段曉燕 范建高

第61屆美國(guó)肝病研究學(xué)會(huì)（the American Association for the Study of Liver Diseases，AASLD）年會(huì)于 2010年10月28日至11月2日在美國(guó)波士頓召開。以下就本次會(huì)議上有關(guān)非酒精性脂肪性肝?。∟AFLD）和酒精性肝?。ˋLD）的研究進(jìn)展簡(jiǎn)述如下：

一、NAFLD

（一）發(fā)病機(jī)制

1、炎癥 美國(guó)Csak通過(guò)體內(nèi)實(shí)驗(yàn)證實(shí)NASH存在炎癥活動(dòng)，而脂肪酸可通過(guò)致敏LPS誘導(dǎo)的肝細(xì)胞炎癥活動(dòng)而參與NASH發(fā)生[1]。美國(guó)Zhang報(bào)道了小鼠缺乏硫酯酶超家族成員1（THEM1）/STARD14可對(duì)抗飲食誘導(dǎo)的肝脂變的發(fā)生，白色脂肪組織炎癥反應(yīng)在其中起一定作用[2]。日本Kamada報(bào)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(jìn)展并可增加巨噬細(xì)胞浸潤(rùn)[3]。英國(guó)Banz報(bào)道了枯否細(xì)胞依賴IL-17分泌和Th17細(xì)胞募集而促進(jìn)鼠類NASH的發(fā)生[4]。美國(guó)Thapaliya通過(guò)體內(nèi)實(shí)驗(yàn)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(guó)Dixon報(bào)道了飲食誘導(dǎo)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(guó)Rangwala報(bào)道了NASH時(shí)氣球樣變的肝細(xì)胞sonic hedgehog（SHH）產(chǎn)生增加與纖維化進(jìn)展有關(guān)[7]。

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

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

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

6、遺傳和環(huán)境因素 美國(guó)Baffy報(bào)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(guó)Dasarathy報(bào)道了在飲食誘導(dǎo)的NAFLD中，飲食和遺傳背景對(duì)肝microRNA的表達(dá)具有不同作用[16]。美國(guó)Pasricha報(bào)道了脂肪性肝病的數(shù)量性狀遺傳位點(diǎn)分析[17]。

7、血管反應(yīng) 比利時(shí)Francque報(bào)道了特異性環(huán)氧合酶2相關(guān)機(jī)制介導(dǎo)肝脂變誘導(dǎo)的門脈高壓中血管的低反應(yīng)性[18]。比利時(shí)Coulon報(bào)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(guó)Buck報(bào)道了TNF-α誘導(dǎo)的C/EBPβ絲氨酸-239磷酸化對(duì)肥胖和脂肪肝的發(fā)生是至關(guān)重要的[20]。美國(guó)Moylan報(bào)道了來(lái)自NAFLD患者纖維化肝臟的一些信號(hào)分子可能促進(jìn)糖尿病和肥胖的發(fā)生[21]。比利時(shí)Lanthier報(bào)道了枯否細(xì)胞與脂肪組織之間的“對(duì)話”在IR發(fā)生中的作用[22]。美國(guó)Stoll報(bào)道了磷酸卵磷酯轉(zhuǎn)移蛋白（PC-TP）缺乏小鼠可對(duì)抗飲食誘導(dǎo)的由于肝糖產(chǎn)生減少所致的糖尿病[23]。美國(guó)Song報(bào)道了一種新的肥胖相關(guān)脂肪肝的機(jī)制，即高果糖喂養(yǎng)可致銅缺乏[24]。美國(guó)Siddiqui報(bào)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(guó)Syn報(bào)道了骨橋蛋白可促進(jìn)NAFLD進(jìn)展[26]。澳大利亞Skoien通過(guò)體外實(shí)驗(yàn)證實(shí)，脂肪酸誘導(dǎo)的肝細(xì)胞衰老參與NASH的發(fā)生[27]。德國(guó)Kanuri報(bào)道了纖溶酶原激活物抑制劑（PAI-1）、微粒體甘油三酯轉(zhuǎn)運(yùn)蛋白（MTTP）以及NKT細(xì)胞在果糖誘導(dǎo)的小鼠肝脂變發(fā)生中的重要作用[28]。西班牙Ariazu報(bào)道了SPP1可促進(jìn)蛋氨酸膽堿缺乏飲食喂養(yǎng)的小鼠NASH的發(fā)生[29]。美國(guó)Kang報(bào)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(guó)Sydor報(bào)道了游離脂肪酸增加人原代培養(yǎng)肝細(xì)胞FABP-1和cFLIPL的表達(dá)，與介導(dǎo)細(xì)胞凋亡和ERK激活的死亡受體減少有關(guān)[31]。法國(guó)Zufiiga報(bào)道了維生素D受體失活可促進(jìn)肝脂變的發(fā)生[32]。英國(guó)Lokman通過(guò)體外肝脂變模型證明了游離脂肪酸和活性氧對(duì)CIDE-B表達(dá)有影響[33]。美國(guó)Softic報(bào)道了胰島素信號(hào)分子會(huì)以U型劑量依賴的方式通過(guò)脂肪酸運(yùn)載蛋白（FATPS）介導(dǎo)肝脂變的發(fā)生[34]。日本Imajo報(bào)道了在鼠類NASH模型中，脂多糖可誘導(dǎo)肝微粒體甘油三酯轉(zhuǎn)運(yùn)蛋白mRNA水平降低以及肝組織病理學(xué)的進(jìn)展[35]。

