非酒精性脂肪性肝病临床特征及其褪黑素防治作用的研究
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摘要
研究背景
越来越多的研究证实非酒精性脂肪性肝病(Non-alcoholic fatty liver disease, NAFLD)可进展为终末期肝病及肝细胞癌。NAFLD疾病谱广泛,包括单纯性脂肪变性到由其演变的脂肪性肝炎、脂肪性肝纤维化和肝硬化。NAFLD影响三分之一的一般人群的健康,并涉及到任何年龄和种族,是一般人群第二主要的死亡原因。NAFLD已经显示是重大的公共卫生问题。在中国,NAFLD作为肝硬化的原因之一,也许很快会超过乙型肝炎所致的肝硬化,成为慢性肝病最常见的原因。有效地防治NAFLD可降低终末期肝病的发生率和肝病相关的死亡率,但目前缺乏有效的治疗。因此,探寻有效的治疗NAFLD的药物有非常重要的意义。褪黑素(Melatonin,MEL)主要是松果体合成的吲哚类物质,有许多生理和生化的功能,具有强大的抗氧化特性,能清除活性氧(ROS),能抗衰老、抗癌、抗肝脏损伤和动脉粥样硬化。研究表明MEL对人及实验动物脂质代谢有影响,可降低肝内TG和TC沉积,并对药物性、毒物性、免疫性及胆汁郁积性等急慢肝损害有治疗作用。但迄今为止,未见MEL防治NAFLD的相关报道。考虑到MEL的降血脂、抗氧化和肝脏保护作用,可能对NAFLD有防治作用。因此,设计本课题,在分析大样本体检人群NAFLD易患因素及临床生化参数的基础上,建立高脂饮食诱导的NAFLD大鼠模型,同时观察MEL对其的防治作用及可能机制。
目的
(1)了解NAFLD在人群中的发病情况以及其临床特点。
(2)观察褪黑素对高脂饮食诱导的大鼠NAFLD作用,并对其作用机制进行探讨。
方法
(1)2006年7月～2006年8月某单位中老年职工体检人群,进行简单调查问卷,调查内容包括年龄、性别、饮酒史、既往疾病史、药物及毒物接触史、病毒性肝炎病史。清晨空腹状态下测量人体测量学指标,包括身高、体重、坐位安静状态下测收缩压和舒张压,并计算体重指数(BMI)。肝脏超声检查。全自动生化分析仪检测血清丙氨酸氨基转移酶(ALT)、血清天门冬氨酸氨基转移酶(AST)、血清甘油三酯(TG)、总胆固醇(TC)、极低密度脂蛋白(VLDL)、空腹血糖(FPG)。所有诊断为NAFLD的患者中,选取临床资料和血标本较为完整的78例患者,进入NAFLD组。体检人群中,临床、生化及B超检查排除脂肪肝、高血压、高血脂、糖尿病等疾病,按照病例对照研究方法,选取年龄和性别相匹配的78例进入正常对照组。放射免疫法(RIA)测定血浆空腹胰岛素水平,计算胰岛素抵抗指数(IRI)。
(2)雄性Wistar大鼠50只,随机分成5组,每组10只。正常对照组给予普通饲料,模型组、MEL低剂量组、MEL中剂量组、MEL高剂量组予以高脂饮食12周。各MEL干预组依次给予MEL(含≤1%无水乙醇) 2.5mg·kg-1?d-1,5.0mg·kg-1?d-1和10.0 mg·kg-1?d-1腹腔注射,正常对照组、模型组给予等量生理盐水(含1%无水乙醇)腹腔注射,12周末处死动物,称体重及肝湿重并计算肝指数,进行肝脏病理学检查,生物化学方法测定ALT,AST,TG,TC,FFA水平及血糖和血清胰岛素含量;生物化学方法检测肝匀浆TG,TC,FFA,超氧化物歧化酶(SOD)、谷胱苷肽过氧化物酶(GSH-Px)活性和丙二醛(MDA)含量,采用稳态模型评估(HOMA)法公式“HOMA-IRI=(空腹胰岛素×空腹血糖)/22.5”评估胰岛素抵抗指数(insulin resistance index , IRI);稳态寿命荧光光谱法检测肝脏和小肠微粒体甘油三酯转运蛋白(MTP)活性,Western blot检测肝脏和小肠微粒体MTP蛋白表达。免疫组织化学法和Western blot测定肝脏细胞色素P450 2E1(CYP 2E1)的表达。
结果
(1)1277例受检者中,共检出脂肪性肝病453例,现患率为35.47%(453/1277)。其中男性脂肪性肝病236例,占检出总数52.10%,女性脂肪性肝病217例,占检出总数47.90%,男性脂肪性肝病的检出率明显高于女性(P<0.01)。脂肪性肝病检出率最高的年龄组为51～60岁组,检出率为45.34%;男性中脂肪性肝病检出率最高的年龄组为51～60岁组,检出率为55.29%;女性中脂肪性肝病检出率最高的年龄组为61～70岁组,检出率为44.68%;在≤60岁人群中,男性脂肪性肝病的检出率显著高于女性(P<0.01)。453例脂肪性肝病患者中,非酒精性脂肪性肝病占75.72%(343/453)NAFLD组中,合并代谢综合征中高血压、肥胖、高脂血症和2型糖尿病四种组分2项或2项以上者53例(67.95%,53/78),合并代谢代谢综合征者26例(33.33%,26/78)。与正常对照组比较,NAFLD组BMI, Sbp, Dbp, ALT, AST, TG, TC, VLDL, FPG, FINS和IRI值显著升高(P<0.01)。
(2)12周高脂饮食成功复制大鼠NAFLD模型。与正常对照组比较,血清ALT,FPG,AST,TC, FFA值和HOMA-IRI(P<0.05)明显升高;肝匀浆TG, TC, FFA(P<0.05)值明显升高,肝匀浆SOD,GSH-Px水平明显减低(P <0.01,P<0.05),但MDA值升高(P<0.05);肝脏微粒体CYP2E1的表达和蛋白含量明显增加(P<0.05);肝脏和小肠微粒体的MTP活性和蛋白表达量明显降低(P <0.05);模型组大鼠肝湿重及肝指数明显增高(P<0.01),肝细胞呈中-重度脂肪变性,肝小叶内见灶性炎细胞浸润和点状坏死。药物干预组中以MEL中、高剂量组药理作用明显。与模型组比,各MEL干预组大鼠肝细胞脂肪变性及炎性细胞浸润有不同程度的改善,多呈轻-中度脂肪变性,其中MEL中等剂量(5.0mg/kg)及高剂量(10.0mg/kg)干预显著改善NAFLD大鼠肝脏病理变化(P<0.001),明显减低炎症活动度积分(P<0.05)。