KLF10 transcription factor regulates hepatic glucose metabolism in mice
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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-like factor 10 (KLF10) in regulating hepatic glucose metabolism in mice.
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 glucose levels were measured. GTTs and pyruvate tolerance tests were performed. The molecular mechanism by which KLF10 regulates hepatic glucose metabolism was explored.
Hepatic KLF10 expression was regulated by nutritional status in wild-type mice and upregulated in diabetic, obese and DIO mice. 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.
KLF10 is an important regulator of hepatic glucose metabolism and modulation of KLF10 expression in the liver may be an attractive approach for the treatment of type 2 diabetes.
KeywordsGluconeogenesis KLF10 PGC-1α Type 2 diabetes
Adenovirus expressing green fluorescent protein
Adenovirus expressing Krüppel-like factor 10
Control adenovirus expressing short-hairpin RNA against luciferase
Adenovirus expressing short-hairpin RNA against Krüppel-like factor 10
Adenovirus expressing short-hairpin RNA against peroxisome proliferator-activated receptor, gamma, coactivator 1, alpha
Cyclic AMP response element-binding protein
Peroxisome proliferator-activated receptor, gamma, coactivator 1α
Pyruvate tolerance test
Small interfering RNA
Sterol regulatory element-binding transcription factor
The data that support the findings of this study are available from the corresponding author upon reasonable request.
This work was supported by the National Natural Science Foundation of China (grant nos. 81471049, 81670749, 81700768 and 81730024).
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
YC contributed to the conception and design of the study. XY and QC contributed to the study design and acquisition and analysis of data. LS, HZ, LY, XC, YG and FF contributed to the analysis and interpretation of data. XY, QC and YC contributed to drafting or revising the article. All authors critically revised the manuscript and approved the final version. YC is the guarantor of this work.