过氧化物酶体增殖活化受体γ共激活因子-1α（PGC-1α）是能量代谢途径中众多转录因子的共激活因子，在能量代谢平衡中起到至关重要的作用，且PGC-1α的表达和活性异常与代谢型疾病之间存在紧密关联。发现骨骼肌中PGC-1α活性调节剂可能成为改善代谢综合症的新策略。
上海药物所李佳研究组联合沈竞康研究组针对PGC-1α小分子调节剂进行了合作研究。建立了人PGC-1α启动子驱动的萤光素酶报告基因高通量筛选模型，通过对国家化合物样品库48000个化合物的随机筛选和数据挖掘，发现小分子化合物ZLN005能显着提高大鼠L6肌管细胞中PGC-1α的mRNA水平，并刺激L6肌管细胞对葡萄糖的摄取和对棕榈酸的氧化能力。ZLN005长期给药可显着上调自发性2型糖尿病db/db小鼠骨骼肌中PGC-1α的mRNA水平、线粒体生物合成基因的表达和线粒体数目；ZLN005慢性治疗可改善肝脏中PGC-1α的mRNA水平及肝糖异生关键基因的表达。动物体内药效学研究表明PGC-1α转录调节剂ZLN005慢性治疗可显着降低db/db小鼠的高血糖和高血脂症状、有效改善db/db小鼠的胰岛素抵抗、丙酮酸耐受以及葡萄糖耐受能力。作用机制研究表明ZLN005促进PGC-1α的mRNA水平以及下游基因的表达是依赖于转录因子MEF2以及AMPK信号通路。
该项研究成果首次证实靶向基于PGC-1α共激活因子的转录水平调节，可有效促进骨骼肌线粒体生成从而改善代谢综合症，已于2012年12月18日在线发表于美国糖尿病学会杂志Diabetes。该项研究主要由李静雅研究员的博士研究生张丽娜在李静雅研究员、李佳研究员和沈竞康研究员共同指导下完成。(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.
