Thioredoxin-Interacting Protein Stimulates Its Own Expression via a Positive Feedback Loop.
Chen, Junqin; Jing, Gu; Xu, Guanlan; Shalev, Anath
[Article] Molecular Endocrinology. 28(5):674-680, May 2014.

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Thioredoxin-interacting protein (TXNIP) has emerged as a key regulator of important cellular processes including redox state, inflammation, and apoptosis and plays a particularly critical role in pancreatic [beta]-cell biology and diabetes development. High glucose and diabetes induce TXNIP expression, whereas inhibition of TXNIP expression or TXNIP deficiency protects against pancreatic [beta]-cell apoptosis and diabetes. We now have discovered that TXNIP stimulates its own expression by promoting dephosphorylation and nuclear translocation of its transcription factor, carbohydrate response element-binding protein (ChREBP), resulting in a positive feedback loop as well as regulation of other ChREBP target genes playing important roles in glucose and lipid metabolism. Considering the detrimental effects of elevated TXNIP in [beta]-cell biology, this novel pathway sheds new light onto the vicious cycle of increased TXNIP, leading to even more TXNIP expression, oxidative stress, inflammation, [beta]-cell apoptosis, and diabetes progression. Moreover, the results demonstrate, for the first time, that TXNIP modulates ChREBP activity and thereby uncover a previously unappreciated link between TXNIP signaling and cell metabolism.

Copyright (C) 2014 by The Endocrine Society