-L1 adipocytes from insulin resistance induced by mitochondrial dysfunction. Biochem Biophys Res Commun.2009.378(4):772-6.
[26]Hilder TL, Tou JC, Grindeland RE,et al. Phosphorylation of insulin receptor substrate-1 serine 307 correlates with JNK activity in atrophic skeletal muscle. FEBS Lett.2003.553(1-2):63-7.
[27]Piro S, Spadaro L, Russello M, et al. Molecular determinants of insulin resistance, cell apoptosis and lipid accumulation in non-alcoholic steatohepatitis. Nutr Metab Cardiovasc Dis.2008.18(8):545-52.
[28]Piro S, Spadaro L, Russello M, et al. Molecular determinants of insulin resistance,cell apoptosis and lipid accumulation in non-alcoholic steatohepatitis. Nutr Metab Cardiovasc Dis.2008.18(8):545-52
[29]Bourass I, Sels JP, Driessen A, et al.Non-alcoholic steatohepatitis:review of a growing medical problem. Eur J Intern Med.2004.15(1):10-21
[30]Biddinger SB, Kahn CR. From mice to men:insights into the insulin resistance syndromes. Annu Rev Physiol 2006.68:123-158.
[31]Fernandez-Veledo S, Vila-Bedmar R, Nieto-Vazquez I,et al. c-Jun N-terminal kinase 1/2 activation by tumor necrosis factor-alpha induces insulin resistance in human visceral but not subcutaneous adipocytes:reversal by liver X receptor agonists. J Clin Endocrinol Metab.2009.94(9):3583-93.
[32]Shoelson SE, Lee J and Goldfine AB. Inflammation and insulin resistance. J Clin Invest 2006.116:1793-1801.
[33]Fletcher B and Lamendola C. Insulin resistance syndrome. J Cardiovasc Nurs 2004.19:339-345.
[34]Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005.115(5):1111-9.
[35]Saltiel AR. New perspectives into the molecular pathogenesis and treatment of type 2 diabetes. Cell.2001.104(4):517-29.
[36]. Hotamisligil GS, Murray DL, Choy LN, et al.Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Proc Natl Acad Sci USA 1994. 91:4854-4858.
[37]Malhi H, Bronk SF, Werneburg NW, et al. Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis.J Biol Chem.2006. 28;281(17):12093-101.
[38]Zhang W, Kudo H, Kawai K, et al. Tumor necrosis factor-alpha accelerates apoptosis of steatotic hepatocytes from a murine model of non-alcoholic fatty liver disease. Biochem Biophys Res Commun.2010.391(4):1731-6.
[39]Matsuzawa-Nagata N, Takamura T, Ando H, et al. Increased oxidative stress precedes the onset of high-fat diet-induced insulin resistance and obesity. Metabolism.2008.57(8):1071-7.
[40]Schenk S, Saberi M, Olefsky JM. Insulin sensitivity:modulation by nutrients and inflammation. J Clin Invest.2008.118(9):2992-3002.
[1]Adams LA, Angulo P, Lindor KD. Nonalcoholic fatty liver disease. CMAJ. 2005.172(7):899-905.
[2]Chitturi S, Farrell GC, Hashimoto E, Saibara T, Lau GK, Sollano JD. Non-alcoholic fatty liver disease in the Asia-Pacific region:definitions and overview of proposed guidelines. J Gastroenterol Hepatol.2007.22(6): 778-87.
[3]Shifflet A, Wu GY. Non-alcoholic steatohepatitis:an overview. J Formos Med Assoc.2009.108(1):4-12.
[4]Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis:summary of an AASLD Single Topic Conference. Hepatology.2003.37(5):1202-19.
[5]Tarantino G, Saldalamacchia G, Conca P, Arena A. Non-alcoholic fatty liver disease:further expression of the metabolic syndrome. J Gastroenterol Hepatol. 2007.22(3):293-303.
[6]Kaneto H, Matsuoka TA, Katakami N, et al. Oxidative stress and the JNK pathway are involved in the development of type 1 and type 2 diabetes. Curr Mol Med.2007.7(7):674-86.
[7]Tuncman G, Hirosumi J, Solinas G, Chang L, Karin M, Hotamisligil GS. Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance. Proc Natl Acad Sci U S A.2006.103(28):10741-6.
[8]Nguyen MT, Satoh H, Favelyukis S, et al. JNK and tumor necrosis factor-alpha mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes. J Biol Chem.2005.280(42):35361-71.
[9]Aguirre V, Werner ED, Giraud J, Lee YH, Shoelson SE, White MF. Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem.2002.277(2): 1531-7.
[10]Hirosumi J, Tuncman G, Chang L, et al. A central role for JNK in obesity and insulin resistance. Nature.2002.420(6913):333-6.
[11]Nakatani Y, Kaneto H, Kawamori D, et al. Modulation of the JNK pathway in liver affects insulin resistance status. J Biol Chem.2004.279(44):45803-9.
[12]张佳妮,刘慧霞,陈金虎等.DN-JNK基因重组腺病毒的构建和鉴定.中国医师杂志.2009.11(1):28-31.
[13]Kraegen EW, James DE, Bennett SP, Chisholm DJ. In vivo insulin sensitivity in the rat determined by euglycemic clamp. Am J Physiol.1983.245(1):E1-7.
[14]中华医学会肝脏病学分会脂肪肝和酒精性肝病学组,Association FLaALDSGotCLD.非酒精性脂肪性肝病诊疗指南.中华肝脏病杂志.2006.14(3):161-163.
[15]王泰龄,刘霞,周元平.慢性肝炎炎症活动度及纤维化程度计分方案.中华肝脏病杂志.1998.6(4):195.
[16]非酒精性脂肪性肝病诊疗指南.中华肝脏病杂志.2006.(03):161-163.
