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Mol Endocrinol. 2014 May;28(5):674-80. doi: 10.1210/me.2014-1041. Epub 2014 Mar 14.

Thioredoxin-interacting protein stimulates its own expression via a positive feedback loop.

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Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama 35294.


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 β-cell biology and diabetes development. High glucose and diabetes induce TXNIP expression, whereas inhibition of TXNIP expression or TXNIP deficiency protects against pancreatic β-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 β-cell biology, this novel pathway sheds new light onto the vicious cycle of increased TXNIP, leading to even more TXNIP expression, oxidative stress, inflammation, β-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.

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