2010年AASLD年会脂肪性肝病纪要

段晓燕 范建高

第61届美国肝病研究学会（the American Association for the Study of Liver Diseases，AASLD）年会于 2010年10月28日至11月2日在美国波士顿召开。以下就本次会议上有关非酒精性脂肪性肝病（NAFLD）和酒精性肝病（ALD）的研究进展简述如下：

一、NAFLD

（一）发病机制

1、炎症 美国Csak通过体内实验证实NASH存在炎症活动，而脂肪酸可通过致敏LPS诱导的肝细胞炎症活动而参与NASH发生[1]。美国Zhang报道了小鼠缺乏硫酯酶超家族成员1（THEM1）/STARD14可对抗饮食诱导的肝脂变的发生，白色脂肪组织炎症反应在其中起一定作用[2]。日本Kamada报道了雌激素缺乏可加剧高脂高胆固醇饮食喂养小鼠脂肪性肝炎的进展并可增加巨噬细胞浸润[3]。英国Banz报道了枯否细胞依赖IL-17分泌和Th17细胞募集而促进鼠类NASH的发生[4]。美国Thapaliya通过体内实验证明了BAX激活在脂肪性肝炎发生中的作用[5]。

2、纤维化 美国Dixon报道了饮食诱导的脂肪性肝炎中半胱天冬酶1参与肝纤维形成的调节[6]。美国Rangwala报道了NASH时气球样变的肝细胞sonic hedgehog（SHH）产生增加与纤维化进展有关[7]。

3、细胞增殖和肿瘤 日本Kumamoto报道了饮食果糖而不是脂肪可影响二乙基亚硝胺诱导的大鼠肝肿瘤发生率[8]。德国Sydor报道了西餐可增加70%肝切除小鼠模型死亡受体和脂肪酸运载体的表达，并可致肝细胞增殖增加[9]。

4、免疫 日本Ikejima报道了自然杀伤细胞（NKT）缺失可增加小鼠对饮食诱导的脂肪性肝炎的易感性[10]。日本Sawada报道了高脂饮食诱导的NAFLD小鼠模型中，肝脏和肠道TLR信号分子的分布情况[11]。

5、氧应激 美国Ji报道了去除肝特异性关键分子伴侣GRP78/BIP可加剧急、慢性应激诱导的肝损伤[12]。美国Soon报道了应激信号通路在蛋氨酸胆碱缺乏饮食诱导的鼠类脂肪性肝病模型中的作用[13]。日本Kon报道了反式脂肪酸可通过加重KK-AY小鼠脂变肝脏的氧化应激而诱导肝细胞凋亡[14]。

6、遗传和环境因素 美国Baffy报道了NAFLD发生是遗传和环境因素相互作用的结果[15]。美国Dasarathy报道了在饮食诱导的NAFLD中，饮食和遗传背景对肝microRNA的表达具有不同作用[16]。美国Pasricha报道了脂肪性肝病的数量性状遗传位点分析[17]。

7、血管反应 比利时Francque报道了特异性环氧合酶2相关机制介导肝脂变诱导的门脉高压中血管的低反应性[18]。比利时Coulon报道了NASH小鼠模型存在肝血管发生及VEGF 的上调[19]。

8、代谢综合征 美国Buck报道了TNF-α诱导的C/EBPβ丝氨酸-239磷酸化对肥胖和脂肪肝的发生是至关重要的[20]。美国Moylan报道了来自NAFLD患者纤维化肝脏的一些信号分子可能促进糖尿病和肥胖的发生[21]。比利时Lanthier报道了枯否细胞与脂肪组织之间的“对话”在IR发生中的作用[22]。美国Stoll报道了磷酸卵磷酯转移蛋白（PC-TP）缺乏小鼠可对抗饮食诱导的由于肝糖产生减少所致的糖尿病[23]。美国Song报道了一种新的肥胖相关脂肪肝的机制，即高果糖喂养可致铜缺乏[24]。美国Siddiqui报道了高脂饮食喂养的A/J小鼠抗代谢综合征，其SREBP-1c活性和功能降低[25]。