[17]Mizuguchi H, Hayakawa T. Targeted adenovirus vectors. Hum Gene Ther. 2004.15(11):1034-44.
[18]施明,王福生,高兰兴.腺病毒载体的研究进展.世界华人消化杂志.2000.(11):1282-1286.
[19]Jalkanen J, Leppanen P, Narvanen O, Greaves DR, Yla-Herttuala S. Adenovirus-mediated gene transfer of a secreted decoy human macrophage scavenger receptor (SR-AI) in LDL receptor knock-out mice. Atherosclerosis. 2003.169(1):95-103.
[20]Binley K, Askham Z, Martin L, et al. Hypoxia-mediated tumour targeting. Gene Ther.2003.10(7):540-9.
[21]Nakatani T, Kuriyama S, Tominaga K, et al. Assessment of efficiency and safety of adenovirus mediated gene transfer into normal and damaged murine livers. Gut.2000.47(4):563-70.
[22]Uprichard SL, Boyd B, Althage A, Chisari FV. Clearance of hepatitis B virus from the liver of transgenic mice by short hairpin RNAs. Proc Natl Acad Sci U S A.2005.102(3):773-8.
[23]Nakatani Y, Kaneto H, Kawamori D, et al. Modulation of the JNK pathway in liver affects insulin resistance status. J Biol Chem.2004.279(44):45803-9.
[24]Yang R, Wilcox DM, Haasch DL, et al. Liver-specific knockdown of JNK1 up-regulates proliferator-activated receptor gamma coactivator 1 beta and increases plasma triglyceride despite reduced glucose and insulin levels in diet-induced obese mice. J Biol Chem.2007.282(31):22765-74.
[25]Carmona S, Ely A, Crowther C, et al. Effective inhibition of HBV replication in vivo by anti-HBx short hairpin RNAs. Mol Ther.2006.13(2):411-21.
[26]Bennett BL, Sasaki DT, Murray BW, et al. SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci U S A.2001.98(24): 13681-6.
[27]Sabapathy K, Hu Y, Kallunki T, et al. JNK2 is required for efficient T-cell activation and apoptosis but not for normal lymphocyte development. Curr Biol.1999.9(3):116-25.
[28]Dong C, Yang DD, Tournier C, et al. JNK is required for effector T-cell function but not for T-cell activation. Nature.2000.405(6782):91-4.
[29]Waetzig V, Herdegen T. Context-specific inhibition of JNKs:overcoming the dilemma of protection and damage. Trends Pharmacol Sci.2005.26(9): 455-61.
[30]Kaneto H, Nakatani Y, Miyatsuka T, et al. Possible novel therapy for diabetes with cell-permeable JNK-inhibitory peptide. Nat Med.2004.10(10):1128-32.
[1]James 0, Day C. Non-alcoholic steatohepatitis:another disease of affluence. Lancet.1999.353(9165):1634-6.
[2]Greenfield V, Cheung O, Sanyal AJ. Recent advances in nonalcholic fatty liver disease. Curr Opin Gastroenterol.2008.24(3):320-7.
[3]Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis:summary of an AASLD Single Topic Conference. Hepatology.2003.37(5):1202-19.
[4]Farrell GC, Larter CZ. Nonalcoholic fatty liver disease:from steatosis to cirrhosis. Hepatology.2006.43(2 Suppl 1):S99-S112.
[5]Polyzos SA, Kountouras J, Zavos C. Nonalcoholic fatty liver disease:the pathogenetic roles of insulin resistance and adipocytokines. Curr Mol Med. 2009.9(3):299-314.
[6]Kashi MR, Torres DM, Harrison SA. Current and emerging therapies in nonalcoholic fatty liver disease. Semin Liver Dis.2008.28(4):396-406.
[7]Day CP, James OF. Steatohepatitis:a tale of two "hits". Gastroenterology. 1998.114(4):842-5.
[8]Amarapurkar DN, Patel ND. Prevalence of metabolic syndrome in non-diabetic and non-cirrhotic patients with non-alcoholic steatohepatitis. Trop Gastroenterol.2004.25(3):125-9.
[9]Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest.2000. 106(2):171-6.
[10]Postic C, Dentin R, Denechaud PD, Girard J. ChREBP, a transcriptional regulator of glucose and lipid metabolism. Annu Rev Nutr.2007.27:179-92.
[11]Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature.2006.444(7121):847-53.
[12]Leclercq IA, Da SMA, Schroyen B, Van Hul N, Geerts A. Insulin resistance in hepatocytes and sinusoidal liver cells:mechanisms and consequences. J Hepatol.2007.47(1):142-56.
[13]Saltiel AR. New perspectives into the molecular pathogenesis and treatment of type 2 diabetes. Cell.2001.104(4):517-29.
[14]Svegliati-Baroni G, Candelaresi C, Saccomanno S, et al. A model of insulin resistance and nonalcoholic steatohepatitis in rats:role of peroxisome proliferator-activated receptor-alpha and n-3 polyunsaturated fatty acid treatment on liver injury. Am J Pathol.2006.169(3):846-60.
[15]Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005.115(5):1111-9.
[16]Jump DB, Botolin D, Wang Y, Xu J, Christian B, Demeure O. Fatty acid regulation of hepatic gene transcription. J Nutr.2005.135(11):2503-6.
[17]Bobard A, Hainault I, Ferre P, Foufelle F, Bossard P. Differential regulation of sterol regulatory element-binding protein 1c transcriptional activity by insulin and liver X receptor during liver development. J Biol Chem.2005.280(1): 199-206.
[18]艾正琳,陈东风,刘重阳,兰春慧,王军.固醇调节元件结合蛋白-1c 在大鼠非酒精性脂肪性肝炎中的表达及意义.重庆医学.2007.(08):695-697.
[19]Hirosumi J, Tuncman G, Chang L, et al. A central role for JNK in obesity and insulin resistance. Nature.2002.420(6913):333-6.
