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

Title
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;Yong Ho Ahn;Tae Hyun Kim;Joo Man Park
Issue Date
2013
Journal Title
Diabetologia
ISSN
0012-186X
Citation
Diabetologia, Vol.56(12) : 2723~2732, 2013
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.
URI
http://link.springer.com/article/10.1007%2Fs00125-013-3050-6

http://ir.ymlib.yonsei.ac.kr/handle/22282913/88450
DOI
10.1007/s00125-013-3050-6
Appears in Collections:
1. 연구논문 > 1. College of Medicine > Dept. of Biochemistry & Molecular Biology
Yonsei Authors
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