Yan Aili, Zhao Yanyan, Zhang Lijun, Liang Xiangyan, Zhang Xiaochun, Liang Fenli, Nian Shen, Li Xinhua, Sun Zhuo, Li Ke, Zhao Yu-Feng
Institute of Basic Medical Sciences, Xi'an Medical University, Xi'an, 710021, China.
Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, 710021, China.
Open Life Sci. 2022 Aug 10;17(1):856-864. doi: 10.1515/biol-2022-0095. eCollection 2022.
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 and in mice , 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.
成纤维细胞生长因子21（FGF21）由肝细胞作为一种肽类激素分泌，以调节葡萄糖和脂质代谢。FGF21促进肝脏生酮作用，并在饥饿时增加酮体的利用。组蛋白是调节肝脏代谢稳态中营养物质的靶分子。然而，酮体对FGF21表达的影响以及组蛋白在其中的作用尚不清楚。本研究观察了主要生理性酮体β-羟基丁酸（β-OHB）对人