与模型组比较,MEL中、高剂量组肝湿重及肝指数明显减低(P<0.05);高剂量MEL干预组血清ALT和AST降低有显著差异(P<0.05);高剂量MEL干预组肝脏TC、TG(P<0.01, P<0.05)和中等剂量干预组肝脏TC﹙P<0.05)降低有显著意义;MEL低、中、高剂量干预组血清FFA以及MEL中、高剂量干预组肝组织FFA降低均有显著差异(P<0.05); MEL中、高剂量干预组肝脏CYP 2E1表达和高剂量组肝脏微粒体CYP 2E1蛋白量降低有显著意义( P<0.05);MEL中、高剂量干预组肝脏微粒体MTP活性升高,但没有显著差异; MEL高剂量干预组大鼠小肠微粒体MTP活性升高有显著差异( P<0.05); MEL高剂量干预组肝脏和小肠微粒体MTP蛋白表达升高有显著差异( P<0.05)。
结论
1.本次体检人群中脂肪性肝病检出率为35.47%,其中NAFLD占75.72%。NAFLD发病与肥胖、高脂血症、糖尿病和代谢综合征关系密切。
2.长期高脂饮食诱导的NAFLD大鼠肝脏和小肠MTP活性及蛋白表达下降。
3.MEL明显改善高脂饮食诱导的NAFLD大鼠肝组织形态学变化、血清转氨酶以及肝脏脂质,对NAFLD的形成有明显的防治作用,且与剂量呈正相关。其作用机制可能与MEL改善氧应激,抑制脂质过氧化反应,干预肝脏和小肠脂质代谢有关。
Background
Non-alcoholic fatty liver disease (NAFLD) is an increasingly recognized condition that may progress to end-stage liver disease and hepatocellular carcinoma, which ranges from simple steatosis to steatohepatitis, advanced fibrosis, and cirrhosis. NAFLD is present in up to one-third of the general population and affects any age and ethnic group, making this liver disease the second leading cause of death in the general population. NAFLD has emerged as a substantial public health concern throughout the world. In China, NAFLD may soon be rivaling chronic hepatitis B as a cause of cirrhosis and become the commonest cause of chronic liver disease. To protect and treat NAFLD efficaciously can lower the incidence of end-stage liver disease and the mortality related to liver disease. However, there is lack of effective treatment for NAFLD at present. Therefore, it is of significance to explore the efficaciously pharmacological agents for NAFLD. Melatonin, a lipophilic indoleamine derived from tryptophan, is synthesized chiefly by the pineal gland but has recently been detected in many other tissues as well. It has a variety of important physiological and biochemical functions. It also has been shown to be a powerful antioxidant which scavenges reactive oxygen and reactive nitrogen species. The antioxidant properties of melatonin have been shown experimentally to protect against aging, cancer, liver injury, and atherosclerosis. Melatonin shows marked protective effects against liver injuries in experimental animals induced by a variety of agents and processes. However, there is not any report about preventive and therapeutic effect of melatonin on NAFLD until now. Therefore, we investigate the fatty liver disease incidence and its clinical characters, as well as establish rat model of NAFLD in order to investigate the effects of melatonin on NAFLD and its possible mechanism.
Objective
