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Adenovirus-mediated overexpression of Tcfe3 ameliorates hyperglycaemia in a mouse model of diabetes by upregulating glucokinase in the liver

 M. Y. Kim  ;  S. H. Jo  ;  J. M. Park  ;  T. H. Kim  ;  S. S. Im  ;  Y. H. Ahn 
 DIABETOLOGIA, Vol.56(3) : 635-643, 2013 
Journal Title
Issue Date
Adenoviridae/genetics* ; Animals ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism* ; Chromatin Immunoprecipitation ; Diabetes Mellitus, Experimental/enzymology ; Diabetes Mellitus, Experimental/metabolism ; Diabetes Mellitus, Experimental/therapy* ; Glucokinase/genetics ; Glucokinase/metabolism* ; Glucose Tolerance Test ; Hep G2 Cells ; Humans ; Hyperglycemia/enzymology ; Hyperglycemia/metabolism ; Hyperglycemia/therapy* ; Insulin/metabolism ; Liver/enzymology* ; Liver/metabolism* ; Male ; Mice ; Mice, Inbred C57BL ; Promoter Regions, Genetic/genetics ; RNA, Small Interfering
Liver-type glucokinase (Gck) ; TFE3 ; Transcription factor E3 ; Type 1 diabetes mellitus ; Transcriptional regulation ; Streptozotocin
AIMS/HYPOTHESIS: Transcription factor E3 (TFE3) has been shown to increase insulin sensitivity by activating insulin-signalling pathways. However, the role of TFE3 in glucose homeostasis is not fully understood. Here, we explored the possible therapeutic potential of TFE3 for the control of hyperglycaemia using a streptozotocin-induced mouse model of diabetes. METHODS: We achieved overabundance of TFE3 in streptozotocin mice by administering an adenovirus (Ad) or adeno-associated virus serotype 2 (AAV2). We also performed an oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). To explore molecular mechanisms of blood glucose control by TFE3, transcriptional studies on the regulation of genes involved in hepatic glucose metabolism were performed using quantitative real-time PCR and chromatin immunoprecipitation assay. The binding site of TFE3 in the liver Gck gene promoter was identified using deletion and site-specific mutation studies. RESULTS: Overabundance of TFE3 resulted in reduced hyperglycaemia as shown by the OGTT and ITT in streptozotocin-treated mice. We observed that TFE3 can upregulate Gck in a state of insulin deficiency. However, glucose-6-phosphatase and cytosolic phosphoenolpyruvate carboxykinase mRNA levels were decreased by Ad-mediated overexpression of Tcfe3. Biochemical studies revealed that the anti-hyperglycaemic effect of TFE3 is due to the upregulation of Gck. In primary cultured hepatocytes, TFE3 increased expression of Gck mRNA. Conversely, small interfering RNA-mediated knockdown of TFE3 resulted in a decrease in Gck mRNA. CONCLUSIONS/INTERPRETATION: This study demonstrates that TFE3 counteracts hyperglycaemia in streptozotocin-treated mice. This effect could be due to the upregulation of Gck by binding of TFE3 to its cognitive promoter region.
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1. College of Medicine (의과대학) > Dept. of Biochemistry and Molecular Biology (생화학-분자생물학교실) > 1. Journal Papers
Yonsei Authors
Kim, Mi Young(김미영)
Kim, Tae Hyun(김태현)
Park, Joo Man(박주만)
Ahn, Yong Ho(안용호) ORCID logo https://orcid.org/0000-0002-4133-0757
Jo, Seong Ho(조성호)
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