[20]Yang R, Wilcox DM, Haasch DL, et al. Liver-specific knockdown of JNK1 up-regulates proliferator-activated receptor gamma coactivator 1 beta and increases plasma triglyceride despite reduced glucose and insulin levels in diet-induced obese mice. J Biol Chem.2007.282(31):22765-74.
[21]Medina J, Fernandez-Salazar LI, Garcia-Buey L, Moreno-Otero R. Approach to the pathogenesis and treatment of nonalcoholic steatohepatitis. Diabetes Care.2004.27(8):2057-66.
[22]Kim JK, Kim YJ, Fillmore JJ, et al. Prevention of fat-induced insulin resistance by salicylate. J Clin Invest.2001.108(3):437-46.
[23]Yuan M, Konstantopoulos N, Lee J, et al. Reversal of obesity-and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science.2001.293(5535):1673-7.
[24]Arkan MC, Hevener AL, Greten FR, et al. IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med.2005.11(2):191-8.
[25]Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA.2001. 286(3):327-34.
[26]Li Z, Yang S, Lin H, et al. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology.2003.37(2):343-50.
[27]Evans RM, Barish GD, Wang YX. PPARs and the complex journey to obesity. Nat Med.2004.10(4):355-61.
[28]Bocher V, Pineda-Torra I, Fruchart JC, Staels B. PPARs:transcription factors controlling lipid and lipoprotein metabolism. Ann N Y Acad Sci.2002.967: 7-18.
[29]Landrier JF, Thomas C, Grober J, et al. Statin induction of liver fatty acid-binding protein (L-FABP) gene expression is peroxisome proliferator-activated receptor-alpha-dependent. J Biol Chem.2004.279(44): 45512-8.
[30]Ameen C, Edvardsson U, Ljungberg A, et al. Activation of peroxisome proliferator-activated receptor alpha increases the expression and activity of microsomal triglyceride transfer protein in the liver. J Biol Chem.2005. 280(2):1224-9.
[31]Linden D, Lindberg K, Oscarsson J, et al. Influence of peroxisome proliferator-activated receptor alpha agonists on the intracellular turnover and secretion of apolipoprotein (Apo) B-100 and ApoB-48. J Biol Chem.2002. 277(25):23044-53.
[32]Gibbons G. Old fat, make way for new fat. Nat Med.2005.11(7):722-3.
[33]Inoue I, Goto S, Matsunaga T, et al. The ligands/activators for peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma increase Cu2+,Zn2+-superoxide dismutase and decrease p22phox message expressions in primary endothelial cells. Metabolism.2001.50(1):3-11.
[34]Lefebvre P, Chinetti G, Fruchart JC, Staels B. Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest.2006. 116(3):571-80.
[35]Leclercq IA. Pathogenesis of steatohepatitis:insights from the study of animal models. Acta Gastroenterol Belg.2007.70(1):25-31.
[36]Hertz R, Bar-Tana J. Peroxisome proliferator-activated receptor (PPAR) alpha activation and its consequences in humans. Toxicol Lett.1998.102-103: 85-90.
[37]Cariello NF, Romach EH, Colton HM, et al. Gene expression profiling of the PPAR-alpha agonist ciprofibrate in the cynomolgus monkey liver. Toxicol Sci. 2005.88(1):250-64.
[38]Ip E, Farrell G, Hall P, Robertson G, Leclercq I. Administration of the potent PPARalpha agonist, Wy-14,643, reverses nutritional fibrosis and steatohepatitis in mice. Hepatology.2004.39(5):1286-96.
[39]Saibara T, Onishi S, Ogawa Y, Yoshida S, Enzan H. Bezafibrate for tamoxifen-induced non-alcoholic steatohepatitis. Lancet.1999.353(9166): 1802.
[40]Laurin J, Lindor KD, Crippin JS, et al. Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis:a pilot study. Hepatology. 1996.23(6):1464-7.
[41]Yoneda M, Endo H, Nozaki Y, et al. Life style-related diseases of the digestive system:gene expression in nonalcoholic steatohepatitis patients and treatment strategies. J Pharmacol Sci.2007.105(2):151-6.
[42]戴林,于洪波,左中,张劲风,冯亮.非酒精性脂肪性肝炎大鼠血清肿瘤坏死因子α变化和肝组织过氧化物酶体增殖物激活受体γ的表达.胃肠病学和肝病学杂志.2006.(06):590-592.
[43]Videla LA, Rodrigo R, Orellana M, et al. Oxidative stress-related parameters in the liver of non-alcoholic fatty liver disease patients. Clin Sci (Lond).2004. 106(3):261-8.
[44]Sanyal AJ, Campbell-Sargent C, Mirshahi F, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology.2001.120(5):1183-92.
[45]Robertson G, Leclercq I, Farrell GC. Nonalcoholic steatosis and steatohepatitis. Ⅱ. Cytochrome P-450 enzymes and oxidative stress. Am J Physiol Gastrointest Liver Physiol.2001.281(5):G1135-9.
[46]Leclercq IA, Farrell GC, Field J, Bell DR, Gonzalez FJ, Robertson GR. CYP2E1 and CYP4A as microsomal catalysts of lipid peroxides in murine nonalcoholic steatohepatitis. J Clin Invest.2000.105(8):1067-75.
[47]Schulze-Osthoff K, Bakker AC, Vanhaesebroeck B, Beyaert R, Jacob WA, Fiers W. Cytotoxic activity of tumor necrosis factor is mediated by early damage of mitochondrial functions. Evidence for the involvement of mitochondrial radical generation. J Biol Chem.1992.267(8):5317-23.
[48]Pessayre D, Berson A, Fromenty B, Mansouri A. Mitochondria in steatohepatitis. Semin Liver Dis.2001.21(1):57-69.
[49]Chavin KD, Yang S, Lin HZ, et al. Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion. J Biol Chem.1999. 274(9):5692-700.