(1)To investigate non-alcoholic fatty liver disease incidence and its clinical characters.
(2)To establish rat model of non-alcoholic fatty liver disease induced by high fat diet in order to observe the effects of melatonin on rat non-alcoholic fatty liver disease and investigate its possible mechanism.
Methods
(1)Questionnaire investigation were taken by middle-old employees in a certain enterprise between July and August 2006. It contains age, sex, history of drinking, past medical history, history of taking drugs and poisons, history of viral hepatitis. Authropometry indexes were measured on an empty stomach in early morning, including height, weight, Sbp, Dbp, BMI is calculated out by height and weight. Liver ultrasonic inspection was carried out, serum ALT, AST, TG, TC, VLDL, FPG were detected by automatic biochemistry analyzer. 78 NAFLD patients with intact clinical data and blood sample were choosed to become the NAFLD group. 78 age- and sex- matched normal subjects were choosed from all health examination subjects to become the normal control group, excluded fatty liver disease, hypertension, hyperlipemia, diabetes and other diseases, with case control study method. Fasting insulin were detected by RIA, HOMA-IRI were calculated by“IRI =(FINS×FPG)/22.5”.
(2)Fifty male Wistar rats were divided into five groups with ten for each randomly. The melatonin in low does, moderate does, high does group and model group were fed with high fat diet while the normal control group with common diet for 12 weeks. Melatonin ( contain≤1%dehydrated alcohol ) was intraperitoneally injected to the rats in various melatonin groups ( 2.5mg/kg, 5.0mg/kg and 10.0mg/kg , respectively ) and equal does of saline ( contain 1%dehydrated alcohol ) to control and model group once a day. After 12 weeks experiment, all rats were sacrificed. Histopathological changes in liver, liver humid weight and liver index were observed. The level of AST, ALT, glucose, insulin in serum; TG, TC, and FFA in serum and liver tissue homogenates; SOD,MDA and GSH-Px in liver tissue homogenates were measured by biochemical methods. IR was assessed by the homeostasis model assessment (HOMA) method using the formula“IRI=(FBG x FINS) /22.5”. MTP activities in liver and small intestine microsome were observed by Fluorescence Lifetime and Steady State Spectrometer, the level of MTP protein in liver and small intestine were determined by western blot. The expression of CYP2E1 in liver was observed by immunohistochemical method and western blot.
