Regulation of Thioredoxin-Interacting Protein in response to changes in metabolic and energetic state

Thioredoxin-interacting protein (TXNIP) plays an important role in regulating glucose metabolism. The expression of TXNIP is directly regulated by the MondoA:Mlx transcription factor complexes in response to changes in metabolic and energetic state. MondoA:Mlx complexes activate TXNIP expression by sensing glucose-6-phosphate (G6P), the first intermediate of glycolysis. Here, we investigate how bioenergetic changes regulate MondoA:Mlx activity and TXNIP expression. We show that TXNIP expression is also stimulated by 5-aminoimidazole-4-carboxamide ribofuranoside (AICAR) and adenosine. This effect of AICAR and adenosine is mediated by MondoA:Mlx transcriptional activity, but is independent of adenosine monophosphate (AMP)-activated protein kinase (AMPK). Consistent with the role of MondoA in glucose-dependent transcription, AICAR and adenosine effect on TXNIP expression depends on glucose availability. To activate TXNIP expression, AICAR and adenosine must enter into cells and be converted to adenine nucleotides. These findings suggest that MondoA:Mlx complexes sense the levels of adenine nucleotides as well as G6P. We also show that oxidative phosphorylation (OXPHOS) inhibitors suppress adenosine-induction of TXNIP. This repressive effect of OXPHOS inhibitors is most likely mediated by increased glycolytic rate and decreased mitochondrial adenosine triphosphate (ATP) levels, which might deplete G6P levels. The suppression of TXNIP by OXPHOS inhibitors was partially restored by combination of 2-deoxyglucose (2DG) and adenosine but not by iv 2DG alone, suggesting the involvement of mitochondrial ATP on TXNIP expression. In addition to transcriptional regulation, we show that TXNIP protein levels were reduced by AMPK activation with AICAR. High dose of AICAR treatment accelerates TXNIP protein degradation in an AMPK-dependent manner. With the fact that TXNIP negatively regulate glucose uptake, our findings imply that cells control TXNIP-dependent feedback loop of glucose flux by regulating TXNIP levels through MondoA and AMPK in response to metabolic and energetic changes. Thus, we propose that TXNIP is a critical mediator of integrating information about metabolic and energetic status to maintain energy homeostasis.