外周血sTRAIL水平及TRAIL基因多态性与中国汉族人脂肪肝的相关性研究
摘要
背景:
脂肪性肝病(fatty liver disease,FLD)简称脂肪肝,是一种由多种病因引起的、病变主要在肝小叶,以肝细胞内甘油三酯异常储积为主要表现的临床病理综合征,近年来,随着人们生活饮食结构的变化,FLD的发病率有进一步增高的趋势,有统计,在校正了年龄、性别和居住地区等因素后,脂肪肝、酒精性脂肪肝(alcoholic fatty liver disease,AFLD)和非酒精性脂肪肝(nonalcoholic fatty liverdisease,NAFLD)总的标准发病率为11.3%,2.2%和9.1%(成人为14.5%,2.9%和11.7%),日趋超越病毒性肝炎,是导致肝脏相关性致残和死亡的重要原因,已成为全球普遍关注的医学问题和社会问题。脂肪肝的发病与多种因素有关,是多种因子相互作用的结果。目前,凋亡因子在肝脂肪变过程中的作用已引起许多学者的关注。
肿瘤坏死因子相关凋亡诱导配体(tumor necrosis factor related apoptosisinducing ligand,TRAIL),是1995年由Wiley发现并命名的,人TRAIL基因定位于染色体3q26,由5个外显子组成,编码1.77 kb mRNA,并可编码281个氨基酸残基组成的分子量为32.5 KDa的Ⅱ型跨膜蛋白。TRAIL属于TNF超家族成员,其结构与该家族的其他成员相仿。TRAIL可通过与其受体结合,诱导细胞凋亡,或发挥其他生物学作用。近几年通过临床资料及动物实验研究,发现TRAIL的表达水平与人外周血脂质水平呈现相关性,并且TRAIL在病毒感染和摄入酒精后可诱导肝脂肪变,但TRAIL在肝脂肪变中的具体作用尚不明了。FLD的发病与多种凋亡相关因子的多态性有关,但TRAIL的多态性是否与FLD的发生有关尚未见报道。
目的:
通过检测人外周血TRAIL、转氨酶、血糖、血脂等生化指标和检测非酒精性脂肪肝、酒精性脂肪肝、健康对照和嗜酒无脂肪肝四组人群TRAIL基因第五外显子3'-非编码区1525G/A、1595C/T位点基因多态性,推测脂肪肝与TRAIL及其等位基因和基因型的关联性。
方法:
采用病例对照的方法,对体检人群用B超筛选出163例脂肪肝患者,其中NAFLD组84例,AFLD组79例,同时选择同期体检的102例对照者,其中80例健康对照者,22例嗜酒无脂肪肝者。全部选择对象均空腹检测转氨酶、血糖、血脂等各项生化指标,从中随机选择44例NAFLD患者、35例健康对照者,用酶联免疫吸附试验(enzyme-linked immunosorbent assay,ELISA)法检测血清可溶性TRAIL的水平。通过聚合酶链式反应-限制性内切酶片段长度多态性(polymerase chain reaction-Restriction fragment length polymorphism,PCR-RFLP)法检测四组人群TRAIL基因第五外显子3'-非编码区(3'-untranslatedregion,3'-UTR)1525/1595两位点基因多态性。同时从中选择部分对象通过基因测序验证PCR-RFLP法的正确性。
结果:
(1)非酒精性脂肪肝组血清可溶性TRAIL的表达量明显高于健康对照组(p=0.017,p＜0.05)。(2)血清可溶性TRAIL浓度与甘油三酯(triglyceride,TG)含量呈正相关(r=0.368,P=0.014,P＜0.05)。(3)中国汉族人群存在TRAIL基因1525G/A、1595C/T突变。(4)对中国汉族265名人员TRAIL基因第五外显子3'-UTR区1525、1595位点进行多态性分析,发现同一个体两位点G/A、C/T基因突变情况完全一致。(5)NAFLD、AFLD组1525/1595位点基因型分布与健康对照组比较均具有显著性差异(p=0.016,p＜0.05;p=0.013,p＜0.05);NAFLD组1525/1595位点G/C等位基因频率明显高于健康对照组(p=0.017,p＜0.05);AFLD组1525/1595位点G/C等位基因的频率明显高于健康对照组(p=0.022,p＜0.05);(6)NAFLD组1525/1595位点GG/CC基因型TG量显著高于AA/TT基因型个体的TG量(p=0.035,p＜0.05);(7)NAFLD组血清丙氨酸氨基转移酶(alanine aminotransferase,ALT)、天门冬氨酸氨基转移酶(aspartateaminotransferase,AST)、γ-谷氨酰转肽酶(glutamyl transpeptidase,GGT)、血糖(Blood Glucose,GLU)、胆固醇(cholesterol,CH)、TG血清浓度高于健康对照组(无饮酒史)有统计学意义(p＜0.05);(8)AFLD组ALT、GLU、CH、TG血清浓度高于嗜酒无脂肪肝病组(p＜0.05);(9)AFLD组ALT、AST、GGT、GLU、CH、TG水平高于健康对照组(无饮酒史)(p＜0.05);(10)非条件多因素Logistic回归分析身体质量指数(body mass index,BMI)、腰臀比(waist hipratio,WHR)、高血脂、GGT均是NAFLD的危险因素。
结论:
PCR-RFLP方法检测TRAIL基因型特异性高,成熟,稳定;中国汉族人群存在TRAIL基因第五外显子3'-非编码区1525G/A、1595C/T突变。(1)研究发现NAFLD患者血清TRAIL水平与肝脂肪病变有关,血清sTRAIL浓度与血清TG水平呈正相关。(2)发现中国汉族人群TRAIL基因第五外显子3'-UTR1525G、1595C等位基因是与脂肪肝发病相关联的基因。(3)研究发现TRAIL基因第五外显子3'-UTR各位点基因突变一致,即一些相互邻近的多态位点趋向于在一起共同遗传,属于一种单体型。(4)TRAIL 1525/1595位点为GG/CC基因型的个体易患高血脂。(5)肥胖、高血脂、高GGT水平是非酒精性脂肪肝的危险因素。
Background:
Fatty liver disease(FLD) also called fatty liver,is a clinical pathological syndrome caused by a variety of causations.The lesion of FLD mainly lies in liver foliole,and it is characterized as triglycerides accumulation superfluously in hepatocytes.In recent years,with the improvement of people's lives and the change of diet structure,the incidence rate of FLD has further increased.According to statistics, in the correction of age,sex and residential area,and other factors,the standard incidence rate of FLD,alcoholic fatty liver disease(alcoholic fatty liver disease,AFLD) and non-alcoholic fatty liver(nonalcoholic fatty liver disease,NAFLD) were 11.3%,2.2%and 9.1%separately(in adult,they were 14.5%,2.9%and 11.7% separately),so the incidence rate of FLD has the growing trend beyond viral hepatitis.In addition,FLD may lead to liver-related disability and deaths,which has become a global medical issues of common concern and social problems.Fatty liver disease is the result of a variety of factors interaction.At present,the relationships between apoptotic factors and hepatocyte steatosis aroused the concern by many scholars.
