2010年AASLD年會脂肪性肝病紀要

段曉燕 范建高

第61屆美國肝病研究學會（the American Association for the Study of Liver Diseases，AASLD）年會于 2010年10月28日至11月2日在美國波士頓召開。以下就本次會議上有關非酒精性脂肪性肝病（NAFLD）和酒精性肝?。ˋLD）的研究進展簡述如下：

一、NAFLD

（一）發(fā)病機制

1、炎癥 美國Csak通過體內(nèi)實驗證實NASH存在炎癥活動，而脂肪酸可通過致敏LPS誘導的肝細胞炎癥活動而參與NASH發(fā)生[1]。美國Zhang報道了小鼠缺乏硫酯酶超家族成員1（THEM1）/STARD14可對抗飲食誘導的肝脂變的發(fā)生，白色脂肪組織炎癥反應在其中起一定作用[2]。日本Kamada報道了雌激素缺乏可加劇高脂高膽固醇飲食喂養(yǎng)小鼠脂肪性肝炎的進展并可增加巨噬細胞浸潤[3]。英國Banz報道了枯否細胞依賴IL-17分泌和Th17細胞募集而促進鼠類NASH的發(fā)生[4]。美國Thapaliya通過體內(nèi)實驗證明了BAX激活在脂肪性肝炎發(fā)生中的作用[5]。

2、纖維化 美國Dixon報道了飲食誘導的脂肪性肝炎中半胱天冬酶1參與肝纖維形成的調(diào)節(jié)[6]。美國Rangwala報道了NASH時氣球樣變的肝細胞sonic hedgehog（SHH）產(chǎn)生增加與纖維化進展有關[7]。

3、細胞增殖和腫瘤 日本Kumamoto報道了飲食果糖而不是脂肪可影響二乙基亞硝胺誘導的大鼠肝腫瘤發(fā)生率[8]。德國Sydor報道了西餐可增加70%肝切除小鼠模型死亡受體和脂肪酸運載體的表達，并可致肝細胞增殖增加[9]。

4、免疫 日本Ikejima報道了自然殺傷細胞（NKT）缺失可增加小鼠對飲食誘導的脂肪性肝炎的易感性[10]。日本Sawada報道了高脂飲食誘導的NAFLD小鼠模型中，肝臟和腸道TLR信號分子的分布情況[11]。

5、氧應激 美國Ji報道了去除肝特異性關鍵分子伴侶GRP78/BIP可加劇急、慢性應激誘導的肝損傷[12]。美國Soon報道了應激信號通路在蛋氨酸膽堿缺乏飲食誘導的鼠類脂肪性肝病模型中的作用[13]。日本Kon報道了反式脂肪酸可通過加重KK-AY小鼠脂變肝臟的氧化應激而誘導肝細胞凋亡[14]。

6、遺傳和環(huán)境因素 美國Baffy報道了NAFLD發(fā)生是遺傳和環(huán)境因素相互作用的結(jié)果[15]。美國Dasarathy報道了在飲食誘導的NAFLD中，飲食和遺傳背景對肝microRNA的表達具有不同作用[16]。美國Pasricha報道了脂肪性肝病的數(shù)量性狀遺傳位點分析[17]。

7、血管反應 比利時Francque報道了特異性環(huán)氧合酶2相關機制介導肝脂變誘導的門脈高壓中血管的低反應性[18]。比利時Coulon報道了NASH小鼠模型存在肝血管發(fā)生及VEGF 的上調(diào)[19]。

8、代謝綜合征 美國Buck報道了TNF-α誘導的C/EBPβ絲氨酸-239磷酸化對肥胖和脂肪肝的發(fā)生是至關重要的[20]。美國Moylan報道了來自NAFLD患者纖維化肝臟的一些信號分子可能促進糖尿病和肥胖的發(fā)生[21]。比利時Lanthier報道了枯否細胞與脂肪組織之間的“對話”在IR發(fā)生中的作用[22]。美國Stoll報道了磷酸卵磷酯轉(zhuǎn)移蛋白（PC-TP）缺乏小鼠可對抗飲食誘導的由于肝糖產(chǎn)生減少所致的糖尿病[23]。美國Song報道了一種新的肥胖相關脂肪肝的機制，即高果糖喂養(yǎng)可致銅缺乏[24]。美國Siddiqui報道了高脂飲食喂養(yǎng)的A/J小鼠抗代謝綜合征，其SREBP-1c活性和功能降低[25]。

