肾气丸对非酒精性脂肪性肝炎大鼠Bcl-2/Bax、Fas/FasL信号通路的影响

目的:观察Bcl-2/Bax、Fas/Fas L介导的信号转导通路在高脂饮食诱导的非酒精性脂肪性肝炎大鼠的作用及肾气丸对其的影响。方法:采用高脂饲料连续喂养12周建立大鼠非酒精性脂肪性肝炎模型,同时以肾气丸进行干预12周。HE染色观察大鼠肝组织病理组织学变化,免疫组织化学检测肝组织中Fas、Fas L、Bcl-2、Bax、Caspase-8蛋白的表达;Realtime-PCR法检测肝组织Caspase-8 mRNA表达。结果:模型组大鼠肝组织Bcl-2、Bax、Fas、Fas L蛋白以及Caspase-8 mRNA和蛋白表达均较正常组显著增加(P<0.01),Bcl-2/Bax比值较正常组明显的降低(P<0.05);大鼠肝组织Caspase-8蛋白表达与Fas、Fas L蛋白表达均呈明显正相关(r分别为0.907、0.804,P均<0.01);予以肾气丸干预后,Bax、Fas、Fas L蛋白的表达以及Caspase-8 mRNA和蛋白的表达均较模型组明显的降低(P<0.05),Bcl-2/Bax比值较模型组明显的增加(P<0.05),Bcl-2蛋白的表达与模型组比较差异无显著性意义(P>0.05)。结论:肾气丸可能通过影响Bcl-2/Bax、Fas/Fas L信号转导通路,下调Bax、Fas、Fas L、Caspase-8表达,减少肝细胞的脂性凋亡,从而防治大鼠非酒精性脂肪性肝炎的发生发展。     

大黄酸对大鼠非酒精性脂肪性肝炎的影响

非酒精性脂肪肝炎（NASH）是一种常见的肝病，可进展为终末期肝硬化。NASH目前缺乏有效的治疗手段。近年来，研究发现大黄酸具有广泛的药理作用，对NASH可能有治疗作用。但有关大黄酸对大鼠NASH防治作用的研究鲜见报道。[第一段]     

丹酚酸B对非酒精性脂肪性肝炎大鼠肝细胞凋亡的影响

目的探讨丹酚酸B对非酒精性脂肪性肝炎(NASH)大鼠肝细胞凋亡的影响及对NASH的治疗作用。方法清洁级雄性SD大鼠60只,随机分为对照组、NASH模型组、丹酚酸B治疗组,每组20只。对照组以普通饲料喂养,其余2组以高脂饲料连续喂养12周复制NASH模型。第13周开始治疗组每天以浓度为1 mg/ml的丹酚酸B溶液20 ml/kg灌胃,模型组以20 ml/kg蒸馏水灌胃。治疗12周后,处死大鼠,取血及肝组织,计算肝指数,检测血清ALT、AST、甘油三酯(TG)、总胆固醇(TC),观察肝组织病理学变化,免疫组织化学法检测肝组织细胞色素C(Cyt C)、caspase-3蛋白的表达,逆转录-聚合酶链反应(RT-PCR)检测肝组织p53、Bax、Bcl-2 mRNA的表达。结果模型组大鼠肝指数、ALT、AST、TG、TC较对照组增高,肝组织炎症明显;Cyt C及caspase-3蛋白表达增加(P值均0.01);Bcl-2 mRNA表达降低,p53、Bax mRNA表达增高(P值均0.01)。治疗组与模型组相比肝指数、ALT、AST、TG、TC降低,炎症减轻;Cyt C及caspase-3蛋白表达减少(P值均0.01);Bcl-2 mRNA表达升高(P0.05),p53 mRNA表达降低(P0.05),Bax mRNA表达降低(P0.01)。结论丹酚酸B可通过调节Bcl-2、p53、Bax mRNA表达,降低Cyt C及caspase-3蛋白的表达,抑制肝细胞凋亡,对NASH起治疗作用。     

儿童非酒精性脂肪性肝炎

作为非酒精性脂肪性肝病(nonalcoholic fatty liver disease NAFLD)的一种组织学类型,非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)的概念于1980年首次被提出。当时其特指那些组织学肝损害与酒精性脂肪性肝炎相似而又无过量饮酒史的成人患者。3年后又首次报道该病也可发生于儿童,该报道中的2例男孩和一名女孩均患有无其他原因可解释的肝病,其组织学与成人NASH相似。目前,NASH已成为全球性问题,而人们最为关心的是该病可进展为肝硬化,甚至有8岁儿童患NASH肝硬化的个案报告。     

非酒精性脂肪性肝病与肝细胞凋亡调控机制的研究进展

非酒精性脂肪性肝病的发病机制至今尚不十分清楚.近年来众多研究表明,本病存在肝细胞凋亡的异常,说明肝细胞凋亡与本病的发生密切相关.调控细胞凋亡的机制可分正向/负向两个方面的调控因素.本文就近几年在非酒精性脂肪性肝病肝细胞凋亡调控机制方面的研究进展作一综述.     

