Covalent Binding of Thioredoxin to TXNIP is Required for Diet-induced Hepatic Insulin Resistance
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ABSTRACT: Among vertebrate animals, mammals have retained a unique molecular change that allows an intracellular arrestin domain-containing protein to bind covalently to thioredoxin. This interaction of Thioredoxin-Interacting Protein (TXNIP) with thioredoxin can only occur when thioredoxin is in the reduced state, allowing TXNIP to "sense" the cellular oxidized environment1. Here we show that a single cysteine in TXNIP mediates the development of hepatic insulin resistance in the setting of a high fat diet (HFD). Mice with exchange of TXNIP Cysteine 247 for Serine (C247S) showed improved whole-body and hepatic insulin sensitivities compared to wildtype (WT) controls following an 8-week HFD. The inhibition of the TXNIP-thioredoxin interaction under chow and HFD also regulated plasma and liver lipids and reduced free fatty acid accumulation in the livers following HFD. We also show molecularly that in HFD-fed TXNIP C247S mice livers, Toll-like Receptor 4 (TLR4)-mediated Nuclear factor kappa B (NFkB) activation and TLR4-mediating WD repeat and FYVE domain containing 1 (wdfy1) mRNA expressions were decreased, as well as PKC activity as a potential molecular mechanism to improve insulin/Akt signaling. These data show that mammals have a single amino acid enabling interaction of redox state with TXNIP that mediates insulin resistance in the setting of a high-fat diet. This reveals a potential evolutionarily-conserved mechanism for hepatic insulin resistance in metabolic syndromes.
ORGANISM(S): Mus musculus
PROVIDER: GSE253334 | GEO | 2024/01/20
REPOSITORIES: GEO
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