Results
(1)453 fatty liver disease were detected in 1277 subjects, the prevalence is 35.47%(453/1277). In the total fatty liver disease patients, male is 236, account for 52.10% while female is 217, account for 47.90%. The male prevalence is obviously higher than female (P<0.01). The maximal fatty liver disease prevalence group is between 51~60 in all patients, account for 45.34%. The maximal fatty liver prevalence group is between 51~60 in male, account for 55.29%, while the maximal fatty liver prevalence group is between 61~70 in female, account for 44.68%. The fatty liver disease prevalence in male is obviously higher than female in subjects who’s age≤60(P<0.01). According to etiological factor, nonalcoholic fatty liver disease patients account for 75.72%, alcoholic liver disease patients account for 13.25%, hepatitis fatty liver patients account for 5.30% and other reason caused fatty liver patients account for 5.73% in 453 fatty liver disease patients. In NAFLD group, those who accompany with two or more than two symptoms in metabolism syndrome, such as hypertension, obesity, hyperlipidemia and T2DM, account for 53 (67.95%, 53/78). And there are 26 NAFLD patients accompany with metabolism syndrome (33.33%, 26/78). Compared with the normal control group, BMI, Sbp, Dbp, ALT, AST, TG, TC, VLDL, FBG, FINS, IRI in NAFLD group is significantly increased(P<0.01).
(2) NAFLD rat model was successfully established with high fat diet for twelve weeks. Compared with control group, the model group developed moderate - serious steatosis and focus infiltration of inflammatory cells and punctiform necrosis in hepatic lobules, with significant increasing liver humid weight, liver index, level of serum AST, ALT, TC, FFA, FPG(P<0.05)and TC,TG , MDA and FFA in liver (P<0.05), simultaneously with decreasing hepatic SOD , GSH-Px (P<0.05). The expression and protein level of CYP2E1 in liver was also increased. MTP activities and protein level in liver and small intestine microsome were reduced(P<0.05, P<0.001). Compared with model group, hepatic steatosis , integration of histological activity index (P<0.05), liver index and liver humid weight(P<0.05), MDA level in liver of high dose of MEL group was improved, simultaneously with increasing of SOD and GSH-PX in liver in moderate and high does of MEL group(P<0.05,P<0.01). The level of serum AST, ALT, hepatic TC,TG in high does of MEL group and the level of hepatic TC in moderate does of MEL group were lower significantly than model group(P<0.05). Compared with model group, serum FFA level in melatonin-treated groups and hepatic FFA level in a moderate or high dose of MEL group was reduced( P<0.05, P<0.01 respectively). Expression of CYP2E1 in liver of rats treated with moderate or high dose of MEL and protein level of CYP 2E1 in liver of rats treated with high does of MEL was decreased (P<0.05 ). MTP activities in small intestine microsome in high dose of MEL group , MTP protein level in liver and small intestine microsome in high dose of MEL group were higher than that in model group, respectively(P<0.05,P<0.05, P<0.01).
Conclusions
(1)The fatty liver disease prevalence is 35.47% in this health examination crowd, with nonalcoholic fatty liver disease accounting for 75.72%. NAFLD is closely correlated with obesity, hyperlipidemia, diabetes and metabolic syndrome.
(2)Rat NAFLD induced by chronic feeding of an high fat diet is associated with the decrease of MTP activities and protein level in liver and small intestine microsome.
(3)Melatonin in a dose dependent manner significantly improved liver morphology, serum transaminase,lipid and antioxidase activity in liver, depressed lipid peroxidation,expression of hepatic CYP2E1 and up-regulated MTP activities and protein level of liver and small intestine microsome in NAFLD rats induced by high fat diet, presenting the markedly protective and therapeutic effect against NAFLD. Melatonin may ameliorate oxidative stress,inhibit lipid peroxidation and interfere in lipid metabolism in liver and small intestine to protect rats treated with high fat diet against NAFLD.
