非酒精性脂肪性肝病机制及标志物的蛋白质组学研究
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摘要
非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)已经成为一种常见的慢性肝病,其发病率逐年上升。它包括单纯性脂肪肝(simple steatosis,SS)、脂肪性肝炎(nonalcoholic steatohepatitis,NASH)、肝纤维化和肝硬化。脂肪肝是一种良性疾病,而NASH却可进一步发展、恶化成为终末期肝病,严重者可导致死亡。目前NAFLD的发生发展机制至今仍尚不清楚,认为与氧化应激的增加、线粒体损伤和脂肪因子等因素相关,但对导致进行性肝细胞损伤的机制有待于进一步探讨。蛋白质组学是一门研究机体特定条件下功能状态的前沿技术,更贴近机体已经或正在发生的行为和功能状态,可为疾病诊断和治疗提供大量的理论和实验依据。同时,肝活检是一种损伤性的检测方法,而且取得的肝组织样本也不足于大规模的筛选差异蛋白质。因此,本研究以蛋氨酸和胆碱缺乏(methionine and cholinedeficient,MCD)饮食诱导的NAFLD小鼠模型为研究对象,采用差异凝胶电泳(dimensional difference gel electrophoresis,DIGE)技术筛选出与NAFLD密切相关的肝脏差异蛋白质谱,结合生物信息学手段系统的分析了差异蛋白的功能和调控网络,并筛选出重要的节点分子进行了验证,从而为深入探讨NAFLD发生发展的分子机制奠定了基础。同时本研究还采用血清蛋白质组学分析(serological proteomeanalysis,SERPA)技术筛选出与NAFLD密切相关的自身抗原谱,为挖掘NAFLD潜在的血清标志物而提供了理论依据。
我们分别用正常饮食与MCD饮食饲养小鼠,并在MCD饲养后的2、5、8周,成功复制出不同病变程度的NAFLD动物模型(单纯性脂肪肝(SS),脂肪性肝炎(NASH)及NASH伴早期肝纤维化。我们采用DIGE技术分析了不同造模时间的正常组和模型组小鼠肝脏蛋白质表达谱的差异,并用MALDI-TOF/TOF质谱仪进行差异蛋白质的检测,共鉴定了189个差异蛋白。其中SS阶段的差异蛋白58个,NASH阶段的差异蛋白82个,NASH伴早期肝纤维化阶段的差异蛋白162个。这些差异蛋白多数存在于线粒体(52.2%),其次为细胞外区域(13.4%)、内质网(10.4%)、细胞浆(9.0%)、细胞核(9.0%)、过氧化物酶体(4.5%)和未知定位(1.5%)。通过差异蛋白的功能和调控网络分析,我们发现随着NAFLD病程的进展,参与清除氧自由基相关酶、脂肪酸β氧化的相关酶及糖异生相关酶的表达逐渐降低,而脂肪形成相关酶和细胞骨架蛋白的表达逐渐升高。同时,在NASH伴早期肝纤维化阶段,星状细胞标志蛋白结蛋白(desmin)和胶质纤维酸性蛋白(glialfibrillary acidic protein,GFAP)的表达明显增加,表明NAFLD病程向肝纤维化进一步恶化。
最为显著的是脂肪代谢紊乱始终贯穿NAFLD的发生发展,特别是对NASH伴早期肝纤维化阶段差异蛋白的IPA分析,我们发现两条信号转导通路被激活,分别是Akt/PKB通路和p38MAPK通路。首先,我们在NAFLD模型中,从蛋白水平和mRNA水平验证了DIGE实验结果的可靠性;其次,采用Western blot技术检测到NASH伴早期肝纤维化阶段肝组织pho-Akt和pho-p38的表达明显增加。内脏脂肪素(Visfatin)作为一种新发现的脂肪因子,通过模拟胰岛素样作用和加重炎症反应得到人们的广泛关注。因此,我们采用免疫组化技术和酶联免疫吸附试验,检测到Visfatin不仅在NASH伴早期肝纤维化肝组织中表达明显增加,而且在其血清中也明显增高,因此我们认为Visfatin通过激活Akt/PKB和p38MAPK通路,加重肝细胞内TG的蓄积和肝组织炎症反应,从而在NAFLD发生发展中发挥着重要的作用。
与此同时,我们又采用SERPA技术筛选出18个与NAFLD发展密切相关的自身抗原,通过对自身抗原α-烯醇酶(α-enolase,ENOA)和蛋白二硫键异构酶3(Protein disulfide isomerase associated 3,PDI3)的验证,我们发现抗原的形成与其在疾病状态下表达量的高低没有明显的关系。而且,我们进一步证实了NAFLD患者血清中存在抗ENOA抗体,并且抗体滴度的高低与肝细胞的损伤程度正相关。因此,本研究在蛋白整体水平挖掘了与NAFLD密切相关的自身抗原谱,为筛选潜在的NAFLD分期分型的诊断标志物提供了实验基础。
Nonalcoholic fatty liver disease(NAFLD) is an increasingly recognized cause of liver-related morbidity and mortality.The histologic spectrum of NAFLD ranges from steatosis liver alone to nonalcoholic steatohepatitis(NASH),fibrosis,and cirrhosis. Steatosis is generally a benign disease,wheras NASH may be complicated by progressive end-stage liver disease.However,the pathogenesis of NAFLD is still unclear.It appears that oxidative stress,mitochondrion disfuntion and adipocytokines involve in the patheogenesis of NAFLD.It still needs further elucidate the factors that lead to progressive hepatocellular damage.The proteomic is a new approach which is used to analyze the complements and functions of proteins at the particular period of the body.It is closely associated with the physiology and pathology of