Tumour necrosis factor(TNF)-related apoptosis inducing ligand(TRAIL) was found and named by Wiley in 1995,TRAIL is mapped to the long arm of chromosome 3q26 in humans and is composed of five exons.It encodes approximately 1.77 kb mRNA,32.5 KDa transmembrane(typeⅡ) glycoprotein composed of 281 amino acid.TRAIL belongs to TNF-super family,and its structure is similar to other TNF family members.By combining with its receptor,TRAIL can induce apoptosis or play other biological effects.It has been reported that levels of TRAIL are related to lipid levels of human peripheral blood.In recent years,it is found that TRAIL can induce hepatocyte steatosis after virus infection and after alcohol intaking.However,the mechanism of TRAIL involved in FLD is unclear.It is believed that the occurrence of FLD are related to polymorphisms of many apoptotic factors,but reports on the relation between FLD and TRAIL polymorphisms have not been appeared in the literature.
Objective:
To observe the serum concentration of soluble TRAIL(sTRAIL), aminotransferase,Glucose,lipid among NAFLD,AFLD,healthy controls and excessive drinking controls without liver disease.To observe the polymorphism and gene frequency of TRAIL gene 1525G/A and 1595C/T of the 3'-UTR in Chinese Han nationality population.To further explore the association of TRAIL polymorphism with susceptibility to fatty liver.
Methods:
This study followed a case-control design.A total of 163 FLD subjects(84 NAFLD and 79 AFLD) were analyzed according to generally accepted diagnosis criteria for example B ultrasonic.102 healthy blood donors(80 healthy controls and 22 excessive drinking controls without liver disease) were used as controls.All targets were chosen fasting.The levels of sTRAIL in serum were determined by ELISA(44 NAFLD patients and 35 healthy controls).The polymorphisms of TRAIL gene were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods in 80 patients of alcohol fatty liver disease,79 patients of nonalcoholic fatty liver disease,80 healthy controls and 22 healthy controls with alcohol.At the same time,we selected 10 samples to sequence randomly in order to validate the foregoing of PCR-RFLP results.
Results:
(1) The NAFLD group showed significantly higher levels of sTRAIL in serum than those of healthy control group(p=0.017,p＜0.05);(2) Serum sTRAIL concentrations positively correlated with triglyceride(TG) significantly(r=0.368,P =0.014,P＜0.05).(3)There were TRAIL gene 1525G/A,1595C/T polymorphisms in Chinese Hans.(4)The same mutation happened at position 1525,1595 in exon 5 of TRAIL gene in 265 Chinese Han.(5) The genotype distributions among NAFLD, AFLD and healthy control(without alcohol) were significantly different(p=0.016,p ＜0.05;p=0.013,p＜0.05);1525G allele and 1595C allele were more frequent in FLD patients than in controls(without alcohol)(p=0.017,p＜0.05).(6) In NAFLD patients,the TG concentration of individuals with GG/CC genotype at 1525/1595 was higher than that of AA/TT genotype(p=0.035,p＜0.05).(7) The serum concentration of alanine aminotransferase(ALT),aspartate aminotransferase(AST), glutamyl transpeptidase(GGT),blood Glucose(GLU),cholesterol(CH),TG in NAFLD group were higher than those in healthy control(without alcohol),the differences were statistically significant(p＜0.05).(8) The serum concentration of ALT,GLU,CH,TG in AFLD group were higher than those in excessive drinking controls without liver disease(p＜0.05).(9) The serum concentrations of ALT,AST, GGT,GLU,CH,TG in AFLD group were higher than those in healthy control(without alcohol)(p＜0.05).(10) Obesity,hyperlipidemia,High level of GGT are risk factors of NAFLD by Non-conditions more Logistic regression analysis.
Conclusion:
The PCR-RFLP can detect the TRAIL genotype accurately.There are TRAIL gene 1525G/A,1595C/T polymorphisms in Chinese Hans.(1) The study indicated that sTRAIL concentrations in serum were related to hepatic steatosis and sTRAIL concentrations were positively correlated with TG concentrations.(2)The results showed Chinese Hans people with alleles 1525G,1595C in the 3'-UTR of exon 5 of TRAIL are susceptibility to FLD.(3) There is the same genetic variation of TRAIL at position 1525G/A and 1595C/T in Chinese populations.Some nearby polymorphic loci tend to with the common genetic,and it is one type of haplotype.(4) People with GG/CC genotype at 1525/1595 sites of TRAIL are susceptible to high blood lipid.(5) Obesity,hyperlipidemia,High level of GGT are risk factors of NAFLD.
