title: Txnip contributes to impaired glucose tolerance by upregulating the expression of genes involved in hepatic gluconeogenesis in mice.
abstract: OBJECTIVE
  Thioredoxin-interacting protein (TXNIP) is upregulated in the hyperglycaemic state and represses glucose uptake, resulting in imbalanced glucose homeostasis. In this study, we propose a mechanism of how TXNIP impairs hepatic glucose tolerance at the transcriptional level.
  
  
  METHODS
  We administered adenoviral Txnip (Ad-Txnip) to normal mice and performed intraperitoneal glucose tolerance tests (IPGTT), insulin tolerance tests (ITT) and pyruvate tolerance tests (PTT). After Ad-Txnip administration, the expression of genes involved in glucose metabolism, including G6pc and Gck, was analysed using quantitative real-time PCR and western blot. To understand the increased G6pc expression in liver resulting from Txnip overexpression, we performed pull-down assays for TXNIP and small heterodimer partner (SHP). Luciferase reporter assays and chromatin immunoprecipitation using the Txnip promoter were performed to elucidate the interrelationship between carbohydrate response element-binding protein (ChREBP) and transcription factor E3 (TFE3) in the regulation of Txnip expression.
  
  
  RESULTS
  Overabundance of TXNIP resulted in impaired glucose, insulin and pyruvate tolerance in normal mice. Ad-Txnip transduction upregulated G6pc expression and caused a decrease in Gck levels in the liver of normal mice and primary hepatocytes. TXNIP increased G6pc expression by forming a complex with SHP, which is known to be a negative modulator of gluconeogenesis. Txnip expression in mouse models of diabetes was decreased by Ad-Tfe3 administration, suggesting that TFE3 may play a negative role through competition with ChREBP at the E-box of the Txnip promoter.
  
  
  CONCLUSIONS
  We demonstrated that TXNIP impairs glucose and insulin tolerance in mice by upregulating G6pc through interaction with SHP.
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: Seong Ho
authors.initials: SH
authors.lastname: Jo
authors.forename: Mi Young
authors.initials: MY
authors.lastname: Kim
authors.forename: Joo Man
authors.initials: JM
authors.lastname: Park
authors.forename: Tae Hyun
authors.initials: TH
authors.lastname: Kim
authors.forename: Yong Ho
authors.initials: YH
authors.lastname: Ahn
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000378:metabolism; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D005943:Gluconeogenesis; D018149:Glucose Intolerance / Q000378:metabolism*; D005951:Glucose Tolerance Test; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D009687:Nuclear Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; C506001:Mlxipl protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; C445672:Txnip protein, mouse; C068486:Tcfe3 protein, mouse; D013879:Thioredoxins; D005952:Glucose-6-Phosphatase; C117983:G6pc2 protein, mouse
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