title: Thioredoxin-interacting protein promotes islet amyloid polypeptide expression through miR-124a and FoxA2.
abstract: Thioredoxin-interacting protein (TXNIP) is up-regulated by glucose and diabetes and plays a critical role in glucotoxicity, inflammation, and beta-cell apoptosis, whereas we have found that TXNIP deficiency protects against diabetes. Interestingly, human islet amyloid polypeptide (IAPP) is also induced by glucose, aggregates into insoluble amyloid fibrils found in islets of most individuals with type 2 diabetes and promotes inflammation and beta-cell cytotoxicity. However, so far no connection between TXNIP and IAPP signaling had been reported. Using TXNIP gain and loss of function experiments, INS-1 beta-cells and beta-cell-specific Txnip knock-out mice, we now found that TXNIP regulates IAPP expression. Promoter analyses and chromatin-immunoprecipitation assays further demonstrated that TXNIP increases IAPP expression at the transcriptional level, and we discovered that TXNIP-induced FoxA2 (forkhead box A2) transcription factor expression was conferring this effect by promoting FoxA2 enrichment at the proximal FoxA2 site in the IAPP promoter. Moreover, we found that TXNIP down-regulates miR-124a expression, a microRNA known to directly target FoxA2. Indeed, miR-124a overexpression led to decreased FoxA2 expression and IAPP promoter occupancy and to a significant reduction in IAPP mRNA and protein expression and also effectively inhibited TXNIP-induced IAPP expression. Thus, our studies have identified a novel TXNIP/miR-124a/FoxA2/IAPP signaling cascade linking the critical beta-cell signaling pathways of TXNIP and IAPP and thereby provide new mechanistic insight into an important aspect of transcriptional regulation and beta-cell biology.
authors.affiliation: Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Gu
authors.initials: G
authors.lastname: Jing
authors.affiliation: Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: Clara
authors.initials: C
authors.lastname: Westwell-Roper
authors.affiliation: Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Junqin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Guanlan
authors.initials: G
authors.lastname: Xu
authors.affiliation: Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada.
authors.forename: C Bruce
authors.initials: CB
authors.lastname: Verchere
authors.affiliation: Comprehensive Diabetes Center and Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Anath
authors.initials: A
authors.lastname: Shalev
mesh_terms: D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D015536:Down-Regulation; D051542:Hepatocyte Nuclear Factor 3-beta / Q000502:physiology*; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000502:physiology*; D051381:Rats; D013879:Thioredoxins / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology
chemical_list: D002352:Carrier Proteins; C496503:Foxa2 protein, mouse; D058228:Islet Amyloid Polypeptide; D035683:MicroRNAs; C540079:Mirn124 microRNA, mouse; C445672:Txnip protein, mouse; D051542:Hepatocyte Nuclear Factor 3-beta; D013879:Thioredoxins
keywords: Beta Cell; Diabetes; Islet Amyloid Polypeptide; MicroRNA; Thioredoxin; Thioredoxin-interacting protein; Transcription Regulation