過氧化物酶體增殖活化受體γ共激活因子-1α（PGC-1α）是能量代謝途徑中眾多轉(zhuǎn)錄因子的共激活因子,，在能量代謝平衡中起到至關(guān)重要的作用,，且PGC-1α的表達和活性異常與代謝型疾病之間存在緊密關(guān)聯(lián)。發(fā)現(xiàn)骨骼肌中PGC-1α活性調(diào)節(jié)劑可能成為改善代謝綜合癥的新策略,。
上海藥物所李佳研究組聯(lián)合沈競康研究組針對PGC-1α小分子調(diào)節(jié)劑進行了合作研究。建立了人PGC-1α啟動子驅(qū)動的螢光素酶報告基因高通量篩選模型,，通過對國家化合物樣品庫48000個化合物的隨機篩選和數(shù)據(jù)挖掘,，發(fā)現(xiàn)小分子化合物ZLN005能顯著提高大鼠L6肌管細胞中PGC-1α的mRNA水平，并刺激L6肌管細胞對葡萄糖的攝取和對棕櫚酸的氧化能力,。ZLN005長期給藥可顯著上調(diào)自發(fā)性2型糖尿病db/db小鼠骨骼肌中PGC-1α的mRNA水平,、線粒體生物合成基因的表達和線粒體數(shù)目；ZLN005慢性治療可改善肝臟中PGC-1α的mRNA水平及肝糖異生關(guān)鍵基因的表達,。動物體內(nèi)藥效學(xué)研究表明PGC-1α轉(zhuǎn)錄調(diào)節(jié)劑ZLN005慢性治療可顯著降低db/db小鼠的高血糖和高血脂癥狀,、有效改善db/db小鼠的胰島素抵抗、丙酮酸耐受以及葡萄糖耐受能力,。作用機制研究表明ZLN005促進PGC-1α的mRNA水平以及下游基因的表達是依賴于轉(zhuǎn)錄因子MEF2以及AMPK信號通路,。
該項研究成果首次證實靶向基于PGC-1α共激活因子的轉(zhuǎn)錄水平調(diào)節(jié)，可有效促進骨骼肌線粒體生成從而改善代謝綜合癥,，已于2012年12月18日在線發(fā)表于美國糖尿病學(xué)會雜志Diabetes,。該項研究主要由李靜雅研究員的博士研究生張麗娜在李靜雅研究員、李佳研究員和沈競康研究員共同指導(dǎo)下完成,。(生物谷Bioon.com)
doi: 10.2337/db12-0703
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Novel Small-Molecule PGC-1α Transcriptional Regulator With Beneficial Effects on Diabetic db/db Mice
Li-Na Zhang, Hua-Yong Zhou, Yan-Yun Fu, Yuan-Yuan Li, Fang Wu, Min Gu, Ling-Yan Wu, Chun-Mei Xia, Tian-Cheng Dong, Jing-Ya Li⇓, Jing-Kang Shen⇓ and Jia Li⇓
Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) has been shown to influence energy metabolism. Hence, we explored a strategy to target PGC-1α expression to treat metabolic syndromes. We developed a high-throughput screening assay that uses the human PGC-1α promoter to drive expression of luciferase. The effects of lead compound stimulation on PGC-1α expression in muscle cells and hepatocytes were investigated in vitro and in vivo. A novel small molecule, ZLN005, led to changes in PGC-1α mRNA levels, glucose uptake, and fatty acid oxidation in L6 myotubes. Activation of AMP-activated protein kinase was involved in the induction of PGC-1α expression. In diabetic db/db mice, chronic administration of ZLN005 increased PGC-1α and downstream gene transcription in skeletal muscle, whereas hepatic PGC-1α and gluconeogenesis genes were reduced. ZLN005 increased fat oxidation and improved the glucose tolerance, pyruvate tolerance, and insulin sensitivity of diabetic db/db mice. Hyperglycemia and dyslipidemia also were ameliorated after treatment with ZLN005. Our results demonstrated that a novel small molecule selectively elevated the expression of PGC-1α in myotubes and skeletal muscle and exerted promising therapeutic effects for treating type 2 diabetes.
