{"doi":"10.1016/j.jbc.2025.110214","title":"Covalent binding of thioredoxin to TXNIP is required for diet-induced insulin resistance in the liver","abstract":"Hepatic insulin resistance is an important pathophysiology in type 2 diabetes, and the mechanisms by which high-caloric diets induce insulin resistance are unclear. Among vertebrate animals, mammals have retained a unique molecular change that allows an intracellular arrestin domain-containing protein called Thioredoxin-Interacting Protein (TXNIP) to bind covalently to thioredoxin, allowing TXNIP to \"sense\" oxidative stress. 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 an exchange of TXNIP Cysteine 247 for Serine (C247S) showed improved whole-body and hepatic insulin sensitivity compared with WT controls following an 8-week HFD. HFD-fed TXNIP C247S mouse livers also showed improved insulin signaling. The Transmembrane 7 Superfamily Member 2 (Tm7sf2) gene encodes for a sterol reductase involved in the process of cholesterol biosynthesis. We identified TM7SF2 as a potential mediator of enhanced insulin signaling in HFD-fed TXNIP C247S mouse livers. TM7SF2 increased Akt phosphorylation and suppressed gluconeogenic markers PCK1 and G6Pc specifically under oxidative stress-induced conditions in HepG2 cells. We also present data suggesting that a heterozygous variant of TXNIP C247 is well tolerated in humans. Thus, mammals have a single redox-sensitive amino acid in TXNIP that mediates insulin resistance in the setting of an HFD. Our results reveal an evolutionarily conserved mechanism for hepatic insulin resistance in obesity.","journal":"Journal of Biological Chemistry","year":2025,"id":533662,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":2,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9512,"is_data_producer":true,"deposit_databanks":{"GEO":["GSE275407"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1073946,"name":"Megan F. 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