body and can provide a theoratical basis in disease research.Meanwhile,the liver biopsy is an invasive examination and the liver tissue sample is too small to be applied to proteomic research.Therefore,we based on the NAFLD model which is induced by methionine and choline deficient diet in mice and combined proteomic approaches and bioinformatics analysis to systematically elucidate the liver proteomes during the development of MCD-induced NAFLD which may help clarify the pathogenesis of NAFLD.By using serological proteome analysis technology,we identidied a variety of autoantigens which were closely associated with the pathogenesis of NAFLD.It will attribute to discover novel biomarkers for noninvasive diagnosis NAFLD.
We detected differently expressed proteins participating in the progression of NAFLD by using difference in gel electrophoresis(DIGE) and MALDI-TOF/TOF technology.Male C57/BL6 mice were fed a methionine/choline deficient diet for 2,5, and 8 weeks respectively,at which times steatosis(SS),NASH and then NASH combined early fibrosis(NCEF) were evident.The mice receiving the normal diet for the corresponding durations served as controls.There were 58,82,and 162 different proteins in the stage of SS,NASH and NCEF respectively.These differently expressed proteins were mainly located in the mithochodria(52.2%),following by excellular region(13.4%),endoplasmic reticulum(10.4%),plasma(9.0%),nucleus(9.0%), peroxisome(4.5%) and unkonwn location(1.5%).Biological functions and network analysis of these proteins exhibited phase-specific characteristics during evolution of the disease.The metabolic enzymes involved in free radical scavenging,fatty acidβ-oxidation and gluconeogenesis were down-regulated during the pathogenesis of NAFLD,wheras those proteins involved in the lipogenesis and cytoskeletal proteins were up-regulated as well as stellate cells marked proteins including desmin and glial fibrillary acidic protein.
More importantly,lipid metabolic disorder runs through the pathogenesis of NAFLD.The pathway analysis of these proteins identified that Akt/PKB pathyway and p38MAPK pathyway were activated in the stage of NCEF.Firstly,we validated the reliability of the DIGE data both at protein level and mRNA level by using Western blot and RT-PCR.Secondly,we verified that pho-Akt and p38MAPK were up-regulated in the stage of NCEF.As is a new adipocytokine,visfatin has been paied more and more attention by its mimicking insulin functions and promoting the inflammation. Furthermore,we identified that visfatin was up-regulated in NCEF not only in the liver tissue but also in the serum by using immunohistochemistry and ELISA.We supposed that visfatin may involve in the pathogenesis of NAFLD by increasing hepatic ligenesis enzymes and decreasing gluconeogenesis enzymes.