[50]Fernandez-Checa JC, Kaplowitz N, Garcia-Ruiz C, Colell A. Mitochondrial glutathione:importance and transport. Semin Liver Dis.1998.18(4):389-401.
[51]Tirmenstein MA, Nicholls-Grzemski FA, Zhang JG, Fariss MW. Glutathione depletion and the production of reactive oxygen species in isolated hepatocyte suspensions. Chem Biol Interact.2000.127(3):201-17.
[52]Schwabe RF, Brenner DA. Mechanisms of Liver Injury. I. TNF-alpha-induced liver injury:role of IKK, JNK, and ROS pathways. Am J Physiol Gastrointest Liver Physiol.2006.290(4):G583-9.
[53]Paradies G, Ruggiero FM, Gadaleta MN, Quagliariello E. The effect of aging and acetyl-L-carnitine on the activity of the phosphate carrier and on the phospholipid composition in rat heart mitochondria. Biochim Biophys Acta. 1992.1103(2):324-6.
[54]Sanchez-Alcazar JA, Schneider E, Martinez MA, et al. Tumor necrosis factor-alpha increases the steady-state reduction of cytochrome b of the mitochondrial respiratory chain in metabolically inhibited L929 cells. J Biol Chem.2000.275(18):13353-61.
[55]Gow AJ, Stamler JS. Reactions between nitric oxide and haemoglobin under physiological conditions. Nature.1998.391(6663):169-73.
[56]Szabo C, Zingarelli B, O'Connor M, Salzman AL. DNA strand breakage, activation of poly (ADP-ribose) synthetase, and cellular energy depletion are involved in the cytotoxicity of macrophages and smooth muscle cells exposed to peroxynitrite. Proc Natl Acad Sci U S A.1996.93(5):1753-8.
[57]Garcia-Ruiz I, Rodriguez-Juan C, Diaz-Sanjuan T, et al. Uric acid and anti-TNF antibody improve mitochondrial dysfunction in ob/ob mice. Hepatology.2006.44(3):581-91.
[58]Begriche K, Igoudjil A, Pessayre D, Fromenty B. Mitochondrial dysfunction in NASH:causes, consequences and possible means to prevent it. Mitochondrion.2006.6(1):1-28.
[59]Schaffler A, Scholmerich J, Buchler C. Mechanisms of disease: adipocytokines and visceral adipose tissue-emerging role in nonalcoholic fatty liver disease. Nat Clin Pract Gastroenterol Hepatol.2005.2(6):273-80.
[60]Rajala MW, Scherer PE. Minireview:The adipocyte-at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology.2003. 144(9):3765-73.
[61]Bokarewa M, Nagaev I, Dahlberg L, Smith U, Tarkowski A. Resistin, an adipokine with potent proinflammatory properties. J Immunol.2005.174(9): 5789-95.
[62]Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest.2003.112(1):91-100.
[63]钟岚,刘菲,王军臣,孙兆金,袁琼英.非酒精性脂肪性肝炎发病机制探讨.中华消化杂志.2006.26(5):324-326.
[64]Svegliati-Baroni G, Candelaresi C, Saccomanno S, et al. A model of insulin resistance and nonalcoholic steatohepatitis in rats:role of peroxisome proliferator-activated receptor-alpha and n-3 polyunsaturated fatty acid treatment on liver injury. Am J Pathol.2006.169(3):846-60.
[65]丁效蕙,赵景民,孙艳玲等.Leptin及其受体在非酒精性脂肪性肝炎患者肝组织中的表达.解放军医学杂志.2007.(09):957-960.
[66]Larter CZ, Farrell GC. Insulin resistance, adiponectin, cytokines in NASH: Which is the best target to treat. J Hepatol.2006.44(2):253-61.
[67]Aller R, de Luis DA, Fernandez L, et al. Influence of insulin resistance and adipokines in the grade of steatosis of nonalcoholic fatty liver disease. Dig Dis Sci.2008.53(4):1088-92.
[68]Marra F, Bertolani C. Adipokines in liver diseases. Hepatology.2009.50(3): 957-69.
[69]Tsochatzis E, Papatheodoridis GV, Archimandritis AJ. The evolving role of leptin and adiponectin in chronic liver diseases. Am J Gastroenterol.2006. 101(11):2629-40.
[70]Musso G, Gambino R, Durazzo M, et al. Adipokines in NASH:postprandial lipid metabolism as a link between adiponectin and liver disease. Hepatology. 2005.42(5):1175-83.
[71]Yalniz M, Bahcecioglu IH, Ataseven H, et al. Serum adipokine and ghrelin levels in nonalcoholic steatohepatitis. Mediators Inflamm.2006.2006(6): 34295.
[72]Targher G, Bertolini L, Rodella S, et al. Associations between plasma adiponectin concentrations and liver histology in patients with nonalcoholic fatty liver disease. Clin Endocrinol (Oxf).2006.64(6):679-83.
[73]Pagano C, Soardo G, Esposito W, et al. Plasma adiponectin is decreased in nonalcoholic fatty liver disease. Eur J Endocrinol.2005.152(1):113-8.
[74]Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH:TNF-alpha or adiponectin. Hepatology.2004. 40(1):46-54.
[75]Kaser S, Moschen A, Cayon A, et al. Adiponectin and its receptors in non-alcoholic steatohepatitis. Gut.2005.54(1):117-21.
[76]Shimada M, Kawahara H, Ozaki K, et al. Usefulness of 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. Am J Gastroenterol.2007.102(9):1931-8.
[77]Chitturi S, Farrell G, Frost L, et al. Serum leptin in NASH correlates with hepatic steatosis but not fibrosis:a manifestation of lipotoxicity. Hepatology. 2002.36(2):403-9.
[78]Unger RH, Orci L. Diseases of liporegulation:new perspective on obesity and related disorders. FASEB J.2001.15(2):312-21.