9、其他 美国Syn报道了骨桥蛋白可促进NAFLD进展[26]。澳大利亚Skoien通过体外实验证实，脂肪酸诱导的肝细胞衰老参与NASH的发生[27]。德国Kanuri报道了纤溶酶原激活物抑制剂（PAI-1）、微粒体甘油三酯转运蛋白（MTTP）以及NKT细胞在果糖诱导的小鼠肝脂变发生中的重要作用[28]。西班牙Ariazu报道了SPP1可促进蛋氨酸胆碱缺乏饮食喂养的小鼠NASH的发生[29]。美国Kang报道了硫酯酶超家族成员2（THEM2）与PC-TP相互作用可限制肝TG分泌[30]。德国Sydor报道了游离脂肪酸增加人原代培养肝细胞FABP-1和cFLIPL的表达，与介导细胞凋亡和ERK激活的死亡受体减少有关[31]。法国Zufiiga报道了维生素D受体失活可促进肝脂变的发生[32]。英国Lokman通过体外肝脂变模型证明了游离脂肪酸和活性氧对CIDE-B表达有影响[33]。美国Softic报道了胰岛素信号分子会以U型剂量依赖的方式通过脂肪酸运载蛋白（FATPS）介导肝脂变的发生[34]。日本Imajo报道了在鼠类NASH模型中，脂多糖可诱导肝微粒体甘油三酯转运蛋白mRNA水平降低以及肝组织病理学的进展[35]。

（二）新的NASH动物模型

美国Viker报道了用快餐饮食喂养小鼠复制了一种新NASH小动物模型，该模型类似于人类发病过程，伴有进展性肝纤维化[36]。美国Wu通过喂养小鼠含共轭亚油酸的饮食而复制了一种新的NASH模型[37]。美国Folli报道了在肥胖/胰岛素抵抗的非人类灵长目动物中，狒狒作为一种NAFLD模型，其肝内脂肪含量增加，胰岛素信号级联反应也受损[38]。

（三）治疗

美国Gupta报道了GLP-1受体激动剂在减少遭受缺血再灌注损伤的ob/ob小鼠肝脂变和凋亡中的作用[39]。美国Rector报道了与热量限制相比，每日运动可削弱OLETF大鼠体重的增加并预防NAFLD的发生[40]。西班牙Solís-Mufioz报道了褪黑激素对伴有NAFLD的ob/ob小鼠线粒体呼吸链复合体及肝病理的影响[41]。日本Ueno报道了脂联素可抑制NASH中的内质网应激[42]。美国Liang报道了抗艾滋病新药Raltegravir可通过增强自噬而阻止HIV蛋白酶抑制剂所致的肝脂变的发生[43]。日本Okada报道了罗苏伐他汀可通过抑制NASH模型大鼠氧化应激而改善肝脏炎症和纤维化[44]。以色列Adar报道了通过口服IgG强化初乳而诱导的CD4+CD25+FOXP3+调节性T细胞可抑制ob/ob小鼠慢性炎症状态，减轻胰岛素抵抗和肝损伤[45]。美国Mells报道了每日给予C57BL6小鼠新型抗糖尿病药利拉鲁肽（liraglutide）可改善高果糖玉米糖浆和反式脂肪酸诱导的NAFLD的有害效应[46]。意大利Salamone报道了水飞蓟素可改善NAFLD小鼠肝损伤和脂肪组织炎症[47]。美国Trevaskis报道了艾塞那肽（exenatide）与西他列汀（sitagliptin）和匹格列酮相比具有显著的对抗糖尿病性LEPOB/LEPOB小鼠肝脂变的作用[48]。法国Lavallard报道了自噬在NASH肝细胞死亡中的作用[49]。巴西Mazo报道了S-亚硝基-N-乙酰半胱氨酸（SNAC）可调节实验性NASH模型肝星状细胞活性，并有抗肝纤维化特性[50]。美国Derdak报道了P53抑制剂，P-硝基pifithrin-α可减轻小鼠NAFLD病变[51]。以色列Adar报道了增加的Akt磷酸化可改善胰岛素抵抗及其相关的肝损伤，且口服胰岛素与β糖脂具有协同作用[52]。日本Kajikawa报道了二十碳五烯酸对NASH肝纤维化大鼠模型的治疗作用[53]。韩国Lee报道了水飞蓟素对蛋氨酸胆碱缺乏饮食诱导的IR的NASH大鼠的治疗作用[54]。美国Malhi报道了C/EBP可对抗小鼠NASH[55]。以色列Adar报道了类固醇诱导的IR及其相关的肝损伤可被β葡萄糖基神经酰胺所逆转，并指出这可作为NASH保肝治疗的新辅助策略[56]。美国Trevaskis报道了GLP-1受体激动剂可改善NASH小鼠模型的生化学和组织学指标[57]。韩国Jun报道了肉毒碱可通过恢复异常线粒体功能而阻止游离脂肪酸诱导的肝脏脂毒性[58]。美国Setshedi报道了在体外肝切片培养模型中，神经酰胺抑制剂和PPAR激动剂可减轻乙醇诱导的脂肪性肝炎[59]。

