树莓酮对非酒精性脂肪性肝炎干预作用及机理研究
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摘要
目的：非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)是一种肝组织病理学改变与酒精性肝病相类似,但无过量饮酒史的临床综合征,随病程的进展而表现不一,包括单纯性脂肪肝(steatosis)、非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)、肝硬化(cirrhosis)三个阶段。NASH是NAFLD的一个重要阶段,如能积极预防,或在发病后给予积极干预,NASH会向单纯脂肪变性阶段转化,甚至可能恢复正常；反之,NASH可能会发展为肝纤维化,甚至肝硬化。本课题在发现树莓酮对NASH有干预作用的基础上,将生物化学、酶组织化学、免疫组织化学、ELISA等现代生物技术运用到本研究中。利用高脂饮食诱发大鼠NASH模型,观察树莓酮对NASH的干预效果,并探讨其作用机制。
方法：选取雌雄各半的SPF级(Sprague Dawley) SD大鼠40只正常喂养1周后,随机分为五组：正常对照组(NC,n=8)普通饲料喂养8周；模型对照组(MC,n=8),高脂饲料(82%普通饲料、8.3%蛋黄粉、9.0%猪油、0.5%胆固醇、0.2%牛胆酸钠)；树莓酮低剂量组(RKL,n=8)、树莓酮中剂量组(RKM,n=8)、树莓酮高剂量组(RKH,n=8)分别在高脂饲料喂养4周后予0.5%、1%和2%树莓酮灌胃,其他组以相同剂量色拉油灌胃,每天灌胃一次,持续4周。实验8周后处死各组大鼠,观察动物体重、食欲、行为、状态、毛发及死亡情况,计算脏器指数；采用全自动生化分析仪测定大鼠血脂指标(TC、TG、HDL-C、LDL-C)、血清肝功能指标(ALT、AST、ALP)和血糖(GLU)；酶联免疫分析法测定血清胰岛素(INS)、瘦素(LEP)、游离脂肪酸(FFA)、肿瘤坏死因子α(TNF-α)、载脂蛋白A (Apo A I)和载脂蛋白B (Apo B);测定大鼠肝组织匀浆过氧化物酶体增殖物激活受体α(PPAP-α)、低密度脂蛋白受体(LDLR)、超敏C-反应蛋白(hs-CRP)、脂联素(APN)；并计算胰岛素抵抗指数(IRI)和胰岛素敏感指数(ISI)；肝组织匀浆生化测定总谷胱甘肽(T-GSH)、超氧化物歧化酶(SOD)、丙二醛(MDA)；各组大鼠肝组织进行HE染色,光学显微镜下评估肝组织脂肪变性和炎症活动程度,并用透射电镜观察肝细胞超微结构变化。
结果：本实验以高脂饲料喂养,经肝组织病理检查证实8周时NASH大鼠模型已复制成功。实验结果经统计学处理发现,与正常组比较,模型组大鼠TG、TC、LDL-C、ALT、AST、ALP、GLU、INS、IRI、FFA、LEP、TNF-α、MDA、hs-CRP水平明显增高(P<0.05, P<0.01); HDL-C、ISI、T-GSH、PPAP-α、LDLR、APN水平显著降低(P<0.05,P<0.01)。树莓酮高、中、低剂量组各项指标较模型组有明显改善(P<0.05,P<0.01)。
结论：本实验成功建立了非酒精性脂肪性肝炎模型,并在高脂膳食的同时应用树莓酮干预脂肪肝。结果显示,树莓酮能降低血清和肝组织中的脂质水平,减少FFA的生成,从而保护肝细胞；可通过改善胰岛素和瘦素抵抗、调节血脂代谢等保护肝细胞免受损伤,减轻肝脏炎症反应的作用；能明显抑制氧应激和脂质过氧化反应,促使氧化与抗氧化机制恢复平衡,从而使肝脏免受损害；能减轻高脂饮食诱导的肝细胞活动性损伤,从而起到保护肝细胞的作用；还可减轻肝脏的炎性损伤和脂肪变性程度,使肝细胞的结构和功能逐渐恢复正常。因此,树莓酮可认为同时兼有保肝和调脂的双重效应,其作用机制可能是：减轻肝细胞脂肪变性、减轻肝组织炎症细胞浸润、纠正血脂代谢紊乱、改善胰岛素和瘦素抵抗、减少FNF-α的释放、提高抗氧化能力。
Objective:Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological term that encompasses a disease spectrum ranging from simple triglyceride accumulation in hepatocytes (hepatic steatosis) to hepatic steatosis with inflammation (nonalcoholic steatohepatitis, NASH) and cirrhosis. NASH is a very important stage. Given appropriate prevention or treatment, NASH can be recovered to steatosis, otherwise, it can evolve to fiborsis, even cirrhosis. In this paper, RK has intervention effect on NASH. Furthermore, the technology of biochemistry, enzyme histochemistry, immunohistochemistry, ELISA and other modern techniques were applied in this study. The intervention effect in nonalcoholic steatohepatitis (NASH) was tested by using high-fat diet induced NASH model, and its mechanism was explored.
