非酒精性脂肪性肝疾?。╪onalcoholic fatty liver disease,，NAFLD）是一種無過量飲酒史，以肝細(xì)胞脂肪變性和脂質(zhì)蓄積為主要特征的臨床病理綜合癥，通常伴隨高血脂、高血糖和胰島素抵抗等代謝綜合征,。過量的甘油三酯在肝臟細(xì)胞中長期堆積會(huì)導(dǎo)致肝臟細(xì)胞壞死，功能喪失,，進(jìn)而發(fā)生肝纖維化,，肝硬化和肝癌。近年來NAFLD發(fā)病率在我國及世界范圍內(nèi)不斷上升,，使得對(duì)于該疾病的研究越來越受到重視,，但其發(fā)病機(jī)理尚不清楚。
近期,，Journal of Hepatology雜志在線發(fā)表了中科院上海生命科學(xué)研究院健康所內(nèi)分泌代謝疾病研究組/瑞金醫(yī)院內(nèi)分泌科寧光教授研究組對(duì)于NAFLD發(fā)病機(jī)制的研究成果Deletion of Steroid receptor coactivator-3 gene ameliorates hepatic steatosis,。本項(xiàng)研究發(fā)現(xiàn)了核受體輔激活蛋白-3 （SRC-3）參與調(diào)控非酒精性脂肪肝的致病機(jī)制。
在寧光教授指導(dǎo)下,，健康所博士生馬欣然和徐凌燕等研究人員發(fā)現(xiàn),，SRC-3基因缺失在HepG2肝臟細(xì)胞系中可以抑制棕櫚酸誘導(dǎo)的脂滴累積，SRC-3敲除小鼠可以抵抗高脂飲食誘導(dǎo)的脂肪肝和炎癥反應(yīng),。研究表明,，這可能是由于SRC-3缺失降低了雞卵清蛋白上游啟動(dòng)子轉(zhuǎn)錄因子（COUP-TFII）,，從而升高了過氧化物酶體增殖物激活受體（PPARa）的表達(dá)水平,，加快肝細(xì)胞中的β氧化而改善肝臟的脂質(zhì)代謝。通過系列分子實(shí)驗(yàn)證實(shí),，在全反式維甲酸ATRA存在下,，SRC-3能夠輔助維甲酸受體RARa結(jié)合于COUP-TFII啟動(dòng)子上游促進(jìn)其轉(zhuǎn)錄。通過對(duì)脂肪肝病人組織芯片染色,，也證實(shí)了SRC-3核表達(dá)與脂肪肝呈正相關(guān),。
該研究首次發(fā)現(xiàn)SRC-3在肝臟脂質(zhì)代謝中的重要生理功能和調(diào)控機(jī)制，揭示了SRC-3在NAFLD發(fā)病進(jìn)程中的重要作用,，提供了新的治療靶點(diǎn),，對(duì)治療NAFLD具有現(xiàn)實(shí)的指導(dǎo)意義。
該項(xiàng)研究工作得到了國家科技部973計(jì)劃,、863計(jì)劃,、國家自然科學(xué)基金委,、上海市科委項(xiàng)目的資助。(生物谷 Bioon.com)
doi:10.1016/j.jhep.2010.11.022
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Deletion of steroid receptor coactivator-3 gene ameliorates hepatic steatosis.
Ma X, Xu L, Wang S, Cui B, Li X, Xu J, Ning G.
Many persistent pain states (pain lasting for hours, days, or longer) are poorly treated because of the limitations of existing therapies. Analgesics such as nonsteroidal anti-inflammatory drugs and opioids often provide incomplete pain relief and prolonged use results in the development of severe side effects. Identification of the key mediators of various types of pain could improve such therapies. Here, we tested the hypothesis that hitherto unrecognized cytokines and chemokines might act as mediators in inflammatory pain. We used ultraviolet B (UVB) irradiation to induce persistent, abnormal sensitivity to pain in humans and rats. The expression of more than 90 different inflammatory mediators was measured in treated skin at the peak of UVB-induced hypersensitivity with custom-made