越来越多的研究证实非酒精性脂肪性肝病(Non-alcoholic fatty liver disease, NAFLD)可进展为终末期肝病及肝细胞癌。NAFLD疾病谱广泛,包括单纯性脂肪变性到由其演变的脂肪性肝炎、脂肪性肝纤维化和肝硬化。NAFLD影响三分之一的一般人群的健康,并涉及到任何年龄和种族,是一般人群第二主要的死亡原因。NAFLD已经显示是重大的公共卫生问题。在中国,NAFLD作为肝硬化的原因之一,也许很快会超过乙型肝炎所致的肝硬化,成为慢性肝病最常见的原因。有效地防治NAFLD可降低终末期肝病的发生率和肝病相关的死亡率,但目前缺乏有效的治疗。因此,探寻有效的治疗NAFLD的药物有非常重要的意义。褪黑素(Melatonin,MEL)主要是松果体合成的吲哚类物质,有许多生理和生化的功能,具有强大的抗氧化特性,能清除活性氧(ROS),能抗衰老、抗癌、抗肝脏损伤和动脉粥样硬化。研究表明MEL对人及实验动物脂质代谢有影响,可降低肝内TG和TC沉积,并对药物性、毒物性、免疫性及胆汁郁积性等急慢肝损害有治疗作用。但迄今为止,未见MEL防治NAFLD的相关报道。考虑到MEL的降血脂、抗氧化和肝脏保护作用,可能对NAFLD有防治作用。因此,设计本课题,在分析大样本体检人群NAFLD易患因素及临床生化参数的基础上,建立高脂饮食诱导的NAFLD大鼠模型,同时观察MEL对其的防治作用及可能机制。
目的
(1)了解NAFLD在人群中的发病情况以及其临床特点。
(2)观察褪黑素对高脂饮食诱导的大鼠NAFLD作用,并对其作用机制进行探讨。
方法
(1)2006年7月～2006年8月某单位中老年职工体检人群,进行简单调查问卷,调查内容包括年龄、性别、饮酒史、既往疾病史、药物及毒物接触史、病毒性肝炎病史。清晨空腹状态下测量人体测量学指标,包括身高、体重、坐位安静状态下测收缩压和舒张压,并计算体重指数(BMI)。肝脏超声检查。全自动生化分析仪检测血清丙氨酸氨基转移酶(ALT)、血清天门冬氨酸氨基转移酶(AST)、血清甘油三酯(TG)、总胆固醇(TC)、极低密度脂蛋白(VLDL)、空腹血糖(FPG)。所有诊断为NAFLD的患者中,选取临床资料和血标本较为完整的78例患者,进入NAFLD组。体检人群中,临床、生化及B超检查排除脂肪肝、高血压、高血脂、糖尿病等疾病,按照病例对照研究方法,选取年龄和性别相匹配的78例进入正常对照组。放射免疫法(RIA)测定血浆空腹胰岛素水平,计算胰岛素抵抗指数(IRI)。
(2)雄性Wistar大鼠50只,随机分成5组,每组10只。正常对照组给予普通饲料,模型组、MEL低剂量组、MEL中剂量组、MEL高剂量组予以高脂饮食12周。各MEL干预组依次给予MEL(含≤1%无水乙醇) 2.5mg·kg-1?d-1,5.0mg·kg-1?d-1和10.0 mg·kg-1?d-1腹腔注射,正常对照组、模型组给予等量生理盐水(含1%无水乙醇)腹腔注射,12周末处死动物,称体重及肝湿重并计算肝指数,进行肝脏病理学检查,生物化学方法测定ALT,AST,TG,TC,FFA水平及血糖和血清胰岛素含量;生物化学方法检测肝匀浆TG,TC,FFA,超氧化物歧化酶(SOD)、谷胱苷肽过氧化物酶(GSH-Px)活性和丙二醛(MDA)含量,采用稳态模型评估(HOMA)法公式“HOMA-IRI=(空腹胰岛素×空腹血糖)/22.5”评估胰岛素抵抗指数(insulin resistance index , IRI);稳态寿命荧光光谱法检测肝脏和小肠微粒体甘油三酯转运蛋白(MTP)活性,Western blot检测肝脏和小肠微粒体MTP蛋白表达。免疫组织化学法和Western blot测定肝脏细胞色素P450 2E1(CYP 2E1)的表达。
结果
(1)1277例受检者中,共检出脂肪性肝病453例,现患率为35.47%(453/1277)。其中男性脂肪性肝病236例,占检出总数52.10%,女性脂肪性肝病217例,占检出总数47.90%,男性脂肪性肝病的检出率明显高于女性(P<0.01)。脂肪性肝病检出率最高的年龄组为51～60岁组,检出率为45.34%;男性中脂肪性肝病检出率最高的年龄组为51～60岁组,检出率为55.29%;女性中脂肪性肝病检出率最高的年龄组为61～70岁组,检出率为44.68%;在≤60岁人群中,男性脂肪性肝病的检出率显著高于女性(P<0.01)。453例脂肪性肝病患者中,非酒精性脂肪性肝病占75.72%(343/453)NAFLD组中,合并代谢综合征中高血压、肥胖、高脂血症和2型糖尿病四种组分2项或2项以上者53例(67.95%,53/78),合并代谢代谢综合征者26例(33.33%,26/78)。与正常对照组比较,NAFLD组BMI, Sbp, Dbp, ALT, AST, TG, TC, VLDL, FPG, FINS和IRI值显著升高(P<0.01)。
(2)12周高脂饮食成功复制大鼠NAFLD模型。与正常对照组比较,血清ALT,FPG,AST,TC, FFA值和HOMA-IRI(P<0.05)明显升高;肝匀浆TG, TC, FFA(P<0.05)值明显升高,肝匀浆SOD,GSH-Px水平明显减低(P <0.01,P<0.05),但MDA值升高(P<0.05);肝脏微粒体CYP2E1的表达和蛋白含量明显增加(P<0.05);肝脏和小肠微粒体的MTP活性和蛋白表达量明显降低(P <0.05);模型组大鼠肝湿重及肝指数明显增高(P<0.01),肝细胞呈中-重度脂肪变性,肝小叶内见灶性炎细胞浸润和点状坏死。药物干预组中以MEL中、高剂量组药理作用明显。与模型组比,各MEL干预组大鼠肝细胞脂肪变性及炎性细胞浸润有不同程度的改善,多呈轻-中度脂肪变性,其中MEL中等剂量(5.0mg/kg)及高剂量(10.0mg/kg)干预显著改善NAFLD大鼠肝脏病理变化(P<0.001),明显减低炎症活动度积分(P<0.05)。与模型组比较,MEL中、高剂量组肝湿重及肝指数明显减低(P<0.05);高剂量MEL干预组血清ALT和AST降低有显著差异(P<0.05);高剂量MEL干预组肝脏TC、TG(P<0.01, P<0.05)和中等剂量干预组肝脏TC﹙P<0.05)降低有显著意义;MEL低、中、高剂量干预组血清FFA以及MEL中、高剂量干预组肝组织FFA降低均有显著差异(P<0.05); MEL中、高剂量干预组肝脏CYP 2E1表达和高剂量组肝脏微粒体CYP 2E1蛋白量降低有显著意义( P<0.05);MEL中、高剂量干预组肝脏微粒体MTP活性升高,但没有显著差异; MEL高剂量干预组大鼠小肠微粒体MTP活性升高有显著差异( P<0.05); MEL高剂量干预组肝脏和小肠微粒体MTP蛋白表达升高有显著差异( P<0.05)。