二、酒精性肝病

（一）基础研究 美国Han报道了在ALD发生过程中，microRNAs在控制肝胆管细胞凋亡和转化中的新作用[60]。台湾Lin报道了增强自噬可减轻乙醇诱导的小鼠脂肪肝[61]。美国Ambade报道了靶向性热休克蛋白90（HSP90），存在于酒精性肝损伤中的一种分子伴侣，可抑制脂多糖诱导的TNFα产生[62]。美国Levin报道了肝细胞缺氧诱导因子1α（HIF-1α）需要通过Toll样受体4依赖的途径才能激活，HIF-1α激活可致长期乙醇喂养的小鼠发生肝脂变[63]。美国Derdak报道了纤维化相关转录因子早期生长反应基因1（EGR-1）可通过激活固醇调节元件结合蛋白1（SREBP1）而促进乙醇喂养的Long Evans大鼠肝脂变的发生[64]。美国Kirpich报道了狂饮乙醇诱导的小泡性肝脂变和肝损伤与肝脏组蛋白去乙酰化酶（HDAC）1、7、9、10、11 下调以及 HDAC 3 上调有关[65]。美国Howarth报道了激活转录因子6（ATF-6）与非折叠蛋白反应（UPR）在急性乙醇诱导的斑马鱼肝脂变中起重要作用[66]。比利时Degré报道了趋化因子配体2（CCL2），亦即单核细胞趋化蛋白1（MCP-1），中性粒细胞募集与酒精性肝炎的疾病严重度有关，而IL-17依赖的途径可能参与其中[67]。美国Ki报道了IL-22治疗可减轻长期狂饮酒精所致的一种鼠类模型酒精性肝损伤，并证明信号转导子和转录激活子3（STAT3）可能参与发病[68]。

（二）临床研究 比利时Trépo报道了几种常见的PNPLA3基因多态性与ALD肝脂变和纤维化的关系[69]。法国Louvet通过分析重度酒精性肝炎患者的长期资料，发现酒精复饮是存活的关键因素[70]。西班牙Altamirano报道了急性肾损伤（AKI）对酒精性肝炎患者的短期存活有负面影响，指出治疗上应加以注意[71]。法国Louvet通过比较几个现有的预后模型发现，预后积分可有效用于皮质激素治疗重度酒精性肝炎患者的预后评估[72]。法国Louvet报道了“应答指导治疗”用于皮质激素治疗重度酒精性肝炎患者的临床情况[73]。Hiramine报道了日本男性中饮酒患者以及脂肪肝的发生风险[74]。法国Amathieu报道了质子磁共振波谱法检测血液代谢化合物变化可用于酒精性肝硬化患者慢性肝衰竭的评估[75]。美国Ellefson报道了激素印迹影响酒精诱导的早期肝损伤[76]。法国Louvet进行了一项前瞻性研究，结果发现重度酒精性肝炎时肝静脉压力梯度与存活率无关[77]。美国Asrani进行了一项基于人群的关于酒精性肝炎患者存活率的研究[78]。美国Singal通过一项大型全国住院病人数据样本研究，调查了HCV感染与急性酒精性肝炎严重度增加的关系[79]。美国Thuluvath报道了HCV和肝性脑病对确诊的酒精性肝炎患者结局的影响[80]。Liangpunsakul报道了在美国住院的酒精性肝炎患者的临床特征和死亡率[81]。

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