title: Adenovirus-mediated overexpression of Tcfe3 ameliorates hyperglycaemia in a mouse model of diabetes by upregulating glucokinase in the liver.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-752, Republic of Korea.
authors.forename: M Y
authors.initials: MY
authors.lastname: Kim
authors.forename: S H
authors.initials: SH
authors.lastname: Jo
authors.forename: J M
authors.initials: JM
authors.lastname: Park
authors.forename: T H
authors.initials: TH
authors.lastname: Kim
authors.forename: S S
authors.initials: SS
authors.lastname: Im
authors.forename: Y H
authors.initials: YH
authors.lastname: Ahn
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology / Q000378:metabolism / Q000628:therapy*; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism*; D005951:Glucose Tolerance Test; D056945:Hep G2 Cells; D006801:Humans; D006943:Hyperglycemia / Q000201:enzymology / Q000378:metabolism / Q000628:therapy*; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000201:enzymology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011401:Promoter Regions, Genetic / Q000235:genetics; D034741:RNA, Small Interfering
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D007328:Insulin; D034741:RNA, Small Interfering; C068486:Tcfe3 protein, mouse; D005941:Glucokinase