非酒精性脂肪肝模型小鼠的建立

背景：以往非酒精性脂肪肝模型建立的常用诱导方法均有其局限性,因此,有必要建立高质量的非酒精性脂肪肝模型。目的：拟利用复合高脂饮食和低浓度四氯化碳诱导小鼠非酒精性脂肪肝模型。方法：取昆明小鼠随机分为3组：对照组,高脂模型组和高脂模型＋四氯化碳组。观察饲养第2,4,6和8周末肝脏形态和病理变化,测定第8周末血清丙氨酸氨基转移酶,天冬氨酸氨基转移酶,胆固醇和三酰甘油,以及肝脏胆固醇和三酰甘油水平。结果与结论：复合高脂饮食＋5%四氯化碳腹腔注射的方式造模,第2周末开始出现炎症细胞浸润,第4周末出现少量脂滴,第6周末出现脂肪病变,第8周末在脂肪病变的基础上,部分小鼠出现了肝纤维化,8周末小鼠肝指数、血清丙氨酸氨基转移酶,天冬氨酸氨基转移酶,胆固醇和三酰甘油,肝脏胆固醇和三酰甘油浓度明显升高（P〈0.05或P〈0.01）。通过8周复合高脂饮食和5%四氯化碳腹腔注射成功建立小鼠非酒精性脂肪肝模型。     

非酒精性脂肪肝模型小鼠的建立

背景:以往非酒精性脂肪肝模型建立的常用诱导方法均有其局限性,因此,有必要建立高质量的非酒精性脂肪肝模型。目的:拟利用复合高脂饮食和低浓度四氯化碳诱导小鼠非酒精性脂肪肝模型。方法:取昆明小鼠随机分为3组:对照组,高脂模型组和高脂模型+四氯化碳组。观察饲养第2,4,6和8周末肝脏形态和病理变化,测定第8周末血清丙氨酸氨基转移酶,天冬氨酸氨基转移酶,胆固醇和三酰甘油,以及肝脏胆固醇和三酰甘油水平。结果与结论:复合高脂饮食+5%四氯化碳腹腔注射的方式造模,第2周末开始出现炎症细胞浸润,第4周末出现少量脂滴,第6周末出现脂肪病变,第8周末在脂肪病变的基础上,部分小鼠出现了肝纤维化,8周末小鼠肝指数、血清丙氨酸氨基转移酶,天冬氨酸氨基转移酶,胆固醇和三酰甘油,肝脏胆固醇和三酰甘油浓度明显升高(P<0.05或P<0.01)。通过8周复合高脂饮食和5%四氯化碳腹腔注射成功建立小鼠非酒精性脂肪肝模型。     

脂必妥治疗非酒精性脂肪性肝炎的临床观察

目的 通过常规护肝降酶治疗和联用调脂治疗对比了解地奥脂必妥对非酒精性脂肪性肝炎的临床疗效及安全性影响。方法 将80例非酒精性脂肪性肝炎（NASH）患者随机分为A、B两组。A组使用护肝降酶药物治疗4周，B组使用上述治疗联合地奥脂必妥口服治疗4周。结果 A组ALT、AST、Tch、TG降低不明显（P〉0．05）；B组的上述指标明显下降到目标水平，与A组比较疗效有显著性差异（P〈0．01）。结论 对NASH患者联用地奥脂必妥和护肝降酶治疗疗效好，可明显降低Tch、TG，并促进ALT、ASF好转，且不会导致肾功能和血糖代谢异常。     

姜黄素防治大鼠非酒精性脂肪性肝炎的实验研究

目的探讨姜黄素防治非酒精性脂肪性肝炎（NASH）的作用及机制。方法采用高脂饮食复制大鼠NASH模型。随机分为正常对照组、空白模型组、姜黄素防治组、东宝肝泰防治组。检测肝功能、血脂变化、肝匀浆超氧化物歧化酶（SOD）活性、丙二醛（MDA）含量的变化，观察肝细胞脂肪变性、炎症活动程度。结果与空白模型组相比，姜黄素防治组大鼠血清ALT、AST、TG、TCH明显降低（P〈0．01）；肝匀浆中SOD活性升高（P〈0．01）、MDA含量显著降低（P〈0．01），脂肪变性、炎症活动程度皆有改善（P〈0．05），部分作用优于东宝肝泰防治组（P〈0．01或P〈0．05）。结论姜黄素对NASH有明显的防治作用，其作用机制与其能减少脂类积聚、抗脂质过氧化有关。     

