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Fibroblast growth factor 21 (FGF21) is secreted by hepatocytes as a peptide hormone to regulate glucose and lipid metabolism. FGF21 promotes hepatic ketogenesis and increases ketone body utilization in starvation. Histones are the target molecules of nutrients in regulating hepatic metabolic homeostasis. However, the effect of ketone bodies on FGF21 expression and the involvement of histones in it is not clear yet. The present study observed the effects of β-hydroxybutyrate (β-OHB), the main physiological ketone body, on FGF21 expression in human hepatoma HepG2 cells  in vitro  and in mice  in vivo , and the role of histone deacetylases (HDACs) in β-OHB-regulated FGF21 expression was investigated. The results showed that β-OHB significantly upregulated FGF21 gene expression and increased FGF21 protein levels while it inhibited HDACs’ activity in HepG2 cells. HDACs’ inhibition by entinostat upregulated FGF21 expression and eliminated β-OHB-stimulated FGF21 expression in HepG2 cells. Intraperitoneal injections of β-OHB in mice resulted in the elevation of serum β-OHB and the inhibition of hepatic HDACs’ activity. Meanwhile, hepatic FGF21 expression and serum FGF21 levels were significantly increased in β-OHB-treated mice compared with the control. It is suggested that β-OHB upregulates FGF21 expression through inhibition of HDACs’ activity in hepatocytes.

β-Hydroxybutyrate upregulates FGF21 expression through inhibition of histone deacetylases in hepatocytes