Method:.There were 40 Sprague Dawley (SD) rats of Specific pathogen free (SPF) grade, and the male to female ratio was 1:1, which were fed with normal diet about a week. Thus these rats were randomly divided into 5 groups:Normal Control group (NC, n=8) fed with normal diet for 8 weeks, Model Control group (MC, n=8) fed with high-fat diet (82% standard diet,8.3% yolk powder,9.0% lard,0.5% cholesterol, and 0.2% sodium taurocholate), raspberry ketone low-dose group (RKL, n=8), raspberry ketone middle-dose group (RKM, n =8), and raspberry ketone high-dose group (RKH, n=8) fed with high-fat diet for 4 weeks. After above treatment, these rats in last three groups were administered intragastrically with 0.5%,1%, and 2% of RK, respectively, the rats of other groups were administered intragastrically with salad oil at the same dose once a day, lasting for 4 weeks. After 8 weeks of experiment, all the rats were executed. The weight, appetite, behavior, state, hair and death rate of the rats were closely observed. Tissue index numbers were calculated. The blood lipid parameters (TC, TG, HDL-C, and LDL-C), the liver function parameters (ALT, AST, and ALP) of serum, and blood sugar (GLU) were tested through automatic biochemistry analyzer. Serum of insulin (INS), leptin (LEP), free fatty acid (FFA), tumor necrosis factorα(TNF-α), apoprotein A (Apo AⅠ), apoprotein B (Apo B), liver homogenate of peroxisome proliferator-activated receptor-α(PPAP-α),the low density lipoprotein receptor (LDLR), high-sensitivity C-reactive protein (hs-CRP), adiponection (APN) were tested by enzyme linked immunosorbent assay (ELISA). Insulin resistance index (IRI) and insulin sensitive index (ISI) were calculated. Liver homogenate of total glutathione (T-GSH), and superoxide dismutase (SOD), malonaldehyde (MDA) were tested by way of tissue homogenate biochemistry. The liver tissues of rats in each group were imaged by electron microsopy with hematoxylin and eosin (HE) as staining agent. Hepatic steatosis and inflammatory activity level were assessed by optical microscope. The ultrastructure of the liver tissues was observed through electron microscope.
Result:In this study, we fed the rats with high-fat diet, and the results showed that the NASH of rat model had been duplicated successfully via pathological examination after 8 weeks. The results were processed by statistical analysis, and compare to NC, the levels of TG, TC, LDL-C, ALT, AST, ALP, GLU, INS, IRI, FFA, LEP, TNF-α, MDA, and hs-CRP of MC rats were significantly increased (P<0.05, P<0.01). Therefore, the levels of HDL-C, ISI, T-GSH, PPAP-a, LDLR, and APN were significantly decreased (P<0.05, P<0.01). Compared with MC, each parameter in RKL, RKM, and RKH was significantly improved (P <0.05, P<0.01).
Conclusion:In this study, we successfully established the NASH model, where we employed RK to inference the steatohepatitis with high fat-diet. The results showed that the RK can reduce the lipid levels in serum and liver tissue, suppress the synthesis of FFA to protect liver cells, improve the resistance of leptin and insulin for the activation of the liver-protection function, regulation of lipid metabolism, and inhibition of inflammation. Furthermore, RK could significantly inhibit the oxidative stress and lipid peroxidation and promote the balance restoration of oxidation and antioxidant mechanisms, so as to prevent the liver from damage. In addition, RK could also reduce the damage of liver cells caused by high fat-diet, so RK could act as liver-protector. Last but not least, RK could diminish the inflammatory damages of liver cells and fatty degeneration, so that it can regenerated the structure and function of liver cells. It was believed that RK had dual effect of liver-protection and fat adjustment, and the mechanism were probably that RK alleviate fatty degeneration of liver cellsto reduce the infiltration of inflammatory cells in liver tissue, to correcte dyslipidemia, to improve of the resistance of leptin and insulin, to reduce the release of TNF-a, and to improve the antioxidant capacity.