非酒精性脂肪性肝炎的治疗

非酒精性脂肪性肝病（nonalcoholic fatty liver diseases，NAFLD）是指l临床病理上从仅出现单纯性脂肪肝到发生非酒精性脂肪性肝炎（nongtlcoholic steatohepatitis，NASH）和进一步演变为肝硬化的一种疾病，其中NASH是指兼具肝脂肪变性及肝脏炎症和（或）纤维化的生化和组织学证据的NAFLD，最初于1980年由Ludwig等人命名。一般所指的是与代谢综合征（或称X综合征，包括腹型肥胖、脂肪肝、Ⅱ型糖尿病、高脂血症和高血压等）有关的原发性NASH。目前，随着城市化的进展，生活行为方式的改变，高脂肪高热量的饮食，NASH在东西方国家均有增长趋势。据美国及西方国家报道约20％～30％的成人有肝内脂肪过度积聚，这些人群中约10％（或2％～3％的成人）符合NASH的诊断，而大约1／3以上的NASH患者可能因持续性肝损伤而导致纤维化进展，与慢性病毒性肝炎和酒精性肝病一样可发展到终末期肝硬化并出现肝硬化严重并发症。     

清肝消脂汤治疗非酒精性脂肪性肝炎疗效观察

目的:观察清肝消脂汤联合阿拓莫兰治疗瘀血湿热内阻型非酒精性脂肪性肝炎(NASH)的临床疗效。方法:将符合入选条件的80例患者随机分成治疗组和对照组各40例。对照组在调整饮食结构、适量有氧运动等基础治疗的同时,给予阿拓莫兰治疗,治疗组在对照组的基础上,加服清肝消脂汤,疗程3个月,观察两组病例中医临床症状、体征和CT检查(肝/脾CT值)、肝功能、血脂疗效的变化。结果:清肝消脂汤联合阿拓莫兰能明显改善NASH患者肝脏影像学变化,减轻临床症状,改善和恢复肝功能,降低患者血清甘油三脂、胆固醇的含量,其总有效率为92.5%,优于对照组的60.0%(P<0.01)。结论:中西医结合治疗NASH疗效显著。     

硫普罗宁联合丹参注射液治疗非酒精性脂肪性肝炎

目的观察硫普罗宁联合丹参注射液治疗非酒精性脂肪性肝炎的临床疗效。方法66例非酒精性脂肪性肝炎随机分为治疗组36例、对照组30例,治疗组用硫普罗宁联合丹参注射液治疗,对照组用硫普罗宁治疗,4周为1疗程,观察治疗前后的肝功能变化。结果治疗组患者综合疗效与对照组比较,有显著统计学意义(P<0.05)。结论硫普罗宁联合丹参注射液对非酒精性脂肪性肝炎疗效显著。     

清脂汤治疗非酒精性脂肪性肝炎临床观察

目的:观察清脂汤治疗非酒精性脂肪性肝炎的临床疗效。方法:将明确为非酒精性脂肪性肝炎的56例患者随机分为治疗组30例和对照组26例,治疗组予清脂汤联合熊胆胶囊治疗,对照组予甘草甜素合熊胆胶囊治疗。3个月后对2组血清肝功能和血脂、血糖及尿酸等指标进行比较。结果:2组治疗后腹胀和肝区不适改善情况均有显著性差异(P<0.01),治疗组优于对照组。②治疗组治疗后ALT、AST、GGT变化均有显著性差异(P<0.01),而对照组只有ALT有显著性差异(P<0.01);治疗后组间比较,AST、GGT变化均有显著性差异(P<0.05)。2组治疗后ALT、AST异常病例数变化比较无显著性差异,GGT异常病例数变化比较有显著性差异(P<0.01)。2组血清胆固醇、甘油三酯、尿酸和血糖异常病例数变化比较均无显著性差异。结论:清脂汤联合熊胆胶囊治疗非酒精性脂肪性肝炎有较的改善症状和肝功能生化指标作用。     