脂肪性肝病(fatty liver disease,FLD)简称脂肪肝,是一种由多种病因引起的、病变主要在肝小叶,以肝细胞内甘油三酯异常储积为主要表现的临床病理综合征,近年来,随着人们生活饮食结构的变化,FLD的发病率有进一步增高的趋势,有统计,在校正了年龄、性别和居住地区等因素后,脂肪肝、酒精性脂肪肝(alcoholic fatty liver disease,AFLD)和非酒精性脂肪肝(nonalcoholic fatty liverdisease,NAFLD)总的标准发病率为11.3%,2.2%和9.1%(成人为14.5%,2.9%和11.7%),日趋超越病毒性肝炎,是导致肝脏相关性致残和死亡的重要原因,已成为全球普遍关注的医学问题和社会问题。脂肪肝的发病与多种因素有关,是多种因子相互作用的结果。目前,凋亡因子在肝脂肪变过程中的作用已引起许多学者的关注。
肿瘤坏死因子相关凋亡诱导配体(tumor necrosis factor related apoptosisinducing ligand,TRAIL),是1995年由Wiley发现并命名的,人TRAIL基因定位于染色体3q26,由5个外显子组成,编码1.77 kb mRNA,并可编码281个氨基酸残基组成的分子量为32.5 KDa的Ⅱ型跨膜蛋白。TRAIL属于TNF超家族成员,其结构与该家族的其他成员相仿。TRAIL可通过与其受体结合,诱导细胞凋亡,或发挥其他生物学作用。近几年通过临床资料及动物实验研究,发现TRAIL的表达水平与人外周血脂质水平呈现相关性,并且TRAIL在病毒感染和摄入酒精后可诱导肝脂肪变,但TRAIL在肝脂肪变中的具体作用尚不明了。FLD的发病与多种凋亡相关因子的多态性有关,但TRAIL的多态性是否与FLD的发生有关尚未见报道。
目的:
通过检测人外周血TRAIL、转氨酶、血糖、血脂等生化指标和检测非酒精性脂肪肝、酒精性脂肪肝、健康对照和嗜酒无脂肪肝四组人群TRAIL基因第五外显子3'-非编码区1525G/A、1595C/T位点基因多态性,推测脂肪肝与TRAIL及其等位基因和基因型的关联性。
方法:
采用病例对照的方法,对体检人群用B超筛选出163例脂肪肝患者,其中NAFLD组84例,AFLD组79例,同时选择同期体检的102例对照者,其中80例健康对照者,22例嗜酒无脂肪肝者。全部选择对象均空腹检测转氨酶、血糖、血脂等各项生化指标,从中随机选择44例NAFLD患者、35例健康对照者,用酶联免疫吸附试验(enzyme-linked immunosorbent assay,ELISA)法检测血清可溶性TRAIL的水平。通过聚合酶链式反应-限制性内切酶片段长度多态性(polymerase chain reaction-Restriction fragment length polymorphism,PCR-RFLP)法检测四组人群TRAIL基因第五外显子3'-非编码区(3'-untranslatedregion,3'-UTR)1525/1595两位点基因多态性。同时从中选择部分对象通过基因测序验证PCR-RFLP法的正确性。
结果:
(1)非酒精性脂肪肝组血清可溶性TRAIL的表达量明显高于健康对照组(p=0.017,p＜0.05)。(2)血清可溶性TRAIL浓度与甘油三酯(triglyceride,TG)含量呈正相关(r=0.368,P=0.014,P＜0.05)。(3)中国汉族人群存在TRAIL基因1525G/A、1595C/T突变。(4)对中国汉族265名人员TRAIL基因第五外显子3'-UTR区1525、1595位点进行多态性分析,发现同一个体两位点G/A、C/T基因突变情况完全一致。(5)NAFLD、AFLD组1525/1595位点基因型分布与健康对照组比较均具有显著性差异(p=0.016,p＜0.05;p=0.013,p＜0.05);NAFLD组1525/1595位点G/C等位基因频率明显高于健康对照组(p=0.017,p＜0.05);AFLD组1525/1595位点G/C等位基因的频率明显高于健康对照组(p=0.022,p＜0.05);(6)NAFLD组1525/1595位点GG/CC基因型TG量显著高于AA/TT基因型个体的TG量(p=0.035,p＜0.05);(7)NAFLD组血清丙氨酸氨基转移酶(alanine aminotransferase,ALT)、天门冬氨酸氨基转移酶(aspartateaminotransferase,AST)、γ-谷氨酰转肽酶(glutamyl transpeptidase,GGT)、血糖(Blood Glucose,GLU)、胆固醇(cholesterol,CH)、TG血清浓度高于健康对照组(无饮酒史)有统计学意义(p＜0.05);(8)AFLD组ALT、GLU、CH、TG血清浓度高于嗜酒无脂肪肝病组(p＜0.05);(9)AFLD组ALT、AST、GGT、GLU、CH、TG水平高于健康对照组(无饮酒史)(p＜0.05);(10)非条件多因素Logistic回归分析身体质量指数(body mass index,BMI)、腰臀比(waist hipratio,WHR)、高血脂、GGT均是NAFLD的危险因素。
结论:
PCR-RFLP方法检测TRAIL基因型特异性高,成熟,稳定;中国汉族人群存在TRAIL基因第五外显子3'-非编码区1525G/A、1595C/T突变。(1)研究发现NAFLD患者血清TRAIL水平与肝脂肪病变有关,血清sTRAIL浓度与血清TG水平呈正相关。(2)发现中国汉族人群TRAIL基因第五外显子3'-UTR1525G、1595C等位基因是与脂肪肝发病相关联的基因。(3)研究发现TRAIL基因第五外显子3'-UTR各位点基因突变一致,即一些相互邻近的多态位点趋向于在一起共同遗传,属于一种单体型。(4)TRAIL 1525/1595位点为GG/CC基因型的个体易患高血脂。(5)肥胖、高血脂、高GGT水平是非酒精性脂肪肝的危险因素。
Background:
Fatty liver disease(FLD) also called fatty liver,is a clinical pathological syndrome caused by a variety of causations.The lesion of FLD mainly lies in liver foliole,and it is characterized as triglycerides accumulation superfluously in hepatocytes.In recent years,with the improvement of people's lives and the change of diet structure,the incidence rate of FLD has further increased.According to statistics, in the correction of age,sex and residential area,and other factors,the standard incidence rate of FLD,alcoholic fatty liver disease(alcoholic fatty liver disease,AFLD) and non-alcoholic fatty liver(nonalcoholic fatty liver disease,NAFLD) were 11.3%,2.2%and 9.1%separately(in adult,they were 14.5%,2.9%and 11.7% separately),so the incidence rate of FLD has the growing trend beyond viral hepatitis.In addition,FLD may lead to liver-related disability and deaths,which has become a global medical issues of common concern and social problems.Fatty liver disease is the result of a variety of factors interaction.At present,the relationships between apoptotic factors and hepatocyte steatosis aroused the concern by many scholars.
