{"doi":"10.3390/ijms19113539","title":"Repression of Transcriptional Activity of Forkhead Box O1 by Histone Deacetylase Inhibitors Ameliorates Hyperglycemia in Type 2 Diabetic Rats","abstract":"<jats:p>Type 2 diabetes mellitus (T2DM) is a chronic disease manifested by hyperglycemia. It is essential to effectively control hyperglycemia to prevent complications of T2DM. Here, we hypothesize that repression of transcriptional activity of forkhead box O1 (FoxO1) via histone deacetylase inhibitors (HDACi) ameliorates hyperglycemia in T2DM rats. Methods: Male Long-Evans Tokushima Otsuka (LETO) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats aged 14 weeks were administered sodium valproate (VPA, 0.71% w/v) dissolved in water for 20 weeks. Electrophoretic mobility shift assay (EMSA) and luciferase assay were performed for elucidation of transcriptional regulation through acetylation of FoxO1 by HDACi. Results: VPA attenuated blood glucose levels in accordance with a decrease in the expression of gluconeogenic genes in hyperglycemic OLETF rats. It has been shown that HDAC class I-specific and HDAC class IIa-specific inhibitors, as well as pan-HDAC inhibitors decrease FoxO1 enrichment at the cis-element of target gene promoters. Mutations in FoxO1 prevent its acetylation, thereby increasing its transcriptional activity. HDAC3 and HDAC4 interact with FoxO1, and knockdown of HDAC3, HDAC4, or their combination increases FoxO1 acetylation, thereby decreasing the expression of gluconeogenic genes. Conclusions: These results indicate that HDACi attenuates the transcriptional activity of FoxO1 by impeding deacetylation, thereby ameliorating hyperglycemia in T2DM rats.</jats:p>","journal":"International Journal of Molecular Sciences","year":2018,"id":13601,"datarank":1.0158682988677186,"base_score":3.295836866004329,"endowment":3.295836866004329,"self_citation_contribution":0.4943755299006494,"citation_network_contribution":0.5214927689670691,"self_endowment_contribution":0.4943755299006494,"citer_contribution":0.5214927689670691,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":26,"citers_with_citation_signal":23,"citers_with_endowment":23,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":110903,"name":"Young Mi Seok","orcid":"0000-0003-1273-3861","position":1,"is_corresponding":false},{"id":110904,"name":"Hae Ahm Lee","orcid":null,"position":2,"is_corresponding":false},{"id":110905,"name":"Minji Song","orcid":null,"position":3,"is_corresponding":false},{"id":110906,"name":"InKyeom Kim","orcid":"0000-0001-8009-5801","position":4,"is_corresponding":false},{"id":110902,"name":"Hyun Min Cho","orcid":"0000-0001-6534-1752","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"base_score":3.295836866004329,"endowment":3.295836866004329,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"30424007","pmcid":"PMC6274985","openalex_id":"https://openalex.org/W2899649808","authors":[],"funders":[{"funder_name":"National Research Foundation of Korea","grant_id":"2017R1A6A3A01004397, 2018R1A2B2005219, and 2018R1D1A1B07046882","title":null}],"total_grants":1,"fwci":1.2058,"citation_percentile":0.79410884,"influential_citations":1,"citation_trend":[{"year":2019,"count":3},{"year":2020,"count":4},{"year":2021,"count":6},{"year":2022,"count":2},{"year":2023,"count":2},{"year":2024,"count":4},{"year":2025,"count":3},{"year":2026,"count":2}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.mdpi.com/1422-0067/19/11/3539/pdf?version=1541768528","host_type":"journal"},{"url":"https://www.mdpi.com/1422-0067/19/11/3539/pdf?version=1541768528","host_type":"GOLD"},{"url":"https://www.mdpi.com/1422-0067/19/11/3539/pdf?version=1541768528","host_type":"publisher"},{"url":"https://www.mdpi.com/1422-0067/19/11/3539/pdf","host_type":"publisher"},{"url":"https://doi.org/10.3390/ijms19113539","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/30424007","host_type":"repository"},{"url":"https://doaj.org/article/935e7aa09afb403b9e1854cb84db79ea","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/6274985","host_type":"repository"},{"url":"http://dx.doi.org/10.3390/ijms19113539","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC6274985","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC6274985?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["FOXO transcription factor regulation","Histone Deacetylase Inhibitors Research","Signaling Pathways in Disease","Medicine","Chemistry","Acetylation","Animals","Diabetes Mellitus, Experimental","Diabetes Mellitus, Type 2","Forkhead Box Protein O1","Gluconeogenesis","Glucose","Glucose-6-Phosphate","Hep G2 Cells","Histone Deacetylase Inhibitors","Histone Deacetylases","Humans","Hyperglycemia","Intracellular Signaling Peptides and Proteins","Male","Phosphoenolpyruvate Carboxykinase (GTP)","Rats, Inbred OLETF","Repressor Proteins","Transcription, Genetic","Valproic Acid","Histone Deacetylase 3"],"mesh_terms":["Forkhead Box Protein O1","Histone Deacetylase 3","Acetylation","Animals","Diabetes Mellitus, Experimental","Diabetes Mellitus, Type 2","Gluconeogenesis","Glucose","Histone Deacetylases","Humans","Hyperglycemia","Male","Phosphoenolpyruvate Carboxykinase (GTP)","Repressor Proteins","Transcription, Genetic","Valproic Acid","Glucose-6-Phosphate","Rats, Inbred OLETF","Intracellular Signaling Peptides and Proteins","Histone Deacetylase Inhibitors","Hep G2 Cells"],"keywords":["Histone deacetylase","Psychological repression","Histone","Chemistry","Acetylation","Forkhead Transcription Factors","Histone deacetylase 5","Pharmacology","Histone deacetylase inhibitor","HDAC11","Cancer research","Biochemistry","Medicine","Transcription factor","Gene expression","Gene","Transcriptional regulation","Type 2 diabetes mellitus","Histone Deacetylase Inhibitors","Foxo1 Acetylation"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and 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