[79]Nagao K, Inoue N, Ujino Y, et al. Effect of leptin infusion on insulin sensitivity and lipid metabolism in diet-induced lipodystrophy model mice. Lipids Health Dis.2008.7:8.
[80]Tilg H, Hotamisligil GS. Nonalcoholic fatty liver disease:Cytokine-adipokine interplay and regulation of insulin resistance. Gastroenterology.2006.131(3): 934-45.
[81]Fishman S, Muzumdar RH, Atzmon G, et al. Resistance to leptin action is the major determinant of hepatic triglyceride accumulation in vivo. FASEB J. 2007.21(1):53-60.
[82]Ikejima K, Okumura K, Lang T, et al. The role of leptin in progression of non-alcoholic fatty liver disease. Hepatol Res.2005.33(2):151-4.
[83]Pittas AG, Joseph NA, Greenberg AS. Adipocytokines and insulin resistance. J Clin Endocrinol Metab.2004.89(2):447-52.
[84]Muse ED, Obici S, Bhanot S, et al. Role of resistin in diet-induced hepatic insulin resistance. J Clin Invest.2004.114(2):232-9.
[85]Higgins SC, Gueorguiev M, Korbonits M. Ghrelin, the peripheral hunger hormone. Ann Med.2007.39(2):116-36.
[86]Barazzoni R, Zanetti M, Cattin MR, et al. Ghrelin enhances in vivo skeletal muscle but not liver AKT signaling in rats. Obesity (Silver Spring).2007. 15(11):2614-23.
[87]Barazzoni R, Zanetti M, Ferreira C, et al. Relationships between desacylated and acylated ghrelin and insulin sensitivity in the metabolic syndrome. J Clin Endocrinol Metab.2007.92(10):3935-40.
[88]Barazzoni R, Bosutti A, Stebel M, et al. Ghrelin regulates mitochondrial-lipid metabolism gene expression and tissue fat distribution in liver and skeletal muscle. Am J Physiol Endocrinol Metab.2005.288(1):E228-35.
[89]Yalniz M, Bahcecioglu IH, Ataseven H, et al. Serum adipokine and ghrelin levels in nonalcoholic steatohepatitis. Mediators Inflamm.2006.2006(6): 34295.
[90]Nobili V, Manco M, Ciampalini P, et al. Leptin, free leptin index, insulin resistance and liver fibrosis in children with non-alcoholic fatty liver disease. Eur J Endocrinol.2006.155(5):735-43.
[91]Lydatakis H, Hager IP, Kostadelou E, Mpousmpoulas S, Pappas S, Diamantis I. Non-invasive markers to predict the liver fibrosis in non-alcoholic fatty liver disease. Liver Int.2006.26(7):864-71.
[92]Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha:direct role in obesity-linked insulin resistance. Science. 1993.259(5091):87-91.
[93]Wellen KE, Hotamisligil GS. Obesity-induced inflammatory changes in adipose tissue. J Clin Invest.2003.112(12):1785-8.
[94]You M, Considine RV, Leone TC, Kelly DP, Crabb DW. Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice. Hepatology.2005.42(3):568-77.
[95]Valenti L, Fracanzani AL, Dongiovanni P, et al. Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease. Gastroenterology.2002.122(2):274-80.
[96]Tokushige K, Takakura M, Tsuchiya-Matsushita N, Taniai M, Hashimoto E, Shiratori K. Influence of TNF gene polymorphisms in Japanese patients with NASH and simple steatosis. J Hepatol.2007.46(6):1104-10.
[97]Poniachik J, Csendes A, Diaz JC, et al. Increased production of IL-1 alpha and TNF-alpha in lipopolysaccharide-stimulated blood from obese patients with non-alcoholic fatty liver disease. Cytokine.2006.33(5):252-7.
[98]Feldstein AE, Werneburg NW, Canbay A, et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology.2004.40(1):185-94.
[99]Tomita K, Tamiya G, Ando S, et al. Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut.2006.55(3):415-24.
[100]Li Z, Yang S, Lin H, et al. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology.2003.37(2):343-50.
[101]Leonarduzzi G, Scavazza A, Biasi F, et al. The lipid peroxidation end product 4-hydroxy-2,3-nonenal up-regulates transforming growth factor betal expression in the macrophage lineage:a link between oxidative injury and fibrosclerosis. FASEB J.1997.11(11):851-7.
[102]Cressman DE, Greenbaum LE, DeAngelis RA, et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science. 1996.274(5291):1379-83.
[103]El-Assal O, Hong F, Kim WH, Radaeva S, Gao B. IL-6-deficient mice are susceptible to ethanol-induced hepatic steatosis:IL-6 protects against ethanol-induced oxidative stress and mitochondrial permeability transition in the liver. Cell Mol Immunol.2004.1(3):205-11.
[104]Teoh N, Field J, Farrell G. Interleukin-6 is a key mediator of the hepatoprotective and pro-proliferative effects of ischaemic preconditioning in mice. J Hepatol.2006.45(1):20-7.
[105]Blindenbacher A, Wang X, Langer I, Savino R, Terracciano L, Heim MH. Interleukin 6 is important for survival after partial hepatectomy in mice. Hepatology.2003.38(3):674-82.
[106]Jin X, Zimmers TA, Perez EA, Pierce RH, Zhang Z, Koniaris LG. Paradoxical effects of short-and long-term interleukin-6 exposure on liver injury and repair. Hepatology.2006.43(3):474-84.
[107]Galli A, Pinaire J, Fischer M, Dorris R, Crabb DW. The transcriptional and DNA binding activity of peroxisome proliferator-activated receptor alpha is inhibited by ethanol metabolism. A novel mechanism for the development of ethanol-induced fatty liver. J Biol Chem.2001.276(1):68-75.