方法：选取雌雄各半的SPF级(Sprague Dawley) SD大鼠40只正常喂养1周后,随机分为五组：正常对照组(NC,n=8)普通饲料喂养8周；模型对照组(MC,n=8),高脂饲料(82%普通饲料、8.3%蛋黄粉、9.0%猪油、0.5%胆固醇、0.2%牛胆酸钠)；树莓酮低剂量组(RKL,n=8)、树莓酮中剂量组(RKM,n=8)、树莓酮高剂量组(RKH,n=8)分别在高脂饲料喂养4周后予0.5%、1%和2%树莓酮灌胃,其他组以相同剂量色拉油灌胃,每天灌胃一次,持续4周。实验8周后处死各组大鼠,观察动物体重、食欲、行为、状态、毛发及死亡情况,计算脏器指数；采用全自动生化分析仪测定大鼠血脂指标(TC、TG、HDL-C、LDL-C)、血清肝功能指标(ALT、AST、ALP)和血糖(GLU)；酶联免疫分析法测定血清胰岛素(INS)、瘦素(LEP)、游离脂肪酸(FFA)、肿瘤坏死因子α(TNF-α)、载脂蛋白A (Apo A I)和载脂蛋白B (Apo B);测定大鼠肝组织匀浆过氧化物酶体增殖物激活受体α(PPAP-α)、低密度脂蛋白受体(LDLR)、超敏C-反应蛋白(hs-CRP)、脂联素(APN)；并计算胰岛素抵抗指数(IRI)和胰岛素敏感指数(ISI)；肝组织匀浆生化测定总谷胱甘肽(T-GSH)、超氧化物歧化酶(SOD)、丙二醛(MDA)；各组大鼠肝组织进行HE染色,光学显微镜下评估肝组织脂肪变性和炎症活动程度,并用透射电镜观察肝细胞超微结构变化。
结果：本实验以高脂饲料喂养,经肝组织病理检查证实8周时NASH大鼠模型已复制成功。实验结果经统计学处理发现,与正常组比较,模型组大鼠TG、TC、LDL-C、ALT、AST、ALP、GLU、INS、IRI、FFA、LEP、TNF-α、MDA、hs-CRP水平明显增高(P<0.05, P<0.01); HDL-C、ISI、T-GSH、PPAP-α、LDLR、APN水平显著降低(P<0.05,P<0.01)。树莓酮高、中、低剂量组各项指标较模型组有明显改善(P<0.05,P<0.01)。
结论：本实验成功建立了非酒精性脂肪性肝炎模型,并在高脂膳食的同时应用树莓酮干预脂肪肝。结果显示,树莓酮能降低血清和肝组织中的脂质水平,减少FFA的生成,从而保护肝细胞；可通过改善胰岛素和瘦素抵抗、调节血脂代谢等保护肝细胞免受损伤,减轻肝脏炎症反应的作用；能明显抑制氧应激和脂质过氧化反应,促使氧化与抗氧化机制恢复平衡,从而使肝脏免受损害；能减轻高脂饮食诱导的肝细胞活动性损伤,从而起到保护肝细胞的作用；还可减轻肝脏的炎性损伤和脂肪变性程度,使肝细胞的结构和功能逐渐恢复正常。因此,树莓酮可认为同时兼有保肝和调脂的双重效应,其作用机制可能是：减轻肝细胞脂肪变性、减轻肝组织炎症细胞浸润、纠正血脂代谢紊乱、改善胰岛素和瘦素抵抗、减少FNF-α的释放、提高抗氧化能力。
Objective:Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological term that encompasses a disease spectrum ranging from simple triglyceride accumulation in hepatocytes (hepatic steatosis) to hepatic steatosis with inflammation (nonalcoholic steatohepatitis, NASH) and cirrhosis. NASH is a very important stage. Given appropriate prevention or treatment, NASH can be recovered to steatosis, otherwise, it can evolve to fiborsis, even cirrhosis. In this paper, RK has intervention effect on NASH. Furthermore, the technology of biochemistry, enzyme histochemistry, immunohistochemistry, ELISA and other modern techniques were applied in this study. The intervention effect in nonalcoholic steatohepatitis (NASH) was tested by using high-fat diet induced NASH model, and its mechanism was explored.
