肝型脂肪酸结合蛋白与非酒精性脂肪肝的关系及药物研究
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摘要
目的：非酒精性脂肪肝(nonalcoholic fatty liver disease, NAFLD)是指与过量饮酒无关的,以肝细胞弥漫性脂肪变性和脂质贮积为主的临床病理综合征。NAFLD的发病率逐年上升,发病年龄逐渐年轻化,已成为全球性的公共卫生问题。然而NAFLD的发病机制尚未明确,临床上仍无有效的治疗手段。目前研究发现,肝型脂肪酸结合蛋白(fatty acid-binding protein, L-FABP)与高甘油三酯血症、高胆固醇血症、肥胖、2-型糖尿病等的形成密切相关。为此,本实验通过高脂饮食建立非酒精性脂肪肝大鼠模型,来观察L-FABP在NAFLD形成过程中的表达,初步探讨L-FABP在NAFLD发病机制中的作用；同时观察降脂益肝冲剂对肝组织中L-FABP mRNA表达的影响,探讨其可能的分子治疗机制,为临床应用提供更加可靠的实验依据。
方法：1.造模与取材雄性清洁级Wistar大鼠80只,重量约为160-220g,适应性喂养1周后,开始正式实验。随机分为8组,每组10只,其中正常组(N1,N2,N3组)以普通饲料喂养,模型组(M1,M2,M3组)和治疗组(D1,D2组)以高脂饲料喂养。每天8：00～9：00am,4：00～5：00pm为喂食和给药的时间。实验动物自由进食和饮水,治疗D1组在给予高脂饮食喂养的同时即给予降脂益肝冲剂16g·Kg-1·d-1(按成年人60kg体质量的剂量(40g／d)计算出大鼠药物剂量),分2次灌胃(ig),共8周；治疗D2组于8周末时给予降脂益肝冲剂,ig(剂量、用法同D1组),共4周。同时模型组和正常组分别给予等量的生活饮用水,ig。在实验第4周末处死正常组(N1组)、模型组(M1组)；在实验第8周末处死正常组(N2组)、模型组(M2组)和治疗组(D1组)大鼠,于12周末处死其余组大鼠。所有大鼠处死前均隔夜禁食并用水合氯醛麻醉,腹主动脉采血,各组大鼠于肝左叶相同部位留取O.1g组织置于1.5mL EP管,-70℃冰箱冻存,用于RT-PCR的检测；另取肝右叶相同部位(1cm×1cm×0.5cm)组织,在4%多聚甲醛中固定,常规制片、HE染色。
2.检测指标：测量各实验鼠的体重、肝脾湿重及体长,并计算肝脾比值、肝指数及Lee's指数等体质指标；将采集的全血用低温离心机迅速分离血浆,丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、血脂(TC,TG)以及肝组织脂质含量在全自动生化分析仪(Olympus Au1000)上测定；采用铜染色法测定血清和肝组织中的FFA水平；采用葡萄糖氧化酶法测定空腹血糖(FBG)；空腹胰岛素(FINS)测定步骤按照放免试剂盒操作步骤进行,并计算胰岛素敏感指数(ISI=ln (1/(FINS×FBG)));在光镜下评估脂肪变性的程度；半定量反转录聚合酶链反应(reverse transcriptase-polymerase chain reaction, RT-PCR)测定L-FABP mRNA的动态表达。
结果：1.正常组(N1,N2,N3组)肝小叶结构完整,肝细胞呈多边形,围绕中央静脉呈放射状,肝窦清晰可见,肝索排列整齐；各项检测指标均在正常范围内,并可观察到L-FABP mRNA的表达。
2.造模4周末(M1组),模型组肝组织呈现轻度脂肪变性；血清转氨酶较正常组有所升高；总胆固醇(TC)、甘油三酯(TG)、FFA升高,开始出现脂质代谢紊乱；FBG, FINS开始升高,ISI有所下降,出现轻度胰岛素抵抗；肝组织L-FABP mRNA的表达较其正常组升高。
3.造模8周末(M2组),模型组肝组织呈中度脂肪变性及部分气球样变,形成单纯性脂肪肝,肝脂肪变以大泡性为主；血清转氨酶(ALT, AST)、血脂(TC, TG, FFA)较正常组显著升高；肝组织L-FABP mRNA的表达较其同期正常组显著升高(P<0.01)。