9、其他 美國Syn報道了骨橋蛋白可促進NAFLD進展[26]。澳大利亞Skoien通過體外實驗證實，脂肪酸誘導的肝細胞衰老參與NASH的發(fā)生[27]。德國Kanuri報道了纖溶酶原激活物抑制劑（PAI-1）、微粒體甘油三酯轉(zhuǎn)運蛋白（MTTP）以及NKT細胞在果糖誘導的小鼠肝脂變發(fā)生中的重要作用[28]。西班牙Ariazu報道了SPP1可促進蛋氨酸膽堿缺乏飲食喂養(yǎng)的小鼠NASH的發(fā)生[29]。美國Kang報道了硫酯酶超家族成員2（THEM2）與PC-TP相互作用可限制肝TG分泌[30]。德國Sydor報道了游離脂肪酸增加人原代培養(yǎng)肝細胞FABP-1和cFLIPL的表達，與介導細胞凋亡和ERK激活的死亡受體減少有關[31]。法國Zufiiga報道了維生素D受體失活可促進肝脂變的發(fā)生[32]。英國Lokman通過體外肝脂變模型證明了游離脂肪酸和活性氧對CIDE-B表達有影響[33]。美國Softic報道了胰島素信號分子會以U型劑量依賴的方式通過脂肪酸運載蛋白（FATPS）介導肝脂變的發(fā)生[34]。日本Imajo報道了在鼠類NASH模型中，脂多糖可誘導肝微粒體甘油三酯轉(zhuǎn)運蛋白mRNA水平降低以及肝組織病理學的進展[35]。

（二）新的NASH動物模型

美國Viker報道了用快餐飲食喂養(yǎng)小鼠復制了一種新NASH小動物模型，該模型類似于人類發(fā)病過程，伴有進展性肝纖維化[36]。美國Wu通過喂養(yǎng)小鼠含共軛亞油酸的飲食而復制了一種新的NASH模型[37]。美國Folli報道了在肥胖/胰島素抵抗的非人類靈長目動物中，狒狒作為一種NAFLD模型，其肝內(nèi)脂肪含量增加，胰島素信號級聯(lián)反應也受損[38]。

（三）治療

美國Gupta報道了GLP-1受體激動劑在減少遭受缺血再灌注損傷的ob/ob小鼠肝脂變和凋亡中的作用[39]。美國Rector報道了與熱量限制相比，每日運動可削弱OLETF大鼠體重的增加并預防NAFLD的發(fā)生[40]。西班牙Solís-Mufioz報道了褪黑激素對伴有NAFLD的ob/ob小鼠線粒體呼吸鏈復合體及肝病理的影響[41]。日本Ueno報道了脂聯(lián)素可抑制NASH中的內(nèi)質(zhì)網(wǎng)應激[42]。美國Liang報道了抗艾滋病新藥Raltegravir可通過增強自噬而阻止HIV蛋白酶抑制劑所致的肝脂變的發(fā)生[43]。日本Okada報道了羅蘇伐他汀可通過抑制NASH模型大鼠氧化應激而改善肝臟炎癥和纖維化[44]。以色列Adar報道了通過口服IgG強化初乳而誘導的CD4+CD25+FOXP3+調(diào)節(jié)性T細胞可抑制ob/ob小鼠慢性炎癥狀態(tài)，減輕胰島素抵抗和肝損傷[45]。美國Mells報道了每日給予C57BL6小鼠新型抗糖尿病藥利拉魯肽（liraglutide）可改善高果糖玉米糖漿和反式脂肪酸誘導的NAFLD的有害效應[46]。意大利Salamone報道了水飛薊素可改善NAFLD小鼠肝損傷和脂肪組織炎癥[47]。美國Trevaskis報道了艾塞那肽（exenatide）與西他列?。╯itagliptin）和匹格列酮相比具有顯著的對抗糖尿病性LEPOB/LEPOB小鼠肝脂變的作用[48]。法國Lavallard報道了自噬在NASH肝細胞死亡中的作用[49]。巴西Mazo報道了S-亞硝基-N-乙酰半胱氨酸（SNAC）可調(diào)節(jié)實驗性NASH模型肝星狀細胞活性，并有抗肝纖維化特性[50]。美國Derdak報道了P53抑制劑，P-硝基pifithrin-α可減輕小鼠NAFLD病變[51]。以色列Adar報道了增加的Akt磷酸化可改善胰島素抵抗及其相關的肝損傷，且口服胰島素與β糖脂具有協(xié)同作用[52]。日本Kajikawa報道了二十碳五烯酸對NASH肝纖維化大鼠模型的治療作用[53]。韓國Lee報道了水飛薊素對蛋氨酸膽堿缺乏飲食誘導的IR的NASH大鼠的治療作用[54]。美國Malhi報道了C/EBP可對抗小鼠NASH[55]。以色列Adar報道了類固醇誘導的IR及其相關的肝損傷可被β葡萄糖基神經(jīng)酰胺所逆轉(zhuǎn)，并指出這可作為NASH保肝治療的新輔助策略[56]。美國Trevaskis報道了GLP-1受體激動劑可改善NASH小鼠模型的生化學和組織學指標[57]。韓國Jun報道了肉毒堿可通過恢復異常線粒體功能而阻止游離脂肪酸誘導的肝臟脂毒性[58]。美國Setshedi報道了在體外肝切片培養(yǎng)模型中，神經(jīng)酰胺抑制劑和PPAR激動劑可減輕乙醇誘導的脂肪性肝炎[59]。