Tumour necrosis factor(TNF)-related apoptosis inducing ligand(TRAIL) was found and named by Wiley in 1995,TRAIL is mapped to the long arm of chromosome 3q26 in humans and is composed of five exons.It encodes approximately 1.77 kb mRNA,32.5 KDa transmembrane(typeⅡ) glycoprotein composed of 281 amino acid.TRAIL belongs to TNF-super family,and its structure is similar to other TNF family members.By combining with its receptor,TRAIL can induce apoptosis or play other biological effects.It has been reported that levels of TRAIL are related to lipid levels of human peripheral blood.In recent years,it is found that TRAIL can induce hepatocyte steatosis after virus infection and after alcohol intaking.However,the mechanism of TRAIL involved in FLD is unclear.It is believed that the occurrence of FLD are related to polymorphisms of many apoptotic factors,but reports on the relation between FLD and TRAIL polymorphisms have not been appeared in the literature.
Objective:
To observe the serum concentration of soluble TRAIL(sTRAIL), aminotransferase,Glucose,lipid among NAFLD,AFLD,healthy controls and excessive drinking controls without liver disease.To observe the polymorphism and gene frequency of TRAIL gene 1525G/A and 1595C/T of the 3'-UTR in Chinese Han nationality population.To further explore the association of TRAIL polymorphism with susceptibility to fatty liver.
Methods:
This study followed a case-control design.A total of 163 FLD subjects(84 NAFLD and 79 AFLD) were analyzed according to generally accepted diagnosis criteria for example B ultrasonic.102 healthy blood donors(80 healthy controls and 22 excessive drinking controls without liver disease) were used as controls.All targets were chosen fasting.The levels of sTRAIL in serum were determined by ELISA(44 NAFLD patients and 35 healthy controls).The polymorphisms of TRAIL gene were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods in 80 patients of alcohol fatty liver disease,79 patients of nonalcoholic fatty liver disease,80 healthy controls and 22 healthy controls with alcohol.At the same time,we selected 10 samples to sequence randomly in order to validate the foregoing of PCR-RFLP results.
Results:
(1) The NAFLD group showed significantly higher levels of sTRAIL in serum than those of healthy control group(p=0.017,p＜0.05);(2) Serum sTRAIL concentrations positively correlated with triglyceride(TG) significantly(r=0.368,P =0.014,P＜0.05).(3)There were TRAIL gene 1525G/A,1595C/T polymorphisms in Chinese Hans.(4)The same mutation happened at position 1525,1595 in exon 5 of TRAIL gene in 265 Chinese Han.(5) The genotype distributions among NAFLD, AFLD and healthy control(without alcohol) were significantly different(p=0.016,p ＜0.05;p=0.013,p＜0.05);1525G allele and 1595C allele were more frequent in FLD patients than in controls(without alcohol)(p=0.017,p＜0.05).(6) In NAFLD patients,the TG concentration of individuals with GG/CC genotype at 1525/1595 was higher than that of AA/TT genotype(p=0.035,p＜0.05).(7) The serum concentration of alanine aminotransferase(ALT),aspartate aminotransferase(AST), glutamyl transpeptidase(GGT),blood Glucose(GLU),cholesterol(CH),TG in NAFLD group were higher than those in healthy control(without alcohol),the differences were statistically significant(p＜0.05).(8) The serum concentration of ALT,GLU,CH,TG in AFLD group were higher than those in excessive drinking controls without liver disease(p＜0.05).(9) The serum concentrations of ALT,AST, GGT,GLU,CH,TG in AFLD group were higher than those in healthy control(without alcohol)(p＜0.05).(10) Obesity,hyperlipidemia,High level of GGT are risk factors of NAFLD by Non-conditions more Logistic regression analysis.
Conclusion:
The PCR-RFLP can detect the TRAIL genotype accurately.There are TRAIL gene 1525G/A,1595C/T polymorphisms in Chinese Hans.(1) The study indicated that sTRAIL concentrations in serum were related to hepatic steatosis and sTRAIL concentrations were positively correlated with TG concentrations.(2)The results showed Chinese Hans people with alleles 1525G,1595C in the 3'-UTR of exon 5 of TRAIL are susceptibility to FLD.(3) There is the same genetic variation of TRAIL at position 1525G/A and 1595C/T in Chinese populations.Some nearby polymorphic loci tend to with the common genetic,and it is one type of haplotype.(4) People with GG/CC genotype at 1525/1595 sites of TRAIL are susceptible to high blood lipid.(5) Obesity,hyperlipidemia,High level of GGT are risk factors of NAFLD.
引文
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4. Bradbury MW, Berk PD. Lipid metabolism in hepatic steatosis[J].Clin liver Dis,2004,8(3):639-71.
5. Herzer K, Ganten TM, Schulze-Bergkamen H, Grosse-Wilde A, Koschny R, Krammer PH, Walczak H.Transforming growth factor beta can mediate apoptosis via the expression of TRAIL in human hepatoma cells[J]. Hepatology, 2005, 42(1):183-92.
6. Mundt B, Kuhnel F, Zender L et al. Involvement of TRAIL and its receptors in viral hepatitis[J]. FASEB J. 2003 ,17(1):94-6.
7. Mundt B, Wirth T, Zender L,et al. Tumour necrosis factor related apoptosis inducing ligand (TRAIL) induces hepatic steatosis in viral hepatitis and after alcohol intake[J]. Gut. 2005,54(11):1590-6.
8. Afford SC and Adams DH. Following the TRAIL from hepatitis C virus and alcohol to fatty liver[J]. Gut ,2005,54 (11): 1518-20.
9. Gray HL, Sorensen EL, Hunt JS,et al. Three polymorphisms in the 3' UTR of the TRAIL(TNF-related apoptosis-inducing ligand) gene[J]. Genes Immun. 2001,2(8):469-70.