非酒精性脂肪性肝炎的诊治

防治非酒精性脂肪性肝炎的重要性非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)是成人和儿童肝功能异常最常见的原因,近年来其患病率及发病率不断增加。NAFLD包括单纯性脂肪肝、非酒精性脂肪性肝炎(non-alcoholic steatohepatitis,NASH)、肝纤维化和肝硬化[1]。由单纯性脂肪肝进展为NASH的重要变化是肝纤维化。一般认为,不合并纤维化和炎症的单纯性脂肪肝在大部分情况下是一个良性的、可逆     

Effect of tocotrienol on the primary progression of nonalcoholic steatohepatitis in a mouse model

Tocotrienol (T3), a vitamin E (Vit E) isoform, is known to have both biological and antioxidant effects. Although alpha-tocopherol (α-Toc), another isoform of Vit E is suggested to be a useful treatment against nonalcoholic steatohepatitis (NASH), the effect of T3 on NASH is unclear. This study aimed to comparatively evaluate the effects of T3 and α-Toc on NASH in the early stage of NASH progression, using a recently established NASH mouse model induced by a choline-deficient l-amino acid-defined high-fat diet (CDAHFD). Six-week-old male mice were divided into four groups (n = 6 per group) and fed the CDAHFD for 1 week. The first group was given no other treatment (Pre). The other three groups continued the CDAHFD plus daily oral administration of Vit E-free corn oil (Control), corn oil containing α-Toc, or corn oil containing T3 for additional 2 weeks. Neither Vit E treatment changed the histologic features of NASH, but T3 significantly reduced the mRNA expression of several genes related to inflammation and fibrosis and α-Toc did not. These results suggested that oral T3 treatment was more effective than α-Toc at suppressing hepatic inflammation and fibrosis in the early stage of NASH progression in CDAHFD model mice.     

综合方法治疗非酒精性脂肪性肝炎临床疗效分析

目的:探讨综合方法治疗非酒精性脂肪性肝炎(NASH)的临床疗效。方法:选择2011年1月至2018年11月在复旦大学附属中山医院内分泌科住院的经肝脏病理学确诊为NASH,并在治疗后接受肝脏病理学检查的患者。分析患者接受的综合治疗方式,判断其肝脏组织学改变情况,并观察治疗前后相关代谢参数改变情况。结果:共10例患者纳入研究,其中男性2例、女性8例,治疗期前平均(54.2±9.6)岁。10例患者中,合并糖代谢异常8例,合并高血压6例,合并血脂异常4例,合并甲状腺功能减退4例。经过1.04(0.73,1.54)年的治疗,80%(8/10)的患者获得NASH改善,其非酒精性脂肪性肝病活动度积分总分下降1 (0.5, 3.5)分,其中7例肝纤维化评分下降了1 (0.5,1.5)分。余20%(2/10)患者出现NASH的进展。患者治疗后体质指数(BMI)减小,同时糖化血红蛋白、丙氨酸氨基转移酶、天冬氨酸氨基转移酶、γ-谷氨酰转肽酶水平均下降(P0.05)。NASH改善患者的体质量降幅更明显,为10.80%(8.62%,20%),血压控制在(128.14±8.8)/(83.14±7.47) mmHg(1 mmHg=0.133 kPa);NASH进展患者体质量未明显下降,且血压控制不佳。结论:综合治疗可改善NASH患者肝脏组织病理情况,该效应可能与体质量下降及血压下降有关。     

营养性肥胖动物模型的建立

目的观察高脂饲料配方对制造营养性肥胖大鼠动物模型的影响。方法用改进的高脂饲料喂养大鼠6周,观察体重及Lees指数、身长、尾长、及肥胖指标,并与普食组进行比较。结果喂养6周后,高脂组大鼠体重为305·50±21·21g,普食组大鼠体重为235·00±17·86g,两者比较差异有显著性意义(P<0·05);另外,高脂组腹腔各部位脂肪重量及肝脏重量与普食组比较也有显著性差异(P<0·05)。结论高脂饮食可以引起大鼠营养性肥胖;总油脂含量18%,猪油含量12%配制的高脂饲料配方组成较为合理,致肥效果明显。     

Need for liver biopsy in pediatric nonalcoholic steatohepatitis diagnosis regardless of improvement in liver damage through weight loss

Liver biopsy is recommended for obese children with fatty liver disease to ensure that nonalcoholic steatohepatitis (NASH) is not overlooked. Even in pediatric cases, regardless of the improvement in liver damage through weight loss, children should be tested and treated with the possibility of NASH in mind.     