二、酒精性肝病

（一）基礎研究 美國Han報道了在ALD發(fā)生過程中，microRNAs在控制肝膽管細胞凋亡和轉(zhuǎn)化中的新作用[60]。臺灣Lin報道了增強自噬可減輕乙醇誘導的小鼠脂肪肝[61]。美國Ambade報道了靶向性熱休克蛋白90（HSP90），存在于酒精性肝損傷中的一種分子伴侶，可抑制脂多糖誘導的TNFα產(chǎn)生[62]。美國Levin報道了肝細胞缺氧誘導因子1α（HIF-1α）需要通過Toll樣受體4依賴的途徑才能激活，HIF-1α激活可致長期乙醇喂養(yǎng)的小鼠發(fā)生肝脂變[63]。美國Derdak報道了纖維化相關轉(zhuǎn)錄因子早期生長反應基因1（EGR-1）可通過激活固醇調(diào)節(jié)元件結(jié)合蛋白1（SREBP1）而促進乙醇喂養(yǎng)的Long Evans大鼠肝脂變的發(fā)生[64]。美國Kirpich報道了狂飲乙醇誘導的小泡性肝脂變和肝損傷與肝臟組蛋白去乙酰化酶（HDAC）1、7、9、10、11 下調(diào)以及 HDAC 3 上調(diào)有關[65]。美國Howarth報道了激活轉(zhuǎn)錄因子6（ATF-6）與非折疊蛋白反應（UPR）在急性乙醇誘導的斑馬魚肝脂變中起重要作用[66]。比利時Degré報道了趨化因子配體2（CCL2），亦即單核細胞趨化蛋白1（MCP-1），中性粒細胞募集與酒精性肝炎的疾病嚴重度有關，而IL-17依賴的途徑可能參與其中[67]。美國Ki報道了IL-22治療可減輕長期狂飲酒精所致的一種鼠類模型酒精性肝損傷，并證明信號轉(zhuǎn)導子和轉(zhuǎn)錄激活子3（STAT3）可能參與發(fā)病[68]。

（二）臨床研究 比利時Trépo報道了幾種常見的PNPLA3基因多態(tài)性與ALD肝脂變和纖維化的關系[69]。法國Louvet通過分析重度酒精性肝炎患者的長期資料，發(fā)現(xiàn)酒精復飲是存活的關鍵因素[70]。西班牙Altamirano報道了急性腎損傷（AKI）對酒精性肝炎患者的短期存活有負面影響，指出治療上應加以注意[71]。法國Louvet通過比較幾個現(xiàn)有的預后模型發(fā)現(xiàn)，預后積分可有效用于皮質(zhì)激素治療重度酒精性肝炎患者的預后評估[72]。法國Louvet報道了“應答指導治療”用于皮質(zhì)激素治療重度酒精性肝炎患者的臨床情況[73]。Hiramine報道了日本男性中飲酒患者以及脂肪肝的發(fā)生風險[74]。法國Amathieu報道了質(zhì)子磁共振波譜法檢測血液代謝化合物變化可用于酒精性肝硬化患者慢性肝衰竭的評估[75]。美國Ellefson報道了激素印跡影響酒精誘導的早期肝損傷[76]。法國Louvet進行了一項前瞻性研究，結(jié)果發(fā)現(xiàn)重度酒精性肝炎時肝靜脈壓力梯度與存活率無關[77]。美國Asrani進行了一項基于人群的關于酒精性肝炎患者存活率的研究[78]。美國Singal通過一項大型全國住院病人數(shù)據(jù)樣本研究，調(diào)查了HCV感染與急性酒精性肝炎嚴重度增加的關系[79]。美國Thuluvath報道了HCV和肝性腦病對確診的酒精性肝炎患者結(jié)局的影響[80]。Liangpunsakul報道了在美國住院的酒精性肝炎患者的臨床特征和死亡率[81]。

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