活化胆碱能抗炎通路对非酒精性脂肪性肝炎炎症反应的抑制作用及其机制

目的 探讨活化胆碱能抗炎通路对非酒精性脂肪性肝炎(NASH)炎症反应的抑制作用及其机制. 方法 建立高脂高糖饮食诱导的NASH小鼠模型,在正常小鼠和NASH小鼠给予烟碱活化胆碱能抗炎通路,通过肝脏病理切片和细胞因子水平观察肝脏炎症情况;体外培养肝脏巨噬细胞系Raw264.7细胞,给予脂多糖处理后加入不同浓度的烟碱,观察细胞上清液中细胞因子肿瘤坏死因子(TNF)α的水平,通过Western blot观察烟碱对信号通路NF-κB和IκB的影响.多组间比较采用单因素方差分析. 结果 通过肝脏病理检查和肝功能生物化学指标检测确定造模成功.NASH小鼠给予烟碱激活胆碱能抗炎通路后,肝组织炎症程度下降;血清中TNFα水平,烟碱治疗组[(21.95±0.8)pg/ml]较等渗盐水组[(38.07±1.7) pg/ml]显著下降(P＜0.05).Raw264.7细胞给予脂多糖处理后加入不同浓度的烟碱后检测上清液中TNFα水平,发现加入5 mmol/L以上浓度烟碱后能明显降低脂多糖引起的TNFα增高(P＜0.05).内毒素刺激后RAw264.7细胞内p-NF-κB水平增加,I-κB水平降低,表明NF-κB通路激活,不同剂量的烟碱能明显下调p-NF-κB水平,升高I-κB水平,并表现出剂量依赖. 结论 活化胆碱能抗炎通路对NASH炎症反应有抑制作用,其作用机制可能为通过NF-κB信号通路抑制炎症反应.     

Fas及其配体诱导非酒精性脂肪性肝炎肝细胞凋亡

脂肪肝的发病日趋增多，在常规行肝穿刺活检患者中1．2％～9％患有非酒精性脂肪性肝炎（NASH），15％～50％的肝硬化与NASH有关。目前，NASH的发病机制尚不清楚。有研究报道NASH肝组织中肝细胞凋亡突出，但关于肝细胞凋亡在NASH发病中的作用及其调节机制有待研究。因此，我们采用高脂、胆碱一甲硫氨酸缺乏饮食（high fat，methionine and choline deficient diet，MCD）方法建立小鼠NASH模型，以探讨凋亡相关基因Fas及其配体（FasL）在NASH中与细胞凋亡及病情进展的关系。     

非酒精性脂肪性肝炎的病理学诊断

非酒精性脂肪性肝病（NAFLD）是肝细胞脂肪变、小叶内和汇管区炎症、肝细胞损伤（如肝细胞气球样变和凋亡）以及纤维化等病变的不同组合。儿童NAFLD的肝脏组织学改变与成人有所不同。肝活检组织学检查是诊断NAFLD的金标准,可区分单纯性脂肪肝与非酒精性脂肪性肝炎（NASH）以及判断肝纤维化程度。本文主要介绍NAFLD肝组织活动性分级和纤维化分期的国际通用评分系统。     

护肝宁片治疗非酒精性脂肪肝疗效观察

[目的]观察护肝宁片治疗非酒精性脂肪肝(NASH)的疗效.[方法]将165例NASH患者随机分为治疗组(110例)和对照组(55例),分别应用护肝宁片和硫普罗宁片治疗.观察两组患者治疗前及治疗6、12周时,肝功能及血脂指标的变化.[结果]两组患者治疗后的肝功能及血脂指标与治疗前比较均得到明显改善(P＜0.05);在治疗后6周及12周时,治疗组与对照组肝功能指标的比较差异无统计学意义(P＞0.05);治疗组治疗后12周时,三酰甘油(TG)降低,与对照组比较差异有统计学意义(P＜0.05).[结论]护肝宁片治疗NASH疗效明显,显著改善患者肝功能;且降低TG的疗效及安全性优于硫普罗宁片,值得临床上推广应用.     