Vitamin E treatment in patients with nonalcoholic steatohepatitis: A six-month, open-label study of sixteen patients

Background

Free radicals have a pivotal role in the pathogenesis of nonalcoholic steatohepatitis (NASH). Decreasing oxidative stress might have beneficial effects on the biochemical and histologic progression of this disease.

Objective

We aimed to determine the therapeutic effect of vitamin E, a potent antioxidant, on liver enzymes and histology in NASH.

Methods

This 6-month, open-label study was conducted at the Departments of Gastroenterology and Pathology, Gazi University School of Medicine (Ankara, Turkey). Patients aged 18 to 70 years with biopsy-proven NASH were included in the study. All patients received vitamin E 800 U/d in 2 divided doses, orally (capsules) for 6 months. Patients were not advised to change their exercise or dietary habits. Body mass index (BMI) was calculated at months 0 (baseline) and 6. Histologic scoring of steatosis, necroinflammatory grade, and fibrosis stage was performed at 0 and 6 months. Liver enzyme activities (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase [ALP], and gamma-glutamyltransferase [GGT]) were monitored monthly. Control biopsy specimens were obtained at the end of the treatment. All of the liver biopsies were read by a single pathologist (G.A.) who was blinded to the clinical, laboratory, and histopathologic data, as well as the sequence of liver biopsies. Assessments of compliance and tolerability of treatment were performed using a pill count and patient interview, respectively, at the end of each month.

Results

Sixteen patients (12 men, 4 women; mean [SD] age, 45.5 [6.9] years [range, 37-60 years]) were enrolled. All patients completed 6 months of treatment. Mean BMI did not change significantly from baseline. Significant improvements in mean (SD) serum liver enzyme activities were observed at 6 months compared with baseline (ALT: 38.6 [16.3] U/L vs 84.8 [22.1] U/L, respectively, P = 0.001; AST: 29.8 [15.4] U/L vs 46.0 [16.0] U/L, respectively, P = 0.001; ALP: 154.6 [64.1] U/L vs 211.5 [70.4] U/L, respectively, P= 0.011; and GGT: 49.8 [38.5] U/L vs 64.7 [54.4] U/L, respectively, P = 0.002), as well as in total cholesterol level (176.2 [42.0] mg/dL vs 199.6 [60.6] mg/dL; P = 0.02). Posttreatment liver biopsy was available in 13 patients (81%). Significant improvements in the mean (SD) scores of steatosis (1.46 [0.66] vs 2.43 [0.62]; P = 0.002) and necroinflammatory grade (0.84 [0.24] vs 1.31 [0.51]; P= 0.006) were observed at 6 months compared with baseline, respectively. However, no significant change was noted in the mean (SD) score of fibrosis stage (0.77 [0.33] vs 1.12 [0.59], respectively). None of the patients reported any adverse effects.

Conclusion

In this small, 6-month, open-label study, vitamin E treatment was safe and well tolerated and led to potential biochemical and histologic improvements (except in fibrosis) in patients with NASH.     

Effects of 5-aminolevulinic acid on a murine model of diet-induced obesity

The effects of 5-aminolevulinic acid (5-ALA) on obesity were investigated using a murine model (diet-induced obese mice). Diet-induced obese mice were divided into 4 groups: a control group (C group), which was fed a high-fat diet; a low-5-ALA dose (10 mg/kg/day) group (10A group); a moderate-5-ALA dose (30 mg/kg/day) group (30A group); and a high-5-ALA dose (100 mg/kg/day) group (100A group). 5-ALA was administered by mixing the high fat diet for 8 weeks. Body weight increases in the 30A and 100A groups were significantly smaller compared with those of the C group. Body fat measurements by X-ray computed tomography indicated that the 100A group showed a tendency toward low visceral fat quantities during the final week of the study. Visceral fat weights in the 30A and 100A groups were slightly low. The levels of serum alanine aminotransferase (ALT) and total cholesterol (TC) in the 10A group was slightly low, whereas the 30A and 100A groups showed significantly lower ALT and TC values. Liver lipid concentration showed a dose-dependent decrease with ALA. Thus, in this diet-induced obese murine model, administration of 5-ALA had a significantly beneficial impact on the visceral fat, serum ALT and TC, and liver lipid concentration.     

