Histone acetylation of glucose-induced thioredoxin-interacting protein gene expression in pancreatic islets

Thioredoxin-interacting protein (TXNIP), also known as vitamin-D3 upregulated protein 1, interacts with reduced thioredoxin. This protein modulates the cellular redox state and plays a role in stress-induced cellular apoptosis. This study examined TXNIP gene expression in prostate cancer cells. In vitro studies by immunoblot assay have shown that elevated glucose levels (1–15 mM) upregulate TXNIP gene expression two- to fourfold in human prostate carcinoma cells (LNCaP) and hepatocellular carcinoma cells (HepG2). Transient gene expression assays reveal that the promoter activity of the TXNIP gene is upregulated by glucose, 3-O-methylglucose, and maltose, but not by mannitol. These results suggest that glucose and 3-O-methylglucose induce TXNIP expression through both glucose metabolism-dependent and -independent pathways. Cotransfection of a plasmid expression carbohydrate response element-binding protein (ChREBP) with a TXNIP reporter vector into LNCaP cells dramatically enhances reporter activity in a low glucose (1 mM) condition. The effects of glucose are apparently mediated in a region located −341 to −324 bp upstream of the translational starting point of the TXNIP gene as indicated by 5′-deletion and site-directed mutagenesis reporter assays. Mutation of the putative carbohydrate response element (ChoRE) from CACGAGGGCAGCACGAG to TTTGAGGGCAGCACGAG abolishes glucose upregulation of TXNIP promoter activity. The present study demonstrates that TXNIP is transcription induced in both LNCaP and HepG2 cells in an increased glucose metabolism-dependent or -independent response, and a putative glucose regulatory system including ChREBP and ChoRE is needed for glucose-induced TXNIP gene in human prostate carcinoma cells.

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MondoA senses adenine nucleotides: transcriptional induction of thioredoxin-interacting protein

Biochemical Journal ◽

10.1042/bj20121126 ◽

2013 ◽

Vol 453 (2) ◽

pp. 209-218 ◽

Cited By ~ 7

Author(s):

Kyoung-Sim Han ◽

Donald E. Ayer

Keyword(s):

Gene Expression ◽

Feedback Inhibition ◽

Adenine Nucleotide ◽

Adenine Nucleotides ◽

Interacting Protein ◽

Kinase Activation ◽

Thioredoxin Interacting Protein ◽

Glucose Homoeostasis ◽

Independent Effects ◽

Adenine Nucleotide Pool

The MondoA–Mlx transcription complex plays a pivotal role in glucose homoeostasis by activating target gene expression in response to G6P (glucose 6-phosphate), the first reaction intermediate in glycolysis. TXNIP (thioredoxin-interacting protein) is a direct and glucose-responsive target of MondoA that triggers a negative-feedback loop by restricting glucose uptake when G6P levels increase. We show in the present study that TXNIP expression is also activated by AICAR (5-amino-4-imidazolecarboxamide ribofuranoside) and adenosine. Using pharmacological inhibitors and genetic knockdowns of purine metabolic enzymes, we establish that TXNIP induction by AICAR and adenosine requires their cellular uptake and metabolism to adenine nucleotides. AICAR induction of TXNIP depended on MondoA, but was independent of AMPK (AMP-activated protein kinase) activation and calcium. The findings of the present study have two important implications. First, in addition to activating AMPK, AICAR may have AMPK-independent effects on gene expression by regulating MondoA–Mlx activity following its flux into the adenine nucleotide pool. Secondly, MondoA–Mlx complexes sense elevated levels of G6P and adenine nucleotides to trigger a TXNIP-dependent feedback inhibition of glycolysis. We propose that this mechanism serves as a checkpoint to restore metabolic homoeostasis.

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Insulin counteracts glucotoxic effects by suppressing thioredoxin-interacting protein production in INS-1E beta cells and in Psammomys obesus pancreatic islets

Diabetologia ◽

10.1007/s00125-009-1274-2 ◽

2009 ◽

Vol 52 (4) ◽

pp. 636-644 ◽

Cited By ~ 34

Author(s):

M. Shaked ◽

M. Ketzinel-Gilad ◽

Y. Ariav ◽

E. Cerasi ◽

N. Kaiser ◽

...

Keyword(s):

Pancreatic Islets ◽

Beta Cells ◽

Protein Production ◽

Psammomys Obesus ◽

Interacting Protein ◽

Thioredoxin Interacting Protein

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High β-cell mass prevents streptozotocin-induced diabetes in thioredoxin-interacting protein-deficient mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90619.2008 ◽

2009 ◽

Vol 296 (6) ◽

pp. E1251-E1261 ◽

Cited By ~ 30

Author(s):

Elodie Masson ◽

Shlomit Koren ◽

Fathima Razik ◽

Howard Goldberg ◽

Edwin P. Kwan ◽

...

Keyword(s):

Cell Death ◽

Insulin Secretion ◽

Pancreatic Islets ◽

Cell Mass ◽

Insulin Content ◽

Β Cell ◽

Interacting Protein ◽

Isolated Pancreatic Islets ◽

Thioredoxin Interacting Protein ◽

Deficient Mice

Thioredoxin-interacting protein (TxNIP) is an endogenous inhibitor of thioredoxin, a ubiquitous thiol oxidoreductase, that regulates cellular redox status. Diabetic mice exhibit increased expression of TxNIP in pancreatic islets, and recent studies suggest that TxNIP is a proapoptotic factor in β-cells that may contribute to the development of diabetes. Here, we examined the role of TxNIP deficiency in vivo in the development of insulin-deficient diabetes and whether it impacted on pancreatic β-cell mass and/or insulin secretion. TxNIP-deficient (Hcb-19/TxNIP−/−) mice had lower baseline glycemia, higher circulating insulin concentrations, and higher total pancreatic insulin content and β-cell mass than control mice (C3H). Hcb-19/TxNIP−/− did not develop hyperglycemia when injected with standard multiple low doses of streptozotocin (STZ), in contrast to C3H controls. Surprisingly, although β-cell mass remained higher in Hcb-19/TxNIP−/− mice compared with C3H after STZ exposure, the relative decrease induced by STZ was as great or even greater in the TxNIP-deficient animals. Consistently, cultured pancreatic INS-1 cells transfected with small-interfering RNA against TxNIP were more sensitive to cell death induced by direct exposure to STZ or to the combination of inflammatory cytokines interleukin-1β, interferon-γ, and tumor necrosis factor-α. Furthermore, when corrected for insulin content, isolated pancreatic islets from TxNIP−/− mice exhibited reduced glucose-induced insulin secretion. These data indicate that TxNIP functions as a regulator of β-cell mass and influences insulin secretion. In conclusion, the relative resistance of TxNIP-deficient mice to STZ-induced diabetes appears to be because of an increase in β-cell mass. However, TxNIP deficiency is associated with sensitization to STZ- and cytokine-induced β-cell death, indicating complex regulatory roles of TxNIP under different physiological and pathological conditions.

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