10. Rashid M, Roberts EA. Nonalcoholic steatohepatitis in children[J]. J Pediatr Gastroenterol Nutr, 2000,30(1):48～53.
11. Bradbury MW, Berk PD. Lipid metabolism in hepatic steatosis[J].Clin liver Dis,2004,8(3):639-71.
12. Malhi H, Barreyro FJ, Isomoto H,et al. Gores, Free fatty acids sensitise hepatocytes to TRAIL mediated cytotoxicity[ J ], Gut. 2007,56 (8)1124-31.
13.Nieto-Vazquez I,Femandez-Veledo S,Kramer DK,et al.Insulin resistance associated to obesity:the link TNF-alpha[J].Arch Physiol Biochem.2008,114(3):183-94.
14.范建高.脂肪肝[M].第一版.上海:上海医科大学出版社,2000,31-121.
15.Pelleymounter MA,Cullen MJ,Baker MB,et al.Effects of the obese gene product on body weight regulation in ob/ob mice[J].Science,1995,269(5223):540-43.
16.McClain CJ,Barve S,Deaciuc I,et al.Cytokines in alcoholic liver disease[J].Semin Liver Dis,1999,19(2):205-19.
17.Enomoto N,Ikejima K,Yamashina S,et al.Kuffer cell sensitization by alcohol involves increased permeability to gut-derived endotoxin[J].Alcohol Clin Exp Res,2001,25(6):51S-54S.
18.Kaneda M,Kashiwamura S,Ueda H,et al.Inflammatory liver steatosis caused by IL-12 and IL-18[J].J Interferon Cytokine Res.2003,23(3):155-62.
19.范建高,曾民德.细胞因子在肝纤维化中的作用[J].上海免疫学杂志,1996,16(2):124-126.
20.陆伦根,曾民德,范建高,等.实验性肝纤维化组织中细胞间粘附分子—1表达的研究[J].中华内科杂志,1999,38(1):37-39.
21.Valenti L,Francanzani AL,Dongiovanni P,et al.Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease [J].Gastroenterology,2002,122(2):274-80.
22.Grove J,Daly AK,Bassendine MF,et al.Association of a tumor necrosis factor promoter polymorphism with susceptibility to alcoholic steatohepatitis[J].Hepatology,1997,26(1):143-6
23.Nair S,Cope K,Risby TH,et al.Obesity and female gender increase breath ethanol concentraion:Potential implications for the pathogenesis of nonalcoholic steatohepatitis[J].Am J Gastroenterol.2001,96(4):1200-4.
24.Wu J,Norton PA.Animal models of liver fibrosis[J].Scand J Gastroenterol,1996,31(2):1137-1143.
25.Barba G,Harper F,Harada T,et al.Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets[J].Proc Natl Acad Sci USA ,1997,94(4): 1200-5.
26. Girelli CM ,Mirata C ,Lesinigo E ,et al .Iron overload and response to alpha -interferon in chronic hepatitis C [J ].Am J Gastroenterol ,1995 ,90(1):170-1.
27. Wiley SR, Schooley K, Smolak PJ, et al. Identification and characterization of a new member of the TNF family that induces apoptosis[J]. Immunity. 1995 ,3(6):673-82.
28. Pitti RM, Marsters SA, Ruppert S, et al. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family[ J ]. J Biol Chem , 1996, 271(22): 12689-90.
29. Gazitt Y. TRAIL is a potent inducer of apoptosis in myeloma cells derived from multiple myeloma patients and is not cytotoxic to hematopoietic stem cells[ J ]. Leukemia, 1999, 13(11): 1817-24.
30. Jo M, Kim TH, Seol DW, et al. Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand[ J ]. Nat Med, 2000, 6(5): 564 - 7.
31. Lamhamedi-Cherradi SE, Zheng SJ, Maguschak KA, et al. Defective thymocyte apoptosis and accelerated autoimmune diseases in TRAIL - / - mice[ J ]. Nat Immunol, 2003, 4(3): 255 - 60.
32. Taimr P, Higuchi H, Kocova E, et al. Activated stellate cells express the TRAIL receptor-2 /death receptor-5 and undergo TRAIL-mediated apoptosis[ J ]. Hepatology, 2003, 37(1): 87-95.
33. A. Anel, A. Bosque, J. Naval, A. Pineiro, L. Larrad, M.A. Alava, M.J. Martinez-Lorenzo, Apo2L/TRAIL and immune regulation, Front Biosci. 12 (2007) 2074-2084.
34. Ren Y, Tang J ,Mok MY, et al. Increased apoptotic neutrophils and macrophages and impaired macrophage phagocytic clearance of apoptotic neutrophils in systemic lupus erythematosus[J ]. Arthritis Rheum, 2003, 48 (10): 2888-97.
35. Rus V , Atamas SP, Shustova V , et al. Expression of cytokine- and chemokine-related genes in peripheral blood mononuclear cells from lupus patients by cDNA array[J ]. Clin Immunol, 2002, 102 (3): 283-90.
36. Kaplan Mi ,Lewis EE, Shelden EA , et al. The apoptotic ligands TRAIL , TWEA K, and Fas ligand mediate monocyte death induced by autologous lupus T cells[J]. J Immunol, 2002, 169 (10): 6020-29.
37. Matsuyama W , Yamamoto M , Higashimoto I, et al.TNF-related apoptosis inducing ligand is involved in neutropenia of systemic lupus erythematosus [ J ]. Blood, 2004, 104(1): 184-91.
38. Rus V , Zernetkina V , Puliaev R, et al. Increased expression and release of functional tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by T cells from lupus patients with active disease [J ]. Clin Immunol, 2005, 117 (1) : 48-56.
39. Lub-de Hooge MN , de Vries EG, de Jong S, et al. Soluble TRAIL concentrations are raised in patients with systemic lupus erythematosus [ J ]. Ann Rheum Dis, 2005, 64: 854-58.
40. Morel J ,Audo R,Hahne M , et al. Tumor necrosis factor-related apoptosis-inducing ligand ( TRAIL ) induces rheumatoid arthritis synovial fibroblast proliferation through mitogen-activated protein kinases and phosphatidylinositol 3-kinase/Akt. [J ]. J Biolchem, 2005,280 (16): 15709-18.
41. Miranda-Carus ME, Balsa A , Benito-Miguel M , et al. Rheumatoid arthritis synovial fluid fibroblasts express TRAIL-R2 (DR5) that is functionally active[J ]. Arthritis Rheum, 2004, 50 (9): 2786-2793.
