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

Abstract

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.

• Authors: Junqin Chen, Gu Jing, Guanlan Xu, Anath Shalev
• Journal: Molecular endocrinology (Baltimore, Md.) (Mol Endocrinol) Vol. 28 Issue 5 Pg. 674-80 (May 2014) ISSN: 1944-9917 [Electronic] United States
• PMID: 24628418 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
• Carrier Proteins
• MLXIPL protein, human
• TXNIP protein, human
• Adenylate Kinase

Topics

• Active Transport, Cell Nucleus
• Adenylate Kinase (metabolism)
• Animals
• Basic Helix-Loop-Helix Leucine Zipper Transcription Factors (metabolism)
• Carrier Proteins (genetics, metabolism)
• Cell Line
• Feedback, Physiological
• Gene Expression Regulation
• Humans
• Male
• Mice, Inbred C57BL
• Phosphorylation
• Promoter Regions, Genetic
• Protein Processing, Post-Translational
• Rats