[108]Berson A, De Beco V, Letteron P, et al. Steatohepatitis-inducing drugs cause mitochondrial dysfunction and lipid peroxidation in rat hepatocytes. Gastroenterology.1998.114(4):764-74.
[109]Yu C, Chen Y, Cline GW, et al. Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle. J Biol Chem.2002.277(52): 50230-6.
[110]Feldstein AE, Canbay A, Angulo P, et al. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology.2003.125(2):437-43.
[111]Wieckowska A, Zein NN, Yerian LM, Lopez AR, McCullough AJ, Feldstein AE. 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.
[112]Ramalho RM, Cortez-Pinto H, Castro RE, et al. Apoptosis and Bcl-2 expression in the livers of patients with steatohepatitis. Eur J Gastroenterol Hepatol.2006.18(1):21-9.
[1]Ekstedt M, Franzen LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology.2006.44(4):865-73.
[2]Fassio E, Alvarez E, Dominguez N, Landeira G, Longo C. Natural history of nonalcoholic steatohepatitis:a longitudinal study of repeat liver biopsies. Hepatology.2004.40(4):820-6.
[3]Adams LA, Lymp JF, St SJ, et al. The natural history of nonalcoholic fatty liver disease:a population-based cohort study. Gastroenterology.2005.129(1): 113-21.
[4]Reaven GM. The metabolic syndrome:requiescat in pace. Clin Chem.2005. 51(6):931-8.
[5]Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology.2003.37(4):917-23.
[6]Day CP, James OF. Steatohepatitis:a tale of two "hits". Gastroenterology. 1998.114(4):842-5.
[7]Pagano G, Pacini G, Musso G, et al. Nonalcoholic steatohepatitis, insulin resistance, and metabolic syndrome:further evidence for an etiologic association. Hepatology.2002.35(2):367-72.
[8]'Clark JM. The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol.2006.40 Suppl 1:S5-10.
[9]Bellentani S, Saccoccio G, Masutti F, et al. Prevalence of and risk factors for hepatic steatosis in Northern Italy. Ann Intern Med.2000.132(2):112-7.
[10]Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States:impact of ethnicity. Hepatology.2004.40(6):1387-95.
[11]Hamaguchi M, Kojima T, Takeda N, et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med.2005.143(10): 722-8.
[12]Kojima S, Watanabe N, Numata M, Ogawa T, Matsuzaki S. Increase in the prevalence of fatty liver in Japan over the past 12 years:analysis of clinical background. J Gastroenterol.2003.38(10):954-61.
[13]Jimba S, Nakagami T, Takahashi M, et al. Prevalence of non-alcoholic fatty liver disease and its association with impaired glucose metabolism in Japanese adults. Diabet Med.2005.22(9):1141-5.
[14]Tsuruta G, Tanaka N, Hongo M, et al. Nonalcoholic fatty liver disease in Japanese junior high school students:its prevalence and relationship to lifestyle habits. J Gastroenterol.2010.
[15]Amarapurkar DN, Hashimoto E, Lesmana LA, Sollano JD, Chen PJ, Goh KL. How common is non-alcoholic fatty liver disease in the Asia-Pacific region and are there local differences. J Gastroenterol Hepatol.2007.22(6):788-93.
[16]Li H, Wang YJ, Tan K, et al. Prevalence and risk factors of fatty liver disease in Chengdu, Southwest China. Hepatobiliary Pancreat Dis Int.2009.8(4): 377-82.
[17]Zhou YJ, Li YY, Nie YQ, et al. Prevalence of fatty liver disease and its risk factors in the population of South China. World J Gastroenterol.2007.13(47): 6419-24.
[18]Wang Z, Xia B, Ma C, Hu Z, Chen X, Cao P. Prevalence and risk factors of fatty liver disease in the Shuiguohu district of Wuhan city, central China. Postgrad Med J.2007.83(977):192-5.
[19]Chen CH, Huang MH, Yang JC, et al. Prevalence and risk factors of nonalcoholic fatty liver disease in an adult population of taiwan:metabolic significance of nonalcoholic fatty liver disease in nonobese adults. J Clin Gastroenterol.2006.40(8):745-52.
[20]Park SH, Jeon WK, Kim SH, et al. Prevalence and risk factors of non-alcoholic fatty liver disease among Korean adults. J Gastroenterol Hepatol. 2006.21(1 Pt 1):138-43.
[21]Petersen KF, Dufour S, Feng J, et al. Increased prevalence of insulin resistance and nonalcoholic fatty liver disease in Asian-Indian men. Proc Natl Acad Sci U S A.2006.103(48):18273-7.
[22]Weston SR, Leyden W, Murphy R, et al. Racial and ethnic distribution of nonalcoholic fatty liver in persons with newly diagnosed chronic liver disease. Hepatology.2005.41(2):372-9.
[23]Fan JG, Zhu J, Li XJ, et al. Fatty liver and the metabolic syndrome among Shanghai adults. J Gastroenterol Hepatol.2005.20(12):1825-32.
[24]Fan JG, Saibara T, Chitturi S, Kim BI, Sung JJ, Chutaputti A. What are the risk factors and settings for non-alcoholic fatty liver disease in Asia-Pacific. J Gastroenterol Hepatol.2007.22(6):794-800.
[25]Fassio E, Alvarez E, Dominguez N, Landeira G, Longo C. Natural history of nonalcoholic steatohepatitis:a longitudinal study of repeat liver biopsies. Hepatology.2004.40(4):820-6.
[26]Adams LA, Lymp JF, St SJ, et al. The natural history of nonalcoholic fatty liver disease:a population-based cohort study. Gastroenterology.2005.129(1): 113-21.
[27]Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease:a spectrum of clinical and pathological severity. Gastroenterology.1999.116(6):1413-9.
[28]Farrell GC, Larter CZ. Nonalcoholic fatty liver disease:from steatosis to cirrhosis. Hepatology.2006.43(2 Suppl 1):S99-S112.