42. Mtsumura R,Umemiya K, Kagami M , et al. Expression of TNF-related apoptosis inducing ligand(TRAIL) on infiltrating cells and of TRAIL receptors on salivary glands in patients with Sjogren' s syndrome [ J ]. Clin Exp Rheumatol, 2002, 20 (6) :791-8.
43. L.H. Han, W.S. Sun, C.H. Ma, L.N. Zhang, S.X. Liu, Q. Zhang, L.F. Gao, Y.H. Chen, Detection of soluble TRAIL in HBV infected patients and its clinical implications, World J Gastroenterol. 8 (2002) 1077-1080.
44. X. Liang, Y. Liu, Q. Zhang, L. Gao, L. Han, C. Ma, L. Zhang, Y.H. Chen, W. Sun, Hepatitis B virus sensitizes hepatocytes to TRAIL-induced apoptosis through Bax, J Immunol. 178 (2007) 503-510.
45. X. Liang, Z. Qu, Z. Zhang, J. Du, Y. Liu, M. Cui, H. Liu, L. Gao, L. Han, S. Liu, L. Cao, P. Zhao, W. Sun, Blockade of preS2 down-regulates the apoptosis of HepG2.2.15 cells induced by TRAIL, Biochem Biophys Res Commun. 369 (2008) 456-463.
46. X. Liang, J. Du, Y. Liu, M. Cui, C. Ma, L. Han, Z. Qu, Z. Zhang, Z. Sun, L. Zhang, Y.H. Chen, W. Sun, The hepatitis B virus protein MHBs(t) sensitizes hepatoma cells to TRAIL-induced apoptosis through ERK2, Apoptosis. 12 (2007) 1827-1836.
47. Choi JW, Song JS, Pai SH. Associations of serum TRAIL concentrations, anthropometric variables, and serum lipid parameters in healthy adults[J]. Ann Clin Lab Sci.2004,34(4):400-4.
48. Fan JG, Xu ZJ, Wang GL, Ding XD,et al. Change of serum endotoxin level in the progress of nonalcoholic steatohepatitis in rats[J], Zhonghua Gan Zang Bing Za Zhi. 2003,11(2):73-6.
49. Rashid A, Wu TC, Huang CC,et al. Mitochondrial proteins that regulate apoptosis and necrosis are induced in mouse fatty liver[J]. Hepatology. 1999 ,29(4): 1131-8
50. Yang S, Lin H, Diehl AM. Fatty liver vulnerability to endotoxin-induced damage despite NF-kappaB induction and inhibited caspase 3 activation[J]. Am J Physiol Gastrointest Liver Physiol. 2001 , 281(2):G382-92.
51. Ribeiro PS, Cortez-Pinto H, Sola S,et al. Hepatocyte apoptosis, expression of death receptors, and activation of NF-kappaB in the liver of nonalcoholic and alcoholic steatohepatitis patients[J]. Am J Gastroenterol. 2004, 99(9): 1708-17
52. Man M, Colell A, Morales A,et al. Mechanism of mitochondrial glutathione-dependent hepatocellular susceptibility to TNF despite NF-kappaB activation[J]. Gastroenterology. 2008 ,134(5):1507-20.
53. Wang Q, Ji Y, Wang X, et al. Isolation and molecular characterization of the 5'-upstream region of the human TRAIL gene[J]. Biochem Biophys Res Commun. 2000,276(2):466-71.
54. Unoki M , Furuta S, Onouchi Y,et al. Association studies of 33 single nucleotide polymorphisms(SNPs) in 29 candidate genes for bronchial asthma:positive association a T924C polymorphism in the thromboxane A2 receptor gene[J].Hum Genet.2000,106(4),440-6.
55.Sookoian S,Castano G,Gemma C,et al.Common genetic variations in CLOCK transcription factor are associated with nonalcoholic fatty liver disease[J],World J Gastroenterol.2007,13(31):4242-8.
56.Kikuchi S,Miyagishi R,Fukazawa T,et al.TNF-related apoptosis inducing ligand (TRAIL) gene polymorphism in Japanese patients with multiple sclerosis.J Neuroimmunol.2005 Oct;167(1-2):170-4.
57.王艳,张军,黄青阳.脂联素基因单核苷酸多态性T45G与湖北汉族人2型糖尿病的遗传关联研究[J].遗传.2008,30(6):711-15.
58.朱忠政:丛:文铭:冼志红等.细胞周期蛋白D1基因多态性与肝细胞癌遗传易感性的相关性[J].中华肿瘤防治杂志.2007,14(20):1521-23.
59.郑咏秋,李欣志.心血管疾病表观遗传机制研究[J].国际心血管病杂志,2008,35(2):108-11.
60.任新鸾,李联祥,韩淑萍等.家族性支气管哮喘的遗传方式分析[J].遗传,2006,28(9):1067-1070.
61.卢蕴容,李惠春.抑郁症的遗传与环境交互作用基础研究进展[J].国际精神病学杂志.2007,34(1):12-15.
62.Sookoian S,Castano G,Gemma C,et al.Common genetic variations in CLOCK transcription factor are associated with nonalcoholic fatty liver disease[J],World J Gastroenterol.2007,13(31):4242-8.
2 . Day CP, James OF. Steatohepatitis:a tale of two hits [J] ? Gastroenterology, 1998, 114(4):842-5.
3. Park JH. Insulin resistance in non-alcoholic fatty liver disease[J]. Korean J Hepatol, 2006 Mar; 12(1): 16-30.
4. Bradbury MW, Berk PD. Lipid metabolism in hepatic steatosis[J].Clin liver Dis,2004,8(3):639-71.
5. Herzer K, Ganten TM, Schulze-Bergkamen H, Grosse-Wilde A, Koschny R, Krammer PH, Walczak H.Transforming growth factor beta can mediate apoptosis via the expression of TRAIL in human hepatoma cells[J]. Hepatology, 2005, 42(1):183-92.
6. Mundt B, Kuhnel F, Zender L et al. Involvement of TRAIL and its receptors in viral hepatitis[J]. FASEB J. 2003 ,17(1):94-6.