（二）新的NASH動(dòng)物模型

美國(guó)Viker報(bào)道了用快餐飲食喂養(yǎng)小鼠復(fù)制了一種新NASH小動(dòng)物模型，該模型類似于人類發(fā)病過(guò)程，伴有進(jìn)展性肝纖維化[36]。美國(guó)Wu通過(guò)喂養(yǎng)小鼠含共軛亞油酸的飲食而復(fù)制了一種新的NASH模型[37]。美國(guó)Folli報(bào)道了在肥胖/胰島素抵抗的非人類靈長(zhǎng)目動(dòng)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(hào)級(jí)聯(lián)反應(yīng)也受損[38]。

（三）治療

美國(guó)Gupta報(bào)道了GLP-1受體激動(dòng)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(guó)Rector報(bào)道了與熱量限制相比，每日運(yùn)動(dòng)可削弱OLETF大鼠體重的增加并預(yù)防NAFLD的發(fā)生[40]。西班牙Solís-Mufioz報(bào)道了褪黑激素對(duì)伴有NAFLD的ob/ob小鼠線粒體呼吸鏈復(fù)合體及肝病理的影響[41]。日本Ueno報(bào)道了脂聯(lián)素可抑制NASH中的內(nèi)質(zhì)網(wǎng)應(yīng)激[42]。美國(guó)Liang報(bào)道了抗艾滋病新藥Raltegravir可通過(guò)增強(qiáng)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(bào)道了羅蘇伐他汀可通過(guò)抑制NASH模型大鼠氧化應(yīng)激而改善肝臟炎癥和纖維化[44]。以色列Adar報(bào)道了通過(guò)口服IgG強(qiáng)化初乳而誘導(dǎo)的CD4+CD25+FOXP3+調(diào)節(jié)性T細(xì)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(guó)Mells報(bào)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(dǎo)的NAFLD的有害效應(yīng)[46]。意大利Salamone報(bào)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(guó)Trevaskis報(bào)道了艾塞那肽（exenatide）與西他列汀（sitagliptin）和匹格列酮相比具有顯著的對(duì)抗糖尿病性LEPOB/LEPOB小鼠肝脂變的作用[48]。法國(guó)Lavallard報(bào)道了自噬在NASH肝細(xì)胞死亡中的作用[49]。巴西Mazo報(bào)道了S-亞硝基-N-乙酰半胱氨酸（SNAC）可調(diào)節(jié)實(shí)驗(yàn)性NASH模型肝星狀細(xì)胞活性，并有抗肝纖維化特性[50]。美國(guó)Derdak報(bào)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(bào)道了增加的Akt磷酸化可改善胰島素抵抗及其相關(guān)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(bào)道了二十碳五烯酸對(duì)NASH肝纖維化大鼠模型的治療作用[53]。韓國(guó)Lee報(bào)道了水飛薊素對(duì)蛋氨酸膽堿缺乏飲食誘導(dǎo)的IR的NASH大鼠的治療作用[54]。美國(guó)Malhi報(bào)道了C/EBP可對(duì)抗小鼠NASH[55]。以色列Adar報(bào)道了類固醇誘導(dǎo)的IR及其相關(guān)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(guó)Trevaskis報(bào)道了GLP-1受體激動(dòng)劑可改善NASH小鼠模型的生化學(xué)和組織學(xué)指標(biāo)[57]。韓國(guó)Jun報(bào)道了肉毒堿可通過(guò)恢復(fù)異常線粒體功能而阻止游離脂肪酸誘導(dǎo)的肝臟脂毒性[58]。美國(guó)Setshedi報(bào)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(dòng)劑可減輕乙醇誘導(dǎo)的脂肪性肝炎[59]。

