科研成果: “KLF10 transcription factor regulates hepatic glucose metabolism in mice”

发布时间:2017-09-04

导读: 常永生课题组于2017年8月在” DIABETOLOGIA” 杂志发表研究论文“KLF10 transcription factor regulates hepatic glucose metabolism in mice”。 

文章链接: https://link.springer.com/article/10.1007%2Fs00125-017-4412-2 


图1:

    临床上广泛使用的二甲双胍主要作用机制就是抑制肝脏的糖异生。所以研究肝脏的糖代谢和能量代谢,有助于找到新的治疗糖尿病的靶点。中国医学科学院基础医学研究所,“医学分子生物学国家重点实验室”的常永生研究团队通过研究发现KLF10可以作为调节pgc1a的一个重要转录因子,同时调控下游糖异生相关基因Pck1和G6pc,进而促进肝脏糖异生并使血糖上升。 


    【摘要】:AIM/HYPOTHESIS:Abnormal activation of hepatic gluconeogenesis leads to hyperglycaemia. However, the molecular mechanisms underlying dysregulated hepatic gluconeogenesis remain to be fully defined. Here, we explored the physiological role of Krüppel-likefactor 10 (KLF10) in regulating hepatic glucose metabolism in mice. METHODS:Hepatic KLF10 expression in wild-type C57BL/6J mice, the db/db mouse model of diabetes, the ob/ob mouse model of obesity and high-fat-diet-induced obese (DIO) mice was measured. Adenoviruses expressing Klf10 or Klf10-specific short-hairpin RNA were injected into wild-type C57BL/6J mice, db/db or DIO mice. Expression of gluconeogenic genes in the liver and blood glucoselevels were measured. GTTs and pyruvate tolerance tests were performed. The molecular mechanism by which KLF10 regulateshepatic glucose metabolism was explored. RESULTS:Hepatic KLF10 expression was regulated by nutritional status in wild-type mice and upregulated in diabetic, obese and DIOmice. Overexpression of KLF10 in primary hepatocytes increased the expression of gluconeogenic genes and cellular glucose output. C57BL/6J mice with KLF10 overexpression in the liver displayed increased blood glucose levels and impaired glucose tolerance. Conversely, hepatic KLF10 knockdown in db/db and DIO mice decreased blood glucose levels and improved glucose tolerance. Furthermore, luciferase reporter gene assay and chromatin immunoprecipitation analysis indicated that KLF10 activates Pgc-1α (also known as Ppargc1a) gene transcription via directly binding to its promoter region. CONCLUSIONS/INTERPRETATION:KLF10 is an important regulator of hepatic glucose metabolism and modulation of KLF10expression in the liver may be an attractive approach for the treatment of type 2 diabetes. 


    本文通讯作者为常永生研究员,共同第一作者杨晓莹和陈琦博士。该研究工作得到了国家自然科学基金的支持。 

 

医学分子生物学国家重点实验室