7. Mundt B, Wirth T, Zender L,et al. Tumour necrosis factor related apoptosis inducing ligand (TRAIL) induces hepatic steatosis in viral hepatitis and after alcohol intake[J]. Gut. 2005,54(11):1590-6.
8. Afford SC and Adams DH. Following the TRAIL from hepatitis C virus and alcohol to fatty liver[J]. Gut ,2005,54 (11): 1518-20.
9. Gray HL, Sorensen EL, Hunt JS,et al. Three polymorphisms in the 3' UTR of the TRAIL(TNF-related apoptosis-inducing ligand) gene[J]. Genes Immun. 2001,2(8):469-70.
10. Rashid M, Roberts EA. Nonalcoholic steatohepatitis in children[J]. J Pediatr Gastroenterol Nutr, 2000,30(1):48～53.
11. Bradbury MW, Berk PD. Lipid metabolism in hepatic steatosis[J].Clin liver Dis,2004,8(3):639-71.
12. Malhi H, Barreyro FJ, Isomoto H,et al. Gores, Free fatty acids sensitise hepatocytes to TRAIL mediated cytotoxicity[ J ], Gut. 2007,56 (8)1124-31.
13.Nieto-Vazquez I,Femandez-Veledo S,Kramer DK,et al.Insulin resistance associated to obesity:the link TNF-alpha[J].Arch Physiol Biochem.2008,114(3):183-94.
14.范建高.脂肪肝[M].第一版.上海:上海医科大学出版社,2000,31-121.
15.Pelleymounter MA,Cullen MJ,Baker MB,et al.Effects of the obese gene product on body weight regulation in ob/ob mice[J].Science,1995,269(5223):540-43.
16.McClain CJ,Barve S,Deaciuc I,et al.Cytokines in alcoholic liver disease[J].Semin Liver Dis,1999,19(2):205-19.
17.Enomoto N,Ikejima K,Yamashina S,et al.Kuffer cell sensitization by alcohol involves increased permeability to gut-derived endotoxin[J].Alcohol Clin Exp Res,2001,25(6):51S-54S.
18.Kaneda M,Kashiwamura S,Ueda H,et al.Inflammatory liver steatosis caused by IL-12 and IL-18[J].J Interferon Cytokine Res.2003,23(3):155-62.
19.范建高,曾民德.细胞因子在肝纤维化中的作用[J].上海免疫学杂志,1996,16(2):124-126.
20.陆伦根,曾民德,范建高,等.实验性肝纤维化组织中细胞间粘附分子—1表达的研究[J].中华内科杂志,1999,38(1):37-39.
21.Valenti L,Francanzani AL,Dongiovanni P,et al.Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease [J].Gastroenterology,2002,122(2):274-80.
22.Grove J,Daly AK,Bassendine MF,et al.Association of a tumor necrosis factor promoter polymorphism with susceptibility to alcoholic steatohepatitis[J].Hepatology,1997,26(1):143-6
23.Nair S,Cope K,Risby TH,et al.Obesity and female gender increase breath ethanol concentraion:Potential implications for the pathogenesis of nonalcoholic steatohepatitis[J].Am J Gastroenterol.2001,96(4):1200-4.
24.Wu J,Norton PA.Animal models of liver fibrosis[J].Scand J Gastroenterol,1996,31(2):1137-1143.
25.Barba G,Harper F,Harada T,et al.Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets[J].Proc Natl Acad Sci USA ,1997,94(4): 1200-5.
26. Girelli CM ,Mirata C ,Lesinigo E ,et al .Iron overload and response to alpha -interferon in chronic hepatitis C [J ].Am J Gastroenterol ,1995 ,90(1):170-1.
27. Wiley SR, Schooley K, Smolak PJ, et al. Identification and characterization of a new member of the TNF family that induces apoptosis[J]. Immunity. 1995 ,3(6):673-82.
28. Pitti RM, Marsters SA, Ruppert S, et al. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family[ J ]. J Biol Chem , 1996, 271(22): 12689-90.
29. Gazitt Y. TRAIL is a potent inducer of apoptosis in myeloma cells derived from multiple myeloma patients and is not cytotoxic to hematopoietic stem cells[ J ]. Leukemia, 1999, 13(11): 1817-24.
30. Jo M, Kim TH, Seol DW, et al. Apoptosis induced in normal human hepatocytes by tumor necrosis factor-related apoptosis-inducing ligand[ J ]. Nat Med, 2000, 6(5): 564 - 7.
31. Lamhamedi-Cherradi SE, Zheng SJ, Maguschak KA, et al. Defective thymocyte apoptosis and accelerated autoimmune diseases in TRAIL - / - mice[ J ]. Nat Immunol, 2003, 4(3): 255 - 60.
32. Taimr P, Higuchi H, Kocova E, et al. Activated stellate cells express the TRAIL receptor-2 /death receptor-5 and undergo TRAIL-mediated apoptosis[ J ]. Hepatology, 2003, 37(1): 87-95.
33. A. Anel, A. Bosque, J. Naval, A. Pineiro, L. Larrad, M.A. Alava, M.J. Martinez-Lorenzo, Apo2L/TRAIL and immune regulation, Front Biosci. 12 (2007) 2074-2084.
34. Ren Y, Tang J ,Mok MY, et al. Increased apoptotic neutrophils and macrophages and impaired macrophage phagocytic clearance of apoptotic neutrophils in systemic lupus erythematosus[J ]. Arthritis Rheum, 2003, 48 (10): 2888-97.
35. Rus V , Atamas SP, Shustova V , et al. Expression of cytokine- and chemokine-related genes in peripheral blood mononuclear cells from lupus patients by cDNA array[J ]. Clin Immunol, 2002, 102 (3): 283-90.
36. Kaplan Mi ,Lewis EE, Shelden EA , et al. The apoptotic ligands TRAIL , TWEA K, and Fas ligand mediate monocyte death induced by autologous lupus T cells[J]. J Immunol, 2002, 169 (10): 6020-29.
37. Matsuyama W , Yamamoto M , Higashimoto I, et al.TNF-related apoptosis inducing ligand is involved in neutropenia of systemic lupus erythematosus [ J ]. Blood, 2004, 104(1): 184-91.