Method:.There were 40 Sprague Dawley (SD) rats of Specific pathogen free (SPF) grade, and the male to female ratio was 1:1, which were fed with normal diet about a week. Thus these rats were randomly divided into 5 groups:Normal Control group (NC, n=8) fed with normal diet for 8 weeks, Model Control group (MC, n=8) fed with high-fat diet (82% standard diet,8.3% yolk powder,9.0% lard,0.5% cholesterol, and 0.2% sodium taurocholate), raspberry ketone low-dose group (RKL, n=8), raspberry ketone middle-dose group (RKM, n =8), and raspberry ketone high-dose group (RKH, n=8) fed with high-fat diet for 4 weeks. After above treatment, these rats in last three groups were administered intragastrically with 0.5%,1%, and 2% of RK, respectively, the rats of other groups were administered intragastrically with salad oil at the same dose once a day, lasting for 4 weeks. After 8 weeks of experiment, all the rats were executed. The weight, appetite, behavior, state, hair and death rate of the rats were closely observed. Tissue index numbers were calculated. The blood lipid parameters (TC, TG, HDL-C, and LDL-C), the liver function parameters (ALT, AST, and ALP) of serum, and blood sugar (GLU) were tested through automatic biochemistry analyzer. Serum of insulin (INS), leptin (LEP), free fatty acid (FFA), tumor necrosis factorα(TNF-α), apoprotein A (Apo AⅠ), apoprotein B (Apo B), liver homogenate of peroxisome proliferator-activated receptor-α(PPAP-α),the low density lipoprotein receptor (LDLR), high-sensitivity C-reactive protein (hs-CRP), adiponection (APN) were tested by enzyme linked immunosorbent assay (ELISA). Insulin resistance index (IRI) and insulin sensitive index (ISI) were calculated. Liver homogenate of total glutathione (T-GSH), and superoxide dismutase (SOD), malonaldehyde (MDA) were tested by way of tissue homogenate biochemistry. The liver tissues of rats in each group were imaged by electron microsopy with hematoxylin and eosin (HE) as staining agent. Hepatic steatosis and inflammatory activity level were assessed by optical microscope. The ultrastructure of the liver tissues was observed through electron microscope.
Result:In this study, we fed the rats with high-fat diet, and the results showed that the NASH of rat model had been duplicated successfully via pathological examination after 8 weeks. The results were processed by statistical analysis, and compare to NC, the levels of TG, TC, LDL-C, ALT, AST, ALP, GLU, INS, IRI, FFA, LEP, TNF-α, MDA, and hs-CRP of MC rats were significantly increased (P<0.05, P<0.01). Therefore, the levels of HDL-C, ISI, T-GSH, PPAP-a, LDLR, and APN were significantly decreased (P<0.05, P<0.01). Compared with MC, each parameter in RKL, RKM, and RKH was significantly improved (P <0.05, P<0.01).
Conclusion:In this study, we successfully established the NASH model, where we employed RK to inference the steatohepatitis with high fat-diet. The results showed that the RK can reduce the lipid levels in serum and liver tissue, suppress the synthesis of FFA to protect liver cells, improve the resistance of leptin and insulin for the activation of the liver-protection function, regulation of lipid metabolism, and inhibition of inflammation. Furthermore, RK could significantly inhibit the oxidative stress and lipid peroxidation and promote the balance restoration of oxidation and antioxidant mechanisms, so as to prevent the liver from damage. In addition, RK could also reduce the damage of liver cells caused by high fat-diet, so RK could act as liver-protector. Last but not least, RK could diminish the inflammatory damages of liver cells and fatty degeneration, so that it can regenerated the structure and function of liver cells. It was believed that RK had dual effect of liver-protection and fat adjustment, and the mechanism were probably that RK alleviate fatty degeneration of liver cellsto reduce the infiltration of inflammatory cells in liver tissue, to correcte dyslipidemia, to improve of the resistance of leptin and insulin, to reduce the release of TNF-a, and to improve the antioxidant capacity.
引文
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