{"doi":"10.1073/pnas.2505263122","title":"Ethanol induction of FGF21 in the liver is dependent on histone acetylation and ligand activation of ChREBP by glycerol-3-phosphate","abstract":"Ethanol rapidly stimulates the liver to synthesize the hormone fibroblast growth factor 21 (FGF21), which then acts on the brain to elicit a multifaceted protective response. We show that in mice, this induction of FGF21 occurs at the level of gene transcription and is regulated by two byproducts of ethanol metabolism, glycerol-3-phosphate (G3P) and acetyl-CoA. Using cell-based reporter and thermal shift binding assays, we show that G3P binds to a conserved domain and activates the transcription factor carbohydrate-responsive element-binding protein (ChREBP), which regulates the Fgf21 gene promoter. The stimulation of Fgf21 gene transcription by ethanol also requires its metabolism to acetyl-CoA and correlates with histone acetylation. Accordingly, a p300/CBP histone acetyltransferase inhibitor blocks histone acetylation, ChREBP recruitment, and transcriptional activation at the Fgf21 promoter. Together, these findings reveal a dual regulatory mechanism driven by both G3P and acetyl-CoA that explains ethanol’s robust stimulatory effect on Fgf21 and possibly other ChREBP target genes in the liver.","journal":"Proceedings of the National Academy of Sciences","year":2025,"id":529678,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":false,"deposit_databanks":null,"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":226857,"name":"Bryan Mackowiak","orcid":"0000-0001-9840-2013","position":1,"is_corresponding":false},{"id":1164262,"name":"Hyung Bum Kim","orcid":"0000-0003-1682-4998","position":2,"is_corresponding":false},{"id":351399,"name":"Genaro Hernandez","orcid":"0000-0003-3666-8769","position":3,"is_corresponding":false},{"id":541114,"name":"Tulip Nandu","orcid":"0000-0001-9786-614X","position":4,"is_corresponding":false},{"id":351403,"name":"Kevin Vale","orcid":"0000-0002-4692-5557","position":5,"is_corresponding":false},{"id":750843,"name":"Yuan Zhang","orcid":"0000-0002-5219-7736","position":6,"is_corresponding":false},{"id":303504,"name":"Lauren G. Zacharias","orcid":null,"position":7,"is_corresponding":false},{"id":563120,"name":"Thomas P. Mathews","orcid":"0000-0002-9355-8243","position":8,"is_corresponding":false},{"id":226858,"name":"Bin Gao","orcid":"0000-0002-0505-2972","position":9,"is_corresponding":false},{"id":264569,"name":"W. Lee Kraus","orcid":"0000-0002-8786-2986","position":10,"is_corresponding":false},{"id":351406,"name":"Steven A. Kliewer","orcid":"0000-0001-5161-641X","position":11,"is_corresponding":false},{"id":351407,"name":"David J. Mangelsdorf","orcid":"0000-0002-4355-0796","position":12,"is_corresponding":false},{"id":513186,"name":"Mi Cheong Cheong","orcid":"0000-0002-7604-6203","position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":null,"created_at":"2026-07-19T02:51:01.235017Z","pmid":"40440069","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}