结论
1.本次体检人群中脂肪性肝病检出率为35.47%,其中NAFLD占75.72%。NAFLD发病与肥胖、高脂血症、糖尿病和代谢综合征关系密切。
2.长期高脂饮食诱导的NAFLD大鼠肝脏和小肠MTP活性及蛋白表达下降。
3.MEL明显改善高脂饮食诱导的NAFLD大鼠肝组织形态学变化、血清转氨酶以及肝脏脂质,对NAFLD的形成有明显的防治作用,且与剂量呈正相关。其作用机制可能与MEL改善氧应激,抑制脂质过氧化反应,干预肝脏和小肠脂质代谢有关。
Background
Non-alcoholic fatty liver disease (NAFLD) is an increasingly recognized condition that may progress to end-stage liver disease and hepatocellular carcinoma, which ranges from simple steatosis to steatohepatitis, advanced fibrosis, and cirrhosis. NAFLD is present in up to one-third of the general population and affects any age and ethnic group, making this liver disease the second leading cause of death in the general population. NAFLD has emerged as a substantial public health concern throughout the world. In China, NAFLD may soon be rivaling chronic hepatitis B as a cause of cirrhosis and become the commonest cause of chronic liver disease. To protect and treat NAFLD efficaciously can lower the incidence of end-stage liver disease and the mortality related to liver disease. However, there is lack of effective treatment for NAFLD at present. Therefore, it is of significance to explore the efficaciously pharmacological agents for NAFLD. Melatonin, a lipophilic indoleamine derived from tryptophan, is synthesized chiefly by the pineal gland but has recently been detected in many other tissues as well. It has a variety of important physiological and biochemical functions. It also has been shown to be a powerful antioxidant which scavenges reactive oxygen and reactive nitrogen species. The antioxidant properties of melatonin have been shown experimentally to protect against aging, cancer, liver injury, and atherosclerosis. Melatonin shows marked protective effects against liver injuries in experimental animals induced by a variety of agents and processes. However, there is not any report about preventive and therapeutic effect of melatonin on NAFLD until now. Therefore, we investigate the fatty liver disease incidence and its clinical characters, as well as establish rat model of NAFLD in order to investigate the effects of melatonin on NAFLD and its possible mechanism.
Objective