肠源性内毒素血症在非酒精性脂肪性肝炎中作用的探讨

目的研究探讨肠源性内毒素血症(IETM)是导致非酒精性脂肪性肝炎早期形成阶段的重要原因。方法W istar雄性大鼠36只,随机分为3组:对照组,模型组(高脂饮食),治疗组(高脂饮食 甘氨酸),造模8周、12周时分批处死,测门静脉、腹主动脉血中内毒素(ET)水平;取肝标本做HE染色和CD14免疫组化;通过13C-美沙西丁呼气试验观察肝细胞损害程度。结果8周、12周模型组门静脉ET水平较对照组明显上升(0.62±0.11 EU/L对0.29±0.02EU/L;0.60±0.09 EU/L对0.28±0.02 EU/L,P<0.01);治疗组ET水平(0.53±0.20 EU/L和0.47±0.09 EU/L)降低,腹主动脉血ET与相对应组门静脉ET比较有显著性差异(t值分别为-7.49、12.05、-6.68和-6.07,P<0.01);13C-美沙西丁呼气试验12周模型组呼气峰值(DOB)较对照组明显升高(28.43±2.14‰对16.27±3.28‰),治疗组DOB有所下降(24.07±3.00‰),达峰时间也随之改变,与肝脏HE染色病变一致;CD14阳性细胞数随着时间的发展已明显增多。结论IETM在非酒精性脂肪性肝炎中起有重要的作用。     

Oltipraz ameliorates the progression of steatohepatitis in Nrf2-null mice fed a high-fat diet

Oltipraz, a synthetic dithiolethione, has chemopreventive effect through nuclear factor erythroid 2-related factor 2 (Nrf2) activation. Nrf2 is known to be involved in the development of experimental steatohepatitis in rodents. In this study, to evaluate the effect of oltipraz on lipid and bile acid metabolism, wild-type and Nrf2-null mice were fed the standard diet (containing 4% soybean oil) with or without oltipraz. Based on these results, we examined the effect of oltipraz on the experimental steatohepatitis in high-fat diet (containing 4% soybean oil and 20% lard) fed Nrf2-null mice. Oltipraz induced hepatic mRNA expression of peroxisome proliferator-activated receptor α, carnitine palmityl transferase 1, and bile salt export pump by Nrf2 independent mechanisms. In Nrf2-null mice fed a high-fat diet for 12 weeks, moderate to severe inflammation and fibrosis were observed. Oral administration of oltipraz suppressed the degree of inflammation and fibrosis in Nrf2-null mouse liver fed a high-fat diet. These histopathological findings approximately corresponded to the data of mRNA expression of tumor necrosis factor α, monocyte chemoattractant protein-1, Timp-1, and collagen type 1α1. These results indicated that oltipraz administration ameliorated liver injury by Nrf2 independent manner in a model of steatohepatitis generated by Nrf2-null mice with high-fat diet.     

Akt与Lpl在高脂饮食大鼠非酒精性脂肪肝形成中的作用

目的探讨丝氨酸/苏氨酸激酶(Akt)和脂蛋白脂酶(Lpl)在高脂饮食大鼠非酒精性脂肪肝(NASH)形成中的作用.方法 40只雄性Wistar大鼠随机分为8周高脂模型组(n=10)、8周正常对照组(n=10)、12周高脂模型组(n=10)以及12周正常对照组(n=10),检测血脂、胆固醇、血糖、胰岛素,并计算胰岛素抵抗指数(IRI);病理学免疫组化检测Akt和Lpl在肝脏的表达;透射电镜观察肝脏的形态学改变.结果 8周高脂模型组大鼠均个体肥胖,形成NASH,肝脏呈现体积增大、外形饱满圆钝、色泽灰黄、切面油腻、质地较脆等特点,并伴有高脂血症,以及肝细胞脂肪变性、肝小叶内炎症细胞浸润和肝细胞坏死;Akt和Lpl在肝脏表达明显减弱,且随着喂养时间的延长,血脂、胆固醇、血糖、胰岛素、IRI均渐进增高,而胰岛素敏感指数(ISI)降低,胰岛素抵抗形成,各组数据均与正常对照组有非常高度显著性差异(P＜0.0001).结论高脂喂养大鼠8周即可形成脂肪肝及胰岛素抵抗,致胰岛素活性和Lpl活性降低,脂肪分解障碍.     

An RNAi therapeutic targeting hepatic DGAT2 in a genetically obese mouse model of nonalcoholic steatohepatitis

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