[29]Ratziu V, Poynard T. Assessing the outcome of nonalcoholic steatohepatitis? It's time to get serious. Hepatology.2006.44(4):802-5.
[30]Tarantino G, Saldalamacchia G, Conca P, Arena A. Non-alcoholic fatty liver disease:further expression of the metabolic syndrome. J Gastroenterol Hepatol. 2007.22(3):293-303.
[31]Ong JP, Elariny H, Collantes R, et al. Predictors of nonalcoholic steatohepatitis and advanced fibrosis in morbidly obese patients. Obes Surg. 2005.15(3):310-5.
[32]Zatloukal K, Stumptner C, Fuchsbichler A, et al. The keratin cytoskeleton in liver diseases. J Pathol.2004.204(4):367-76.
[33]Das K, Das K, Mukherjee PS, et al. Nonobese population in a developing country has a high prevalence of nonalcoholic fatty liver and significant liver disease. Hepatology.2010.
[34]Kim HJ, Kim HJ, Lee KE, et al. Metabolic significance of nonalcoholic fatty liver disease in nonobese, nondiabetic adults. Arch Intern Med.2004.164(19): 2169-75.
[35]Browning JD, Kumar KS, Saboorian MH, Thiele DL. Ethnic differences in the prevalence of cryptogenic cirrhosis. Am J Gastroenterol.2004.99(2):292-8.
[36]Reynet C, Kahn CR. Rad:a member of the Ras family overexpressed in muscle of type II diabetic humans. Science.1993.262(5138):1441-4.
[37]Saibara T, Onishi S, Ogawa Y, Yoshida S, Enzan H. Bezafibrate for tamoxifen-induced non-alcoholic steatohepatitis. Lancet.1999.353(9166): 1802.
[38]Ratziu V, Poynard T. Assessing the outcome of nonalcoholic steatohepatitis? It's time to get serious. Hepatology.2006.44(4):802-5.
[39]Hui JM, Kench JG, Chitturi S, et al. Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C. Hepatology.2003. 38(2):420-7.
[40]Sanyal AJ, Banas C, Sargeant C, et al. Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C. Hepatology. 2006.43(4):682-9.
[41]Marrero JA, Fontana RJ, Su GL, Conjeevaram HS, Emick DM, Lok AS. NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States. Hepatology.2002.36(6): 1349-54.
[42]Ratziu V, Bonyhay L, Di MV, et al. Survival, liver failure, and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis. Hepatology.2002.35(6): 1485-93.
[43]Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of nonalcoholic steatohepatitis:from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology.2002.123(1):134-40.
[44]Shimada M, Hashimoto E, Taniai M, et al. Hepatocellular carcinoma in patients with non-alcoholic steatohepatitis. J Hepatol.2002.37(1):154-60.
[45]Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease:a spectrum of clinical and pathological severity. Gastroenterology.1999.116(6):1413-9.
[46]Chitturi S, Abeygunasekera S, Farrell GC, et al. NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology.2002.35(2):373-9.
[47]Ratziu V, Bonyhay L, Di MV, et al. Survival, liver failure, and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis. Hepatology.2002.35(6): 1485-93.
[48]Sanyal AJ. Review article:non-alcoholic fatty liver disease and hepatitis C-risk factors and clinical implications. Aliment Pharmacol Ther.2005.22 Suppl2:48-51.
[49]Clark JM, Diehl AM. Nonalcoholic fatty liver disease:an underrecognized cause of cryptogenic cirrhosis. JAMA.2003.289(22):3000-4.
[50]中华医学会肝脏病学分会脂肪肝和酒精性肝病学组,Association FLaALDSGotCLD.非酒精性脂肪性肝病诊疗指南.中华肝脏病杂志.2006.14(3):161-163.
[51]Ruhl CE, Everhart JE. Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the United States. Gastroenterology.2003.124(1):71-9.
[52]Sattar N, Scherbakova O, Ford I, et al. Elevated alanine aminotransferase predicts new-onset type 2 diabetes independently of classical risk factors, metabolic syndrome, and C-reactive protein in the west of Scotland coronary prevention study. Diabetes.2004.53(11):2855-60.
[53]Pacifico L, Celestre M, Anania C, Paolantonio P, Chiesa C, Laghi A. MRI and ultrasound for hepatic fat quantification:relationships to clinical and metabolic characteristics of pediatric nonalcoholic fatty liver disease. Acta Paediatr.2007. 96(4):542-7.
[54]Radetti G, Kleon W, Stuefer J, Pittschieler K. Non-alcoholic fatty liver disease in obese children evaluated by magnetic resonance imaging. Acta Paediatr. 2006.95(7):833-7.
[55]Westerbacka J, Corner A, Tiikkainen M, et al. Women and men have similar amounts of liver and intra-abdominal fat, despite more subcutaneous fat in women:implications for sex differences in markers of cardiovascular risk. Diabetologia.2004.47(8):1360-9.
[56]Sattar N, Wannamethee SG, Forouhi NG. Novel biochemical risk factors for type 2 diabetes:pathogenic insights or prediction possibilities. Diabetologia. 2008.51(6):926-40.
[57]Lee SA, Kallianpur A, Xiang YB, et al. Intra-individual variation of plasma adipokine levels and utility of single measurement of these biomarkers in population-based studies. Cancer Epidemiol Biomarkers Prev.2007.16(11): 2464-70.
[58]Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH:TNF-alpha or adiponectin. Hepatology.2004. 40(1):46-54.
[59]Tsochatzis E, Papatheodoridis GV, Hadziyannis E, et al. Serum adipokine levels in chronic liver diseases:association of resistin levels with fibrosis severity. Scand J Gastroenterol.2008.43(9):1128-36.