4.造模12周末(M3组),模型组肝组织脂肪变加剧并出现肝细胞完全气球样变、小叶内混合有炎症细胞浸润以及散在的点状坏死；与正常组相比,血清转氨酶、总胆固醇、甘油三酯较正常组显著升高；与正常组相比,肝组织L-FABP mRNA的表达显著升高(P<0.01)。
5.用药组(D1组),在细胞形态、血脂、转氨酶及肝组织肝型脂肪酸结合蛋白的表达量,与正常组(N1组)比较均无统计学差异,但与4周模型组Ml相比,各项指标均有所改善,具有统计学差异(P<0.01)。
6.用药组(D2组),肝组织仍可见索条状排列的肝细胞,脂变程度较同期模型组明显减轻,仅有轻微的炎性细胞浸润,未见明显坏死灶；与M2组相比,ALT, AST, TC, TG明显降低,FBG, FINS亦显著降低,L-FABP mRNA的表达量明显下调(P<0.01)。
结论：1.高脂高胆固醇饮食可成功的复制NAFLD大鼠模型；胰岛素抵抗及脂质代谢紊乱与NAFLD的发生关系密切。
2.正常大鼠肝脏可表达L-FABP mRNA, NAFLD模型的大鼠L-FABP mRNA增高,且随造模时间延长表达量明显升高,其增高的程度与NAFLD的程度呈正相关。
3.在NAFLD早期,给予降脂益肝冲剂,可有效的预防NAFLD的发病。
4.降脂益肝冲剂可使ALT, AST, TC, TG, FFA显著降低,说明该药不仅能够逆转肝脏的脂质沉积,而且具有很好的降酶保肝的作用；可使FBG, FINS显著降低,证实该药物可通过有效的改善胰岛素抵抗来达到对NAFLD良好的治疗效果；而L-FABP mRNA的表达明显降低,表明降脂益肝冲剂可以通过调节脂质代谢,减轻肝细胞的脂肪变性,从而达到治疗目的。
Objective:Nonalcoholic fatty liver disease is nothing to do with the excessive drinking, clinical syndrome characterized by excessive fat storing in liver and hepatic cellular dif-fuse steatosis. There has been an increase in the incidence rate of NAFLD, and it may occur in very young children, it has become a global public health problem. However, the mechanisms of NAFLD is not clear, there is still no effective treatment. There is no effective therapeutic tool. The current study found that L-FABP is closely related to high hypertriglyceridemia, hypercholesterolemia, obesity,2-diabetes. Through high-fat diet, this study establish the non-alcoholic fatty liver rat model, in order to observate the ex-pression of L-FABP in the formation of NAFLD; to investigate the effect of L-FABP in pathogenesis of NAFLD; moreover, to observe if traditional Chinese medicine-Jiangz-hi Yigan Chongji can treat and prevent NAFLD through regulating the expression of L-FABP mRNA, explore the molecular therapeutic mechanisms, This investigation can pro-vide more reliable experimental evidence for clinical treatment.
