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Txnip contributes to impaired glucose tolerance by upregulating the expression of genes involved in hepatic gluconeogenesis in mice

Authors
 Seong Ho Jo  ;  Mi Young Kim  ;  Joo Man Park  ;  Tae Hyun Kim  ;  Yong Ho Ahn 
Citation
 DIABETOLOGIA, Vol.56(12) : 2723-2732, 2013 
Journal Title
 DIABETOLOGIA 
ISSN
 0012-186X 
Issue Date
2013
MeSH
Animals ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Blotting, Western ; Carrier Proteins/genetics ; Carrier Proteins/metabolism* ; Chromatin Immunoprecipitation ; Diabetes Mellitus, Experimental/metabolism* ; Gluconeogenesis* ; Glucose Intolerance/metabolism* ; Glucose Tolerance Test ; Glucose-6-Phosphatase/genetics ; Glucose-6-Phosphatase/metabolism* ; Liver/metabolism* ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Nuclear Proteins/metabolism ; Promoter Regions, Genetic ; Real-Time Polymerase Chain Reaction ; Thioredoxins/genetics ; Thioredoxins/metabolism* ; Transcription Factors/metabolism ; Transcriptional Activation ; Up-Regulation
Keywords
Animals ; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/metabolism ; Blotting, Western ; Carrier Proteins/genetics ; Carrier Proteins/metabolism* ; Chromatin Immunoprecipitation ; Diabetes Mellitus, Experimental/metabolism* ; Gluconeogenesis* ; Glucose Intolerance/metabolism* ; Glucose Tolerance Test ; Glucose-6-Phosphatase/genetics ; Glucose-6-Phosphatase/metabolism* ; Liver/metabolism* ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred NOD ; Nuclear Proteins/metabolism ; Promoter Regions, Genetic ; Real-Time Polymerase Chain Reaction ; Thioredoxins/genetics ; Thioredoxins/metabolism* ; Transcription Factors/metabolism ; Transcriptional Activation ; Up-Regulation
Abstract
AIMS/HYPOTHESIS: 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/INTERPRETATION: We demonstrated that TXNIP impairs glucose and insulin tolerance in mice by upregulating G6pc through interaction with SHP.
Full Text
http://link.springer.com/article/10.1007%2Fs00125-013-3050-6
DOI
10.1007/s00125-013-3050-6
Appears in Collections:
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)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/88450
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