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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,6,3]]},"abstract":"<jats:p>\n                    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\n                    <jats:italic toggle=\"yes\">Fgf21<\/jats:italic>\n                    gene promoter. The stimulation of\n                    <jats:italic toggle=\"yes\">Fgf21<\/jats:italic>\n                    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\n                    <jats:italic toggle=\"yes\">Fgf21<\/jats:italic>\n                    promoter. Together, these findings reveal a dual regulatory mechanism driven by both G3P and acetyl-CoA that explains ethanol\u2019s robust stimulatory effect on\n                    <jats:italic toggle=\"yes\">Fgf21<\/jats:italic>\n                    and possibly other ChREBP target genes in the liver.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2505263122","type":"journal-article","created":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T11:27:10Z","timestamp":1748518030000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":13,"title":["Ethanol induction of FGF21 in the liver is dependent on histone acetylation and ligand activation of ChREBP by glycerol-3-phosphate"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7604-6203","authenticated-orcid":false,"given":"Mi Cheong","family":"Cheong","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of Texas Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan","family":"Mackowiak","sequence":"additional","affiliation":[{"name":"Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH","place":["Bethesda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyung Bum","family":"Kim","sequence":"additional","affiliation":[{"name":"Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3666-8769","authenticated-orcid":false,"given":"Genaro","family":"Hernandez","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Texas Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tulip","family":"Nandu","sequence":"additional","affiliation":[{"name":"Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Vale","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Texas Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Texas Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren G.","family":"Zacharias","sequence":"additional","affiliation":[{"name":"Children\u2019s Medical Center Research Institute, UT Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas P.","family":"Mathews","sequence":"additional","affiliation":[{"name":"Children\u2019s Medical Center Research Institute, UT Southwestern Medical Center","place":["Dallas"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Gao","sequence":"additional","affiliation":[{"name":"Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH","place":["Bethesda"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8786-2986","authenticated-orcid":false,"given":"W. 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