Ethanol induction of FGF21 in the liver is dependent on histone acetylation and ligand activation of ChREBP by glycerol-3-phosphate
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 <i>Fgf21</i> gene promoter. The stimulation of <i>Fgf21</i> 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 <i>Fgf21</i> promoter. Together, these findings reveal a dual regulatory mechanism driven by both G3P and acetyl-CoA that explains ethanol's robust stimulatory effect on <i>Fgf21</i> and possibly other ChREBP target genes in the liver.
Authors
- David J. Mangelsdorf (ORCID: https://orcid.org/0000-0002-4355-0796)
- Steven A. Kliewer (ORCID: https://orcid.org/0000-0001-5161-641X)
- Kevin Vale (ORCID: https://orcid.org/0000-0002-4692-5557)
- Genaro Hernandez (ORCID: https://orcid.org/0000-0003-3666-8769)
- Thomas P. Mathews (ORCID: https://orcid.org/0000-0002-9355-8243)
- Hyung Bum Kim (ORCID: https://orcid.org/0000-0003-1682-4998)
- W. Lee Kraus (ORCID: https://orcid.org/0000-0002-8786-2986)
- Lauren G. Zacharias (ORCID: https://orcid.org/0009-0007-7413-6460)
- Bryan Mackowiak (ORCID: https://orcid.org/0000-0001-9840-2013)
- Mi Cheong Cheong (ORCID: https://orcid.org/0000-0002-7604-6203)
- Tulip Sunil Nandu (ORCID: https://orcid.org/0000-0001-9786-614X)
- Yuan Zhang (ORCID: https://orcid.org/0000-0002-5219-7736)
- Bin Gao (ORCID: https://orcid.org/0000-0002-0505-2972)
Institutions
- Children's Medical Center (US)
- Southwestern Medical Center (US)
- National Institute on Alcohol Abuse and Alcoholism (US)
- Southwestern Medical Center (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-05-29
- DOI
- https://doi.org/10.1073/pnas.2505263122
- Citations
- 6
- Primary Topic
- Fibroblast Growth Factor Research
- Type
- article
- Field-Weighted Citation Impact
- 4.03
Funders
- Howard Hughes Medical Institute
- Welch Foundation
- Cancer Prevention and Research Institute of Texas
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism
- National Institute of Diabetes and Digestive and Kidney Diseases