Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is a co-activator of many transcription factors in the energy metabolism pathway and plays a vital role in the energy metabolism balance, and PGC-1α Abnormal expression and activity are closely related to metabolic diseases. It was found that the modulator of PGC-1α activity in skeletal muscle may become a new strategy for improving metabolic syndrome.
The Li Jia research group of the Chinese Academy of Sciences Shanghai Institute of Medicine and the Shen Jingkang research group conducted a cooperative study on PGC-1α small molecule modulators. A high-throughput screening model of luciferase reporter gene driven by the human PGC-1α promoter was established. Through random screening and data mining of 48,000 compounds in the National Compound Library, it was found that the small molecule compound ZLN005 can significantly improve the rat L6 muscle MRNA levels of PGC-1α in tube cells and stimulate L6 myotube cells' glucose uptake and palmitic acid oxidizing ability. Long-term administration of ZLN005 can significantly increase the mRNA level of PGC-1α, the expression of mitochondrial biosynthesis genes and the number of mitochondria in skeletal muscle of spontaneous type 2 diabetic db / db mice; chronic treatment of ZLN005 can improve the mRNA level of PGC-1α in the liver And the expression of key genes of gluconeogenesis. Pharmacodynamic studies in animals show that chronic treatment with PGC-1α transcription regulator ZLN005 can significantly reduce the symptoms of hyperglycemia and hyperlipidemia in db / db mice, effectively improve insulin resistance, pyruvate tolerance and glucose tolerance in db / db mice Subject to ability. The mechanism study shows that ZLN005 promotes PGC-1α mRNA level and downstream gene expression is dependent on the transcription factor MEF2 and AMPK signaling pathway.
The research results for the first time confirmed that targeting the transcription level regulation based on PGC-1α coactivator can effectively promote skeletal muscle mitochondrial production and improve metabolic syndrome, which was published online in the American Diabetes Association Diabetes on December 18, 2012. The research was mainly carried out under the guidance of researcher Li Jingya's doctoral student Zhang Lina under the guidance of researcher Li Jingya, researcher Li Jia and researcher Shen Jingkang.
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