Methods:1. Modeling and specimen collection:80 male Wistar rats, weight is about 160-220g, after adaptive feeding 1 week, began to officially experiment.There were ran-domly divided into 8 groups, each group has 10 rats. Normal group (N group) were fed standard diet. Model group(M group) were fed with high-fat and high-cholesterol di-et. Every day in the time of 8:00～9:00am,4:00～5:00pm for the feeding and administra-tion. The eating and drinking of experimental animals is free. Treatment group(Di group) were given Jiangzhi Yigan Chongji 16g·Kg-1·d-1 (calculate the dose in rat by the dose of an adult 60kg body weight, about 40g/d, twice every day, intragastric administration) while fed with high-fat and high-cholesterol diet, a total of 8 weeks; Treatment group (D2 group) were given Jiangzhi YiganChongji(the dosage and usage the same as D1 gr-oup) after the beginning of the study 8 weeks, a total of 4 weeks; meanwhile, the nor-mal and model group were separately given life drinking water by the samemeans. All the rats were sacrificed after 4,8 or 12 weeks. Before all rats were killed, overnight fasting and used pentobarbital anesthesia, abdominal aortic blood,-70℃refrigerator fr-ozen.
2.Measurement Indicators:The following parameters were observed dynamically in each group:body weight, liver and spleen weight, body lenth were detected, at the same ti-me, the retios of liver and spleen, liver index and Lee's index were calculated; the lev-el of aminotransferase, blood fat and lipid in liver tissue were detected by using autom-atic biochemistry analyzer; serum and liver free fatty acid were detected by copper stai-ning method; fasting blood glucose was detected by glucose oxidase method; serum ins-ulin were detected by radio-immunity assay, simultaneously the insulin sensitivity index was calculated; assessing the extent of fatty degeneration with light microscope; The expression of L-FABP mRNA were assayed with reverse transcriptase-polymerase chain reaction(RT-PCR).
Results:1. In normal group(N1, N2, N3 group), the structure of hepatic lobule is integr-ited, cells were polygonal, and the central veins radiate, sinusoids clearly visible, liver cable arranged in neat rows, every biochemical manifestation was all in normal range, the expression of L-FABP mRNA was observed in liver.
2.After 4 weeks, in model group(M1 group), hepatic histopathology show in hepatocyte light steatosis, compared with the normal group, ALT, ALT, TC, TG and FFA increasin-g, occurs lipid metabolic disorder; FBG, FINS began to increase, ISI decline, appears insulin resistance; in model group, the expression of L-FABP is higher than nomal gr-oup.
3.After 8 weeks, model group(M2 group) showed that moderate fatty degeneration of liver tissue, forming simple fatty liver, hepatic steatosis major in Bullous; serum transa-minase(ALT, AST), blood lipids(TC, TG, FFA) was significantly higher than the normal group; the expression of L-FABP mRNA was significantly higher than the normal group in the same period(P<0.01).
4.After 12 weeks, in model group(M3 group), hepatic steatosis is sharply increased, an-d the emergence of hepatocyte completely ballooning, lobular mixed with inflammatory celll, as well as scattered point-like necrosis; compared with normal group, serum trans-aminase, total cholesterol and triglyceride were significantly increased; compared with normal group, the expression of L-FABP mRNA was significantly higher(P<0.01).
5.Compared with normal group, in treatment group(D1 group) the lever of cell morpho-logy, blood lipids, liver transaminases and the expression of L-FABP mRNA were no statistical differences; but compared with the same period in the model group(M1 grou-p), every indicators have improved, and there is significant statistical difference(P<0.01).
6. Treatment group(D2 group), liver tissue was still visible cable strips arranged in liver cells; compared with the same period in the model group, the degree of fatty change has significantly reduced, only slight inflammatory cell infiltration, no significant necros-is; compared with the M2 group, ALT, AST, TC, TG was improved remarkably, FBG, FINS significantly reduced, the expression of L-FABP was significantly lower(P<0.01).
Conclusion:1. The rats model of NAFLD could be successfully established with high-fat and high-cholesterol diet; Insulin resistance and disturbance of lipid metabolism were well associated with the development of NAFLD.
2. Normal rats liver can be expressed fatty acid-binding protein. In NAFLD rat model, the expressiong of L-FABP is increased, and with the extension of modeling time, the expressiong of L-FABP is significantly higher.