(1)To investigate non-alcoholic fatty liver disease incidence and its clinical characters.
(2)To establish rat model of non-alcoholic fatty liver disease induced by high fat diet in order to observe the effects of melatonin on rat non-alcoholic fatty liver disease and investigate its possible mechanism.
Methods
(1)Questionnaire investigation were taken by middle-old employees in a certain enterprise between July and August 2006. It contains age, sex, history of drinking, past medical history, history of taking drugs and poisons, history of viral hepatitis. Authropometry indexes were measured on an empty stomach in early morning, including height, weight, Sbp, Dbp, BMI is calculated out by height and weight. Liver ultrasonic inspection was carried out, serum ALT, AST, TG, TC, VLDL, FPG were detected by automatic biochemistry analyzer. 78 NAFLD patients with intact clinical data and blood sample were choosed to become the NAFLD group. 78 age- and sex- matched normal subjects were choosed from all health examination subjects to become the normal control group, excluded fatty liver disease, hypertension, hyperlipemia, diabetes and other diseases, with case control study method. Fasting insulin were detected by RIA, HOMA-IRI were calculated by“IRI =(FINS×FPG)/22.5”.
(2)Fifty male Wistar rats were divided into five groups with ten for each randomly. The melatonin in low does, moderate does, high does group and model group were fed with high fat diet while the normal control group with common diet for 12 weeks. Melatonin ( contain≤1%dehydrated alcohol ) was intraperitoneally injected to the rats in various melatonin groups ( 2.5mg/kg, 5.0mg/kg and 10.0mg/kg , respectively ) and equal does of saline ( contain 1%dehydrated alcohol ) to control and model group once a day. After 12 weeks experiment, all rats were sacrificed. Histopathological changes in liver, liver humid weight and liver index were observed. The level of AST, ALT, glucose, insulin in serum; TG, TC, and FFA in serum and liver tissue homogenates; SOD,MDA and GSH-Px in liver tissue homogenates were measured by biochemical methods. IR was assessed by the homeostasis model assessment (HOMA) method using the formula“IRI=(FBG x FINS) /22.5”. MTP activities in liver and small intestine microsome were observed by Fluorescence Lifetime and Steady State Spectrometer, the level of MTP protein in liver and small intestine were determined by western blot. The expression of CYP2E1 in liver was observed by immunohistochemical method and western blot.