[60]Bahcecioglu IH, Yalniz M, Ataseven H, et al. Levels of serum hyaluronic acid, TNF-alpha and IL-8 in patients with nonalcoholic steatohepatitis. Hepatogastroenterology.2005.52(65):1549-53.
[61]Lydatakis H, Hager IP, Kostadelou E, Mpousmpoulas S, Pappas S, Diamantis I. Non-invasive markers to predict the liver fibrosis in non-alcoholic fatty liver disease. Liver Int.2006.26(7):864-71.
[62]Sakugawa H, Nakayoshi T, Kobashigawa K, et al. Clinical usefulness of biochemical markers of liver fibrosis in patients with nonalcoholic fatty liver disease. World J Gastroenterol.2005.11(2):255-9.
[63]Yoneda M, Mawatari H, Fujita K, 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. J Gastroenterol.2007. 42(5):375-81.
[64]Shimada M, Kawahara H, Ozaki K, et al. Usefulness of 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. Am J Gastroenterol.2007.102(9):1931-8.
[65]Palekar NA, Naus R, Larson SP, Ward J, Harrison SA. Clinical model for distinguishing nonalcoholic steatohepatitis from simple steatosis in patients with nonalcoholic fatty liver disease. Liver Int.2006.26(2):151-6.
[66]Feldstein AE, Canbay A, Angulo P, et al. Hepatocyte apoptosis and fas expression are prominent features of human nonalcoholic steatohepatitis. Gastroenterology.2003.125(2):437-43.
[67]Wieckowska A, Zein NN, Yerian LM, Lopez AR, McCullough AJ, Feldstein AE. 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.
[68]Gonzalez-Quintela A, Mella C, Perez LF, Abdulkader I, Caparrini AM, Lojo S. Increased serum tissue polypeptide specific antigen (TPS) in alcoholics:a possible marker of alcoholic hepatitis. Alcohol Clin Exp Res.2000.24(8): 1222-6.
[69]Younossi ZM, Jarrar M, Nugent C, et al. A novel diagnostic biomarker panel for obesity-related nonalcoholic steatohepatitis (NASH). Obes Surg.2008. 18(11):1430-7.
[70]Diab DL, Yerian L, Schauer P, et al. Cytokeratin 18 fragment levels as a noninvasive biomarker for nonalcoholic steatohepatitis in bariatric surgery patients. Clin Gastroenterol Hepatol.2008.6(11):1249-54.
[71]Charlton M, Angulo P, Chalasani N, et al. Low circulating levels of dehydroepiandrosterone in histologically advanced nonalcoholic fatty liver disease. Hepatology.2008.47(2):484-92.
[72]Yoneda M, Uchiyama T, Kato S, et al. Plasma Pentraxin3 is a novel marker for nonalcoholic steatohepatitis (NASH). BMC Gastroenterol.2008.8:53.
[73]Yoneda M, Uchiyama T, Kato S, et al. Plasma Pentraxin3 is a novel marker for nonalcoholic steatohepatitis (NASH). BMC Gastroenterol.2008.8:53.
[74]Musso G, Gambino R, De Michieli F, et al. Nitrosative stress predicts the presence and severity of nonalcoholic fatty liver at different stages of the development of insulin resistance and metabolic syndrome:possible role of vitamin A intake. Am J Clin Nutr.2007.86(3):661-71.
[75]Albano E, Mottaran E, Vidali M, et al. Immune response towards lipid peroxidation products as a predictor of progression of non-alcoholic fatty liver disease to advanced fibrosis. Gut.2005.54(7):987-93.
[76]Portincasa P, Grattagliano I, Lauterburg BH, Palmieri VO, Palasciano G, Stellaard F. Liver breath tests non-invasively predict higher stages of non-alcoholic steatohepatitis. Clin Sci (Lond).2006.111(2):135-43.
[77]Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology.2002.123(3):745-50.
[78]Sandrin L, Fourquet B, Hasquenoph JM, et al. Transient elastography:a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol. 2003.29(12):1705-13.
[79]Nguyen-Khac E, Capron D. Noninvasive diagnosis of liver fibrosis by ultrasonic transient elastography (Fibroscan). Eur J Gastroenterol Hepatol. 2006.18(12):1321-5.
[80]Kikuchi M, Tomita K, Nakahara T, et al. Utility of quantitative 99mTc-phytate scintigraphy to diagnose early-stage non-alcoholic steatohepatitis. Scand J Gastroenterol.2009.44(2):229-36.
[81]Joseph AE, Saverymuttu SH, al-Sam S, Cook MG, Maxwell JD. Comparison of liver histology with ultrasonography in assessing diffuse parenchymal liver disease. Clin Radiol.1991.43(1):26-31.
[82]Mottin CC, Moretto M, Padoin AV, et al. The role of ultrasound in the diagnosis of hepatic steatosis in morbidly obese patients. Obes Surg.2004. 14(5):635-7.
[83]Saadeh S, Younossi ZM, Remer EM, et al. The utility of radiological imaging in nonalcoholic fatty liver disease. Gastroenterology.2002.123(3):745-50.
[84]Tsuda N, Okada M, Murakami T. Potential of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) for differential diagnosis of nonalcoholic steatohepatitis and fatty liver in rats using magnetic resonance imaging. Invest Radiol.2007. 42(4):242-7.
[85]Calvert VS, Collantes R, Elariny H, et al. A systems biology approach to the pathogenesis of obesity-related nonalcoholic fatty liver disease using reverse phase protein microarrays for multiplexed cell signaling analysis. Hepatology. 2007.46(1):166-72.
[86]Romeo S, Kozlitina J, Xing C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet.2008.40(12): 1461-5.
[87]Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005.41(6):1313-21.
[88]Piccinino F, Sagnelli E, Pasquale G, Giusti G. Complications following percutaneous liver biopsy. A multicentre retrospective study on 68,276 biopsies. J Hepatol.1986.2(2):165-73.