We also identified 18 autoantigens which were associated with NAFLD by using SERPA and found that there is no correlation between the autoantigens with their expressions in the pathogenesis of NAFLD.We further confirmed the antigenicity of alpha-enolase by using ELISA with recombinant protein in the serum of NAFLD patients.The results showed that the frequency of the autoantibodies to alpha-enolase was positively related with the level of liver injury.Therefore,we screened a series of autoantigens relating to the pathogenesis of NAFLD.It will attribute to discover noninvasive biomarkers of NAFLD in the future.
我们分别用正常饮食与MCD饮食饲养小鼠,并在MCD饲养后的2、5、8周,成功复制出不同病变程度的NAFLD动物模型(单纯性脂肪肝(SS),脂肪性肝炎(NASH)及NASH伴早期肝纤维化。我们采用DIGE技术分析了不同造模时间的正常组和模型组小鼠肝脏蛋白质表达谱的差异,并用MALDI-TOF/TOF质谱仪进行差异蛋白质的检测,共鉴定了189个差异蛋白。其中SS阶段的差异蛋白58个,NASH阶段的差异蛋白82个,NASH伴早期肝纤维化阶段的差异蛋白162个。这些差异蛋白多数存在于线粒体(52.2%),其次为细胞外区域(13.4%)、内质网(10.4%)、细胞浆(9.0%)、细胞核(9.0%)、过氧化物酶体(4.5%)和未知定位(1.5%)。通过差异蛋白的功能和调控网络分析,我们发现随着NAFLD病程的进展,参与清除氧自由基相关酶、脂肪酸β氧化的相关酶及糖异生相关酶的表达逐渐降低,而脂肪形成相关酶和细胞骨架蛋白的表达逐渐升高。同时,在NASH伴早期肝纤维化阶段,星状细胞标志蛋白结蛋白(desmin)和胶质纤维酸性蛋白(glialfibrillary acidic protein,GFAP)的表达明显增加,表明NAFLD病程向肝纤维化进一步恶化。
最为显著的是脂肪代谢紊乱始终贯穿NAFLD的发生发展,特别是对NASH伴早期肝纤维化阶段差异蛋白的IPA分析,我们发现两条信号转导通路被激活,分别是Akt/PKB通路和p38MAPK通路。首先,我们在NAFLD模型中,从蛋白水平和mRNA水平验证了DIGE实验结果的可靠性;其次,采用Western blot技术检测到NASH伴早期肝纤维化阶段肝组织pho-Akt和pho-p38的表达明显增加。内脏脂肪素(Visfatin)作为一种新发现的脂肪因子,通过模拟胰岛素样作用和加重炎症反应得到人们的广泛关注。因此,我们采用免疫组化技术和酶联免疫吸附试验,检测到Visfatin不仅在NASH伴早期肝纤维化肝组织中表达明显增加,而且在其血清中也明显增高,因此我们认为Visfatin通过激活Akt/PKB和p38MAPK通路,加重肝细胞内TG的蓄积和肝组织炎症反应,从而在NAFLD发生发展中发挥着重要的作用。
与此同时,我们又采用SERPA技术筛选出18个与NAFLD发展密切相关的自身抗原,通过对自身抗原α-烯醇酶(α-enolase,ENOA)和蛋白二硫键异构酶3(Protein disulfide isomerase associated 3,PDI3)的验证,我们发现抗原的形成与其在疾病状态下表达量的高低没有明显的关系。而且,我们进一步证实了NAFLD患者血清中存在抗ENOA抗体,并且抗体滴度的高低与肝细胞的损伤程度正相关。因此,本研究在蛋白整体水平挖掘了与NAFLD密切相关的自身抗原谱,为筛选潜在的NAFLD分期分型的诊断标志物提供了实验基础。
Nonalcoholic fatty liver disease(NAFLD) is an increasingly recognized cause of liver-related morbidity and mortality.The histologic spectrum of NAFLD ranges from steatosis liver alone to nonalcoholic steatohepatitis(NASH),fibrosis,and cirrhosis. Steatosis is generally a benign disease,wheras NASH may be complicated by progressive end-stage liver disease.However,the pathogenesis of NAFLD is still unclear.It appears that oxidative stress,mitochondrion disfuntion and adipocytokines involve in the patheogenesis of NAFLD.It still needs further elucidate the factors that lead to progressive hepatocellular damage.The proteomic is a new approach which is used to analyze the complements and functions of proteins at the particular period of the body.It is closely associated with the physiology and pathology of body and can provide a theoratical basis in disease research.Meanwhile,the liver biopsy is an invasive examination and the liver tissue sample is too small to be applied to proteomic research.Therefore,we based on the NAFLD model which is induced by methionine and choline deficient diet in mice and combined proteomic approaches and bioinformatics analysis to systematically elucidate the liver proteomes during the development of MCD-induced NAFLD which may help clarify the pathogenesis of NAFLD.By using serological proteome analysis technology,we identidied a variety of autoantigens which were closely associated with the pathogenesis of NAFLD.It will attribute to discover novel biomarkers for noninvasive diagnosis NAFLD.
We detected differently expressed proteins participating in the progression of NAFLD by using difference in gel electrophoresis(DIGE) and MALDI-TOF/TOF technology.Male C57/BL6 mice were fed a methionine/choline deficient diet for 2,5, and 8 weeks respectively,at which times steatosis(SS),NASH and then NASH combined early fibrosis(NCEF) were evident.The mice receiving the normal diet for the corresponding durations served as controls.There were 58,82,and 162 different proteins in the stage of SS,NASH and NCEF respectively.These differently expressed proteins were mainly located in the mithochodria(52.2%),following by excellular region(13.4%),endoplasmic reticulum(10.4%),plasma(9.0%),nucleus(9.0%), peroxisome(4.5%) and unkonwn location(1.5%).Biological functions and network analysis of these proteins exhibited phase-specific characteristics during evolution of the disease.The metabolic enzymes involved in free radical scavenging,fatty acidβ-oxidation and gluconeogenesis were down-regulated during the pathogenesis of NAFLD,wheras those proteins involved in the lipogenesis and cytoskeletal proteins were up-regulated as well as stellate cells marked proteins including desmin and glial fibrillary acidic protein.
More importantly,lipid metabolic disorder runs through the pathogenesis of NAFLD.The pathway analysis of these proteins identified that Akt/PKB pathyway and p38MAPK pathyway were activated in the stage of NCEF.Firstly,we validated the reliability of the DIGE data both at protein level and mRNA level by using Western blot and RT-PCR.Secondly,we verified that pho-Akt and p38MAPK were up-regulated in the stage of NCEF.As is a new adipocytokine,visfatin has been paied more and more attention by its mimicking insulin functions and promoting the inflammation. Furthermore,we identified that visfatin was up-regulated in NCEF not only in the liver tissue but also in the serum by using immunohistochemistry and ELISA.We supposed that visfatin may involve in the pathogenesis of NAFLD by increasing hepatic ligenesis enzymes and decreasing gluconeogenesis enzymes.
We also identified 18 autoantigens which were associated with NAFLD by using SERPA and found that there is no correlation between the autoantigens with their expressions in the pathogenesis of NAFLD.We further confirmed the antigenicity of alpha-enolase by using ELISA with recombinant protein in the serum of NAFLD patients.The results showed that the frequency of the autoantibodies to alpha-enolase was positively related with the level of liver injury.Therefore,we screened a series of autoantigens relating to the pathogenesis of NAFLD.It will attribute to discover noninvasive biomarkers of NAFLD in the future.
引文
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