姜黄素对NASH肝细胞凋亡及JNK信号通路的影响

目的:探讨姜黄素对非酒精性脂肪性肝炎(NASH)的抗肝细胞凋亡作用及其对JNK信号通路的影响。方法:将HL-7702细胞分为对照组、模型组、低剂量治疗组及高剂量治疗组,对照组予普通培养液培养,模型组培养液中加入浓度为1.0 mmol/L的游离脂肪酸(FFA)诱导NASH模型,高、低剂量治疗组在模型组的基础上分别加入浓度为10μmol/L、20μmol/L的姜黄素干预,48 h后采用流式细胞术检测细胞凋亡情况,Western Blot法检测p-JNK蛋白的表达情况。结果:模型组肝细胞的早期及总凋亡率均明显高于对照组(均P<0.05),高、低剂量治疗组与模型组相比,肝细胞早期及总凋亡率均明显降低(均P<0.05)。模型组肝细胞的p-JNK蛋白表达明显高于对照组(P<0.05),治疗组的p-JNK表达较模型组显著下降(P<0.05),且呈剂量相关。结论:姜黄素可抑制JNK的活化,这可能是其抗细胞凋亡、延缓NASH进展的机制之一。     

荷丹片对非酒精性脂肪性肝炎大鼠脂代谢的影响

[目的]观察荷丹片对非酒精性脂肪性肝炎(NASH)大鼠脂代谢的干预作用。[方法]雄性SD大鼠40只,随机分为4组:正常组、模型组、阳性对照组和治疗组。除正常组外,其余各组给予高脂饲料喂养,8周后开始药物灌胃干预,治疗4周后处死全部动物,应用全自动生化分析仪进行血清生化指标检测,油红0染色光镜下观察大鼠肝细胞脂肪变性情况。[结果]与模型组相比,荷丹片治疗后可明显减低NASH大鼠血清中丙氨酸氨基转移酶、天冬氨酸转氨酶和三酰甘油水平,升高高密度脂蛋白胆固醇水平。光镜观察荷丹片能明显缓解NASH大鼠肝细胞脂肪变性。[结论]荷丹片对高脂饮食诱导的大鼠NASH有一定的治疗作用。     

健脾疏肝方对非酒精性脂肪性肝炎大鼠肝脂代谢分子网络的影响

目的:观察健脾疏肝方对非酒精性脂肪性肝炎(non-alcoholic steatohepatitis,NASH)的疗效以及对NASH大鼠肝脂代谢分子网络的影响.方法:将40只♂SD大鼠随机分成空白组、模型组、健脾疏肝方组、易善复组4组,采用高脂饲料造模连续8wk.模型成立后,改用普通饲料饲喂,同时健脾疏肝方组及易善复组分别予健脾疏肝方浸膏和易善复混悬液灌胃,模型组和空白组予去离子水灌胃,连续4wk;实验结束后处死全部大鼠,观察大鼠肝组织病理改变,测定大鼠肝功、血脂、肝脂以及抗氧化指标水平,观察大鼠肝组织SREBP-1c、SCAP、PPAR、PGC-1、LXR mRNA表达.结果:健脾疏肝方可有效改善大鼠肝组织脂肪变性及炎症损伤,降低肝功、血脂、肝脂水平,提高抗氧化物质,并可同时上调PPAR及PGC-1,下调SREBP-1c及SCAP mRNA表达(P<0.05,P<0.01),且在改善大鼠肝指数、体质量,降低谷丙转氨酶(ALT)水平、肝甘油三酯(TG)、MDA含量,提高GSH-PX含量,上调PPAR、PGC-1mRNA表达等方面优于易善复(P<0.05,P<0.01).结论:健脾疏肝方可通过网络调控NASH肝脂代谢而防治NASH,在今后研究中,可将健脾疏肝方作为基础,结合其他治法,辨证施治.     