38. Rus V , Zernetkina V , Puliaev R, et al. Increased expression and release of functional tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by T cells from lupus patients with active disease [J ]. Clin Immunol, 2005, 117 (1) : 48-56.
39. Lub-de Hooge MN , de Vries EG, de Jong S, et al. Soluble TRAIL concentrations are raised in patients with systemic lupus erythematosus [ J ]. Ann Rheum Dis, 2005, 64: 854-58.
40. Morel J ,Audo R,Hahne M , et al. Tumor necrosis factor-related apoptosis-inducing ligand ( TRAIL ) induces rheumatoid arthritis synovial fibroblast proliferation through mitogen-activated protein kinases and phosphatidylinositol 3-kinase/Akt. [J ]. J Biolchem, 2005,280 (16): 15709-18.
41. Miranda-Carus ME, Balsa A , Benito-Miguel M , et al. Rheumatoid arthritis synovial fluid fibroblasts express TRAIL-R2 (DR5) that is functionally active[J ]. Arthritis Rheum, 2004, 50 (9): 2786-2793.
42. Mtsumura R,Umemiya K, Kagami M , et al. Expression of TNF-related apoptosis inducing ligand(TRAIL) on infiltrating cells and of TRAIL receptors on salivary glands in patients with Sjogren' s syndrome [ J ]. Clin Exp Rheumatol, 2002, 20 (6) :791-8.
43. L.H. Han, W.S. Sun, C.H. Ma, L.N. Zhang, S.X. Liu, Q. Zhang, L.F. Gao, Y.H. Chen, Detection of soluble TRAIL in HBV infected patients and its clinical implications, World J Gastroenterol. 8 (2002) 1077-1080.
44. X. Liang, Y. Liu, Q. Zhang, L. Gao, L. Han, C. Ma, L. Zhang, Y.H. Chen, W. Sun, Hepatitis B virus sensitizes hepatocytes to TRAIL-induced apoptosis through Bax, J Immunol. 178 (2007) 503-510.
45. X. Liang, Z. Qu, Z. Zhang, J. Du, Y. Liu, M. Cui, H. Liu, L. Gao, L. Han, S. Liu, L. Cao, P. Zhao, W. Sun, Blockade of preS2 down-regulates the apoptosis of HepG2.2.15 cells induced by TRAIL, Biochem Biophys Res Commun. 369 (2008) 456-463.
46. X. Liang, J. Du, Y. Liu, M. Cui, C. Ma, L. Han, Z. Qu, Z. Zhang, Z. Sun, L. Zhang, Y.H. Chen, W. Sun, The hepatitis B virus protein MHBs(t) sensitizes hepatoma cells to TRAIL-induced apoptosis through ERK2, Apoptosis. 12 (2007) 1827-1836.
47. Choi JW, Song JS, Pai SH. Associations of serum TRAIL concentrations, anthropometric variables, and serum lipid parameters in healthy adults[J]. Ann Clin Lab Sci.2004,34(4):400-4.
48. Fan JG, Xu ZJ, Wang GL, Ding XD,et al. Change of serum endotoxin level in the progress of nonalcoholic steatohepatitis in rats[J], Zhonghua Gan Zang Bing Za Zhi. 2003,11(2):73-6.
49. Rashid A, Wu TC, Huang CC,et al. Mitochondrial proteins that regulate apoptosis and necrosis are induced in mouse fatty liver[J]. Hepatology. 1999 ,29(4): 1131-8
50. Yang S, Lin H, Diehl AM. Fatty liver vulnerability to endotoxin-induced damage despite NF-kappaB induction and inhibited caspase 3 activation[J]. Am J Physiol Gastrointest Liver Physiol. 2001 , 281(2):G382-92.
51. Ribeiro PS, Cortez-Pinto H, Sola S,et al. Hepatocyte apoptosis, expression of death receptors, and activation of NF-kappaB in the liver of nonalcoholic and alcoholic steatohepatitis patients[J]. Am J Gastroenterol. 2004, 99(9): 1708-17
52. Man M, Colell A, Morales A,et al. Mechanism of mitochondrial glutathione-dependent hepatocellular susceptibility to TNF despite NF-kappaB activation[J]. Gastroenterology. 2008 ,134(5):1507-20.
53. Wang Q, Ji Y, Wang X, et al. Isolation and molecular characterization of the 5'-upstream region of the human TRAIL gene[J]. Biochem Biophys Res Commun. 2000,276(2):466-71.
54. Unoki M , Furuta S, Onouchi Y,et al. Association studies of 33 single nucleotide polymorphisms(SNPs) in 29 candidate genes for bronchial asthma:positive association a T924C polymorphism in the thromboxane A2 receptor gene[J].Hum Genet.2000,106(4),440-6.
55.Sookoian S,Castano G,Gemma C,et al.Common genetic variations in CLOCK transcription factor are associated with nonalcoholic fatty liver disease[J],World J Gastroenterol.2007,13(31):4242-8.
56.Kikuchi S,Miyagishi R,Fukazawa T,et al.TNF-related apoptosis inducing ligand (TRAIL) gene polymorphism in Japanese patients with multiple sclerosis.J Neuroimmunol.2005 Oct;167(1-2):170-4.
57.王艳,张军,黄青阳.脂联素基因单核苷酸多态性T45G与湖北汉族人2型糖尿病的遗传关联研究[J].遗传.2008,30(6):711-15.
58.朱忠政:丛:文铭:冼志红等.细胞周期蛋白D1基因多态性与肝细胞癌遗传易感性的相关性[J].中华肿瘤防治杂志.2007,14(20):1521-23.
59.郑咏秋,李欣志.心血管疾病表观遗传机制研究[J].国际心血管病杂志,2008,35(2):108-11.
60.任新鸾,李联祥,韩淑萍等.家族性支气管哮喘的遗传方式分析[J].遗传,2006,28(9):1067-1070.
61.卢蕴容,李惠春.抑郁症的遗传与环境交互作用基础研究进展[J].国际精神病学杂志.2007,34(1):12-15.
62.Sookoian S,Castano G,Gemma C,et al.Common genetic variations in CLOCK transcription factor are associated with nonalcoholic fatty liver disease[J],World J Gastroenterol.2007,13(31):4242-8.
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