Results
(1)453 fatty liver disease were detected in 1277 subjects, the prevalence is 35.47%(453/1277). In the total fatty liver disease patients, male is 236, account for 52.10% while female is 217, account for 47.90%. The male prevalence is obviously higher than female (P<0.01). The maximal fatty liver disease prevalence group is between 51~60 in all patients, account for 45.34%. The maximal fatty liver prevalence group is between 51~60 in male, account for 55.29%, while the maximal fatty liver prevalence group is between 61~70 in female, account for 44.68%. The fatty liver disease prevalence in male is obviously higher than female in subjects who’s age≤60(P<0.01). According to etiological factor, nonalcoholic fatty liver disease patients account for 75.72%, alcoholic liver disease patients account for 13.25%, hepatitis fatty liver patients account for 5.30% and other reason caused fatty liver patients account for 5.73% in 453 fatty liver disease patients. In NAFLD group, those who accompany with two or more than two symptoms in metabolism syndrome, such as hypertension, obesity, hyperlipidemia and T2DM, account for 53 (67.95%, 53/78). And there are 26 NAFLD patients accompany with metabolism syndrome (33.33%, 26/78). Compared with the normal control group, BMI, Sbp, Dbp, ALT, AST, TG, TC, VLDL, FBG, FINS, IRI in NAFLD group is significantly increased(P<0.01).
(2) NAFLD rat model was successfully established with high fat diet for twelve weeks. Compared with control group, the model group developed moderate - serious steatosis and focus infiltration of inflammatory cells and punctiform necrosis in hepatic lobules, with significant increasing liver humid weight, liver index, level of serum AST, ALT, TC, FFA, FPG(P<0.05)and TC,TG , MDA and FFA in liver (P<0.05), simultaneously with decreasing hepatic SOD , GSH-Px (P<0.05). The expression and protein level of CYP2E1 in liver was also increased. MTP activities and protein level in liver and small intestine microsome were reduced(P<0.05, P<0.001). Compared with model group, hepatic steatosis , integration of histological activity index (P<0.05), liver index and liver humid weight(P<0.05), MDA level in liver of high dose of MEL group was improved, simultaneously with increasing of SOD and GSH-PX in liver in moderate and high does of MEL group(P<0.05,P<0.01). The level of serum AST, ALT, hepatic TC,TG in high does of MEL group and the level of hepatic TC in moderate does of MEL group were lower significantly than model group(P<0.05). Compared with model group, serum FFA level in melatonin-treated groups and hepatic FFA level in a moderate or high dose of MEL group was reduced( P<0.05, P<0.01 respectively). Expression of CYP2E1 in liver of rats treated with moderate or high dose of MEL and protein level of CYP 2E1 in liver of rats treated with high does of MEL was decreased (P<0.05 ). MTP activities in small intestine microsome in high dose of MEL group , MTP protein level in liver and small intestine microsome in high dose of MEL group were higher than that in model group, respectively(P<0.05,P<0.05, P<0.01).
Conclusions
(1)The fatty liver disease prevalence is 35.47% in this health examination crowd, with nonalcoholic fatty liver disease accounting for 75.72%. NAFLD is closely correlated with obesity, hyperlipidemia, diabetes and metabolic syndrome.
(2)Rat NAFLD induced by chronic feeding of an high fat diet is associated with the decrease of MTP activities and protein level in liver and small intestine microsome.
(3)Melatonin in a dose dependent manner significantly improved liver morphology, serum transaminase,lipid and antioxidase activity in liver, depressed lipid peroxidation,expression of hepatic CYP2E1 and up-regulated MTP activities and protein level of liver and small intestine microsome in NAFLD rats induced by high fat diet, presenting the markedly protective and therapeutic effect against NAFLD. Melatonin may ameliorate oxidative stress,inhibit lipid peroxidation and interfere in lipid metabolism in liver and small intestine to protect rats treated with high fat diet against NAFLD.
引文
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240 黎荣山,尹瑞兴,林伟雄,等. 广西黑衣壮族人群微粒体甘油三酯转移蛋白基因多态性与血脂水平的关系. 中华医学杂志, 2005,85:2492-6.
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