Treatment of nonalcoholic steatohepatitis with colestimide

Aim: To clarify the usefulness of colestimide in patients with nonalcoholic steatohepatitis (NASH) with hyperlipidemia. Methods: In an open‐label randomized controlled trial, 17 NASH patients with hyperlipidemia received colestimide (3 g/day) for 24 weeks. There were 21 control patients. All patients received lifestyle modification therapy. Efficacy was assessed based on metabolic profile, insulin resistance, transaminases, serum hepatic fibrosis markers, adipokine levels, visceral fat on computed tomography (CT), and the fatty liver grade on CT. NASH patients with moderate to severe steatosis by histology were also evaluated separately. Results: Baseline clinical characteristics of the two groups were similar. Both groups experienced a significant decrease of BMI with no difference between them. However, visceral fat decreased significantly more in the colestimide group (P = 0.046). Aspartate aminotransferase (AST) showed a significantly greater decrease in the colestimide group compared with the control group (P = 0.042). In patients with moderate to severe histological steatosis, there were significant differences between the two groups regard to HbA_1c, transaminases, and hyaluronic acid (P = 0.018 for HbA_1c, P = 0.003 for AST, P = 0.042 for alanine aminotransferase, and P = 0.042 for hyaluronic acid). Steatosis significantly improved in patients in the colestimide group who had fatty liver on CT (P = 0.049). In the colestimide group, abdominal distension and/or constipation were seen, but mostly tolerable, no other clinical or laboratory adverse events associated with the use of this medicine were not observed. Conclusions: Colestimide seems to increase the efficacy of lifestyle modification in NASH patients with hyperlipidemia. Its beneficial effects were more prominent in NASH patients with moderate to severe histological steatosis.     

Non-invasive diagnosis of nonalcoholic fatty liver and nonalcoholic steatohepatitis

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the USA and many other parts of the world. Its prevalence continues to rise; currently affecting about one in four adults and 10% of children in the USA. NAFLD represents a wide spectrum of conditions ranging from fatty liver, which in general follows a benign, no-progressive clinical course, to nonalcoholic steatohepatitis (NASH), a more serious form of NAFLD that may progress to cirrhosis and end-stage liver disease. Currently, the diagnosis of NASH requires an invasive liver biopsy with drawbacks of sampling and interpretation error. Clinical risk factors for NASH include diabetes and the metabolic syndrome; however, these are not sufficiently predictive of the condition by themselves. Routine liver enzyme levels are not reliable; however, novel plasma hepatocyte cell death markers either alone or in combination with clinical risk factors are potential non-invasive diagnostic tools for the future. This review provides a concise overview of the role non-invasive diagnostic tools for the differentiation of fatty liver from NASH as well as for the determination of presence and extent of fibrosis.     

疏肝消脂颗粒剂治疗非酒精性脂肪性肝炎的临床疗效观察

目的：观察疏肝消脂颗粒剂治疗非酒精性脂肪性肝炎的临床疗效.方法：选择非酒精性脂肪性肝炎患者120例,随机分为治疗组（60例）,对照组（60例）,其中治疗组用疏肝消脂颗粒剂冲服,对照组用多烯磷脂酰胆碱胶囊治疗.两组患者治疗3个月,分别观察其临床症状和体征、肝功能、血脂等指标的变化情况.结果：两组患者临床症状皆能改善,治疗组疗效优于对照组;在改善肝功能、血脂方面,两组患者治疗后均较治疗前有明显改善,差异均有显著性意义（P＜0.05）,治疗组疗效优于对照组,差异有显著性意义（P＜0.05）.结论：疏肝消脂颗粒剂治疗非酒精性脂肪性肝炎的临床疗效确切,可改善患者临床症状和体征、降低肝功能及血脂指标,其疗效优于多烯磷脂酰胆碱胶囊.     

Hepatocellular carcinoma with nonalcoholic steatohepatitis

Nonalcoholic steatohepatitis (NASH) was originally believed to be a benign disease. However, it has been recently revealed that NASH could lead to irreversible liver disease in some patients. We report an unusual case of hepatocellular carcinoma (HCC) in a 76-year-old man with NASH. He had no history of alcohol consumption, drug use, or blood transfusion. He was negative for all serological viral markers and autoantibodies. In addition, he was obese (body mass index [BMI], 30.75kg/m²) and had type 2 diabetes mellitus. A liver biopsy specimen showed moderate steatosis with necroinflammatory changes, ballooning degeneration, Mallory bodies, pericellular fibrosis, and evidence of nodular regeneration. He was diagnosed with NASH with cirrhosis. Simultaneously, a liver tumor, measuring 19mm in diameter, was detected in segment 6. A tumor biopsy specimen revealed well-differentiated HCC, and imaging modalities confirmed the characteristics of HCC. To our knowledge, ten patients who had HCC with NASH were reported. In all patients with NASH and HCC, cirrhosis was present. Patients with NASH and cirrhosis may progress to HCC, and regular screening, based on tumor markers and imaging modalities, is needed to detect HCC in patients with NASH and cirrhosis.