Cheong Mi Cheong, Mackowiak Bryan, Kim Hyung Bum, Hernandez Genaro, Nandu Tulip, Vale Kevin, Zhang Yuan, Zacharias Lauren G, Mathews Thomas P, Gao Bin, Kraus W Lee, Kliewer Steven A, Mangelsdorf David J
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD 20892.
Proc Natl Acad Sci U S A. 2025 Jun 3;122(22):e2505263122. doi: 10.1073/pnas.2505263122. Epub 2025 May 29.
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 gene promoter. The stimulation of 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 promoter. Together, these findings reveal a dual regulatory mechanism driven by both G3P and acetyl-CoA that explains ethanol's robust stimulatory effect on and possibly other ChREBP target genes in the liver.
乙醇能迅速刺激肝脏合成成纤维细胞生长因子21（FGF21），该激素随后作用于大脑，引发多方面的保护反应。我们发现，在小鼠中，FGF21的这种诱导发生在基因转录水平，且受乙醇代谢的两种副产物甘油-3-磷酸（G3P）和乙酰辅酶A调控。通过基于细胞的报告基因和热迁移结合试验，我们发现G3P结合到一个保守结构域并激活转录因子碳水化合物反应元件结合蛋白（ChREBP），后者调控该基因启动子。乙醇对基因转录的刺激作用也需要其代谢生成乙酰辅酶A，且与组蛋白乙酰化相关。因此，一种p300/CBP组蛋白乙酰转移酶抑制剂可阻断组蛋白乙酰化、ChREBP募集以及启动子处的转录激活。这些发现共同揭示了一种由G3P和乙酰辅酶A驱动的双重调控机制，该机制解释了乙醇对肝脏中该基因以及可能的其他ChREBP靶基因的强大刺激作用。