二、酒精性肝病

（一）基礎(chǔ)研究 美國(guó)Han報(bào)道了在ALD發(fā)生過(guò)程中，microRNAs在控制肝膽管細(xì)胞凋亡和轉(zhuǎn)化中的新作用[60]。臺(tái)灣Lin報(bào)道了增強(qiáng)自噬可減輕乙醇誘導(dǎo)的小鼠脂肪肝[61]。美國(guó)Ambade報(bào)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(dǎo)的TNFα產(chǎn)生[62]。美國(guó)Levin報(bào)道了肝細(xì)胞缺氧誘導(dǎo)因子1α（HIF-1α）需要通過(guò)Toll樣受體4依賴的途徑才能激活，HIF-1α激活可致長(zhǎng)期乙醇喂養(yǎng)的小鼠發(fā)生肝脂變[63]。美國(guó)Derdak報(bào)道了纖維化相關(guān)轉(zhuǎn)錄因子早期生長(zhǎng)反應(yīng)基因1（EGR-1）可通過(guò)激活固醇調(diào)節(jié)元件結(jié)合蛋白1（SREBP1）而促進(jìn)乙醇喂養(yǎng)的Long Evans大鼠肝脂變的發(fā)生[64]。美國(guó)Kirpich報(bào)道了狂飲乙醇誘導(dǎo)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(guān)[65]。美國(guó)Howarth報(bào)道了激活轉(zhuǎn)錄因子6（ATF-6）與非折疊蛋白反應(yīng)（UPR）在急性乙醇誘導(dǎo)的斑馬魚肝脂變中起重要作用[66]。比利時(shí)Degré報(bào)道了趨化因子配體2（CCL2），亦即單核細(xì)胞趨化蛋白1（MCP-1），中性粒細(xì)胞募集與酒精性肝炎的疾病嚴(yán)重度有關(guān)，而IL-17依賴的途徑可能參與其中[67]。美國(guó)Ki報(bào)道了IL-22治療可減輕長(zhǎng)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(hào)轉(zhuǎn)導(dǎo)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(shí)Trépo報(bào)道了幾種常見(jiàn)的PNPLA3基因多態(tài)性與ALD肝脂變和纖維化的關(guān)系[69]。法國(guó)Louvet通過(guò)分析重度酒精性肝炎患者的長(zhǎng)期資料，發(fā)現(xiàn)酒精復(fù)飲是存活的關(guān)鍵因素[70]。西班牙Altamirano報(bào)道了急性腎損傷（AKI）對(duì)酒精性肝炎患者的短期存活有負(fù)面影響，指出治療上應(yīng)加以注意[71]。法國(guó)Louvet通過(guò)比較幾個(gè)現(xiàn)有的預(yù)后模型發(fā)現(xiàn)，預(yù)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(yù)后評(píng)估[72]。法國(guó)Louvet報(bào)道了“應(yīng)答指導(dǎo)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(bào)道了日本男性中飲酒患者以及脂肪肝的發(fā)生風(fēng)險(xiǎn)[74]。法國(guó)Amathieu報(bào)道了質(zhì)子磁共振波譜法檢測(cè)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(píng)估[75]。美國(guó)Ellefson報(bào)道了激素印跡影響酒精誘導(dǎo)的早期肝損傷[76]。法國(guó)Louvet進(jìn)行了一項(xiàng)前瞻性研究，結(jié)果發(fā)現(xiàn)重度酒精性肝炎時(shí)肝靜脈壓力梯度與存活率無(wú)關(guān)[77]。美國(guó)Asrani進(jìn)行了一項(xiàng)基于人群的關(guān)于酒精性肝炎患者存活率的研究[78]。美國(guó)Singal通過(guò)一項(xiàng)大型全國(guó)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(yán)重度增加的關(guān)系[79]。美國(guó)Thuluvath報(bào)道了HCV和肝性腦病對(duì)確診的酒精性肝炎患者結(jié)局的影響[80]。Liangpunsakul報(bào)道了在美國(guó)住院的酒精性肝炎患者的臨床特征和死亡率[81]。

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