3. In early times of NAFLD, given Jiangzhi Yigan Chongji can effectively prevent the genesis and development of NAFLD.
4. JYC can reduce the level of ALT, AST, TC, TG, FFA promote the liver function re-vival. It's show that the drug can not only reverse the liver lipid deposition, but also has a very good role in reducing enzyme and protecting liver; JYC can reduce the lev-el of FBG, FINS, it confirmed that the drug can achieve effective treatment effect on NAFLD throngh improve insulin resistance; and the expression of L-FABP mRNA was significantly reduced, indicating that JYC can be adjusted lipid metabolism, reduce the fatty degeneration of hepatic cells, so as to achieve purposes of treatment.
方法：1.造模与取材雄性清洁级Wistar大鼠80只,重量约为160-220g,适应性喂养1周后,开始正式实验。随机分为8组,每组10只,其中正常组(N1,N2,N3组)以普通饲料喂养,模型组(M1,M2,M3组)和治疗组(D1,D2组)以高脂饲料喂养。每天8：00～9：00am,4：00～5：00pm为喂食和给药的时间。实验动物自由进食和饮水,治疗D1组在给予高脂饮食喂养的同时即给予降脂益肝冲剂16g·Kg-1·d-1(按成年人60kg体质量的剂量(40g／d)计算出大鼠药物剂量),分2次灌胃(ig),共8周；治疗D2组于8周末时给予降脂益肝冲剂,ig(剂量、用法同D1组),共4周。同时模型组和正常组分别给予等量的生活饮用水,ig。在实验第4周末处死正常组(N1组)、模型组(M1组)；在实验第8周末处死正常组(N2组)、模型组(M2组)和治疗组(D1组)大鼠,于12周末处死其余组大鼠。所有大鼠处死前均隔夜禁食并用水合氯醛麻醉,腹主动脉采血,各组大鼠于肝左叶相同部位留取O.1g组织置于1.5mL EP管,-70℃冰箱冻存,用于RT-PCR的检测；另取肝右叶相同部位(1cm×1cm×0.5cm)组织,在4%多聚甲醛中固定,常规制片、HE染色。
2.检测指标：测量各实验鼠的体重、肝脾湿重及体长,并计算肝脾比值、肝指数及Lee's指数等体质指标；将采集的全血用低温离心机迅速分离血浆,丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、血脂(TC,TG)以及肝组织脂质含量在全自动生化分析仪(Olympus Au1000)上测定；采用铜染色法测定血清和肝组织中的FFA水平；采用葡萄糖氧化酶法测定空腹血糖(FBG)；空腹胰岛素(FINS)测定步骤按照放免试剂盒操作步骤进行,并计算胰岛素敏感指数(ISI=ln (1/(FINS×FBG)));在光镜下评估脂肪变性的程度；半定量反转录聚合酶链反应(reverse transcriptase-polymerase chain reaction, RT-PCR)测定L-FABP mRNA的动态表达。
结果：1.正常组(N1,N2,N3组)肝小叶结构完整,肝细胞呈多边形,围绕中央静脉呈放射状,肝窦清晰可见,肝索排列整齐；各项检测指标均在正常范围内,并可观察到L-FABP mRNA的表达。
2.造模4周末(M1组),模型组肝组织呈现轻度脂肪变性；血清转氨酶较正常组有所升高；总胆固醇(TC)、甘油三酯(TG)、FFA升高,开始出现脂质代谢紊乱；FBG, FINS开始升高,ISI有所下降,出现轻度胰岛素抵抗；肝组织L-FABP mRNA的表达较其正常组升高。
3.造模8周末(M2组),模型组肝组织呈中度脂肪变性及部分气球样变,形成单纯性脂肪肝,肝脂肪变以大泡性为主；血清转氨酶(ALT, AST)、血脂(TC, TG, FFA)较正常组显著升高；肝组织L-FABP mRNA的表达较其同期正常组显著升高(P<0.01)。
4.造模12周末(M3组),模型组肝组织脂肪变加剧并出现肝细胞完全气球样变、小叶内混合有炎症细胞浸润以及散在的点状坏死；与正常组相比,血清转氨酶、总胆固醇、甘油三酯较正常组显著升高；与正常组相比,肝组织L-FABP mRNA的表达显著升高(P<0.01)。
5.用药组(D1组),在细胞形态、血脂、转氨酶及肝组织肝型脂肪酸结合蛋白的表达量,与正常组(N1组)比较均无统计学差异,但与4周模型组Ml相比,各项指标均有所改善,具有统计学差异(P<0.01)。
6.用药组(D2组),肝组织仍可见索条状排列的肝细胞,脂变程度较同期模型组明显减轻,仅有轻微的炎性细胞浸润,未见明显坏死灶；与M2组相比,ALT, AST, TC, TG明显降低,FBG, FINS亦显著降低,L-FABP mRNA的表达量明显下调(P<0.01)。
结论：1.高脂高胆固醇饮食可成功的复制NAFLD大鼠模型；胰岛素抵抗及脂质代谢紊乱与NAFLD的发生关系密切。
2.正常大鼠肝脏可表达L-FABP mRNA, NAFLD模型的大鼠L-FABP mRNA增高,且随造模时间延长表达量明显升高,其增高的程度与NAFLD的程度呈正相关。
3.在NAFLD早期,给予降脂益肝冲剂,可有效的预防NAFLD的发病。
4.降脂益肝冲剂可使ALT, AST, TC, TG, FFA显著降低,说明该药不仅能够逆转肝脏的脂质沉积,而且具有很好的降酶保肝的作用；可使FBG, FINS显著降低,证实该药物可通过有效的改善胰岛素抵抗来达到对NAFLD良好的治疗效果；而L-FABP mRNA的表达明显降低,表明降脂益肝冲剂可以通过调节脂质代谢,减轻肝细胞的脂肪变性,从而达到治疗目的。
Objective:Nonalcoholic fatty liver disease is nothing to do with the excessive drinking, clinical syndrome characterized by excessive fat storing in liver and hepatic cellular dif-fuse steatosis. There has been an increase in the incidence rate of NAFLD, and it may occur in very young children, it has become a global public health problem. However, the mechanisms of NAFLD is not clear, there is still no effective treatment. There is no effective therapeutic tool. The current study found that L-FABP is closely related to high hypertriglyceridemia, hypercholesterolemia, obesity,2-diabetes. Through high-fat diet, this study establish the non-alcoholic fatty liver rat model, in order to observate the ex-pression of L-FABP in the formation of NAFLD; to investigate the effect of L-FABP in pathogenesis of NAFLD; moreover, to observe if traditional Chinese medicine-Jiangz-hi Yigan Chongji can treat and prevent NAFLD through regulating the expression of L-FABP mRNA, explore the molecular therapeutic mechanisms, This investigation can pro-vide more reliable experimental evidence for clinical treatment.
Methods:1. Modeling and specimen collection:80 male Wistar rats, weight is about 160-220g, after adaptive feeding 1 week, began to officially experiment.There were ran-domly divided into 8 groups, each group has 10 rats. Normal group (N group) were fed standard diet. Model group(M group) were fed with high-fat and high-cholesterol di-et. Every day in the time of 8:00～9:00am,4:00～5:00pm for the feeding and administra-tion. The eating and drinking of experimental animals is free. Treatment group(Di group) were given Jiangzhi Yigan Chongji 16g·Kg-1·d-1 (calculate the dose in rat by the dose of an adult 60kg body weight, about 40g/d, twice every day, intragastric administration) while fed with high-fat and high-cholesterol diet, a total of 8 weeks; Treatment group (D2 group) were given Jiangzhi YiganChongji(the dosage and usage the same as D1 gr-oup) after the beginning of the study 8 weeks, a total of 4 weeks; meanwhile, the nor-mal and model group were separately given life drinking water by the samemeans. All the rats were sacrificed after 4,8 or 12 weeks. Before all rats were killed, overnight fasting and used pentobarbital anesthesia, abdominal aortic blood,-70℃refrigerator fr-ozen.
2.Measurement Indicators:The following parameters were observed dynamically in each group:body weight, liver and spleen weight, body lenth were detected, at the same ti-me, the retios of liver and spleen, liver index and Lee's index were calculated; the lev-el of aminotransferase, blood fat and lipid in liver tissue were detected by using autom-atic biochemistry analyzer; serum and liver free fatty acid were detected by copper stai-ning method; fasting blood glucose was detected by glucose oxidase method; serum ins-ulin were detected by radio-immunity assay, simultaneously the insulin sensitivity index was calculated; assessing the extent of fatty degeneration with light microscope; The expression of L-FABP mRNA were assayed with reverse transcriptase-polymerase chain reaction(RT-PCR).
Results:1. In normal group(N1, N2, N3 group), the structure of hepatic lobule is integr-ited, cells were polygonal, and the central veins radiate, sinusoids clearly visible, liver cable arranged in neat rows, every biochemical manifestation was all in normal range, the expression of L-FABP mRNA was observed in liver.
2.After 4 weeks, in model group(M1 group), hepatic histopathology show in hepatocyte light steatosis, compared with the normal group, ALT, ALT, TC, TG and FFA increasin-g, occurs lipid metabolic disorder; FBG, FINS began to increase, ISI decline, appears insulin resistance; in model group, the expression of L-FABP is higher than nomal gr-oup.
3.After 8 weeks, model group(M2 group) showed that moderate fatty degeneration of liver tissue, forming simple fatty liver, hepatic steatosis major in Bullous; serum transa-minase(ALT, AST), blood lipids(TC, TG, FFA) was significantly higher than the normal group; the expression of L-FABP mRNA was significantly higher than the normal group in the same period(P<0.01).
4.After 12 weeks, in model group(M3 group), hepatic steatosis is sharply increased, an-d the emergence of hepatocyte completely ballooning, lobular mixed with inflammatory celll, as well as scattered point-like necrosis; compared with normal group, serum trans-aminase, total cholesterol and triglyceride were significantly increased; compared with normal group, the expression of L-FABP mRNA was significantly higher(P<0.01).
5.Compared with normal group, in treatment group(D1 group) the lever of cell morpho-logy, blood lipids, liver transaminases and the expression of L-FABP mRNA were no statistical differences; but compared with the same period in the model group(M1 grou-p), every indicators have improved, and there is significant statistical difference(P<0.01).
6. Treatment group(D2 group), liver tissue was still visible cable strips arranged in liver cells; compared with the same period in the model group, the degree of fatty change has significantly reduced, only slight inflammatory cell infiltration, no significant necros-is; compared with the M2 group, ALT, AST, TC, TG was improved remarkably, FBG, FINS significantly reduced, the expression of L-FABP was significantly lower(P<0.01).
Conclusion:1. The rats model of NAFLD could be successfully established with high-fat and high-cholesterol diet; Insulin resistance and disturbance of lipid metabolism were well associated with the development of NAFLD.
2. Normal rats liver can be expressed fatty acid-binding protein. In NAFLD rat model, the expressiong of L-FABP is increased, and with the extension of modeling time, the expressiong of L-FABP is significantly higher.
3. In early times of NAFLD, given Jiangzhi Yigan Chongji can effectively prevent the genesis and development of NAFLD.
4. JYC can reduce the level of ALT, AST, TC, TG, FFA promote the liver function re-vival. It's show that the drug can not only reverse the liver lipid deposition, but also has a very good role in reducing enzyme and protecting liver; JYC can reduce the lev-el of FBG, FINS, it confirmed that the drug can achieve effective treatment effect on NAFLD throngh improve insulin resistance; and the expression of L-FABP mRNA was significantly reduced, indicating that JYC can be adjusted lipid metabolism, reduce the fatty degeneration of hepatic cells, so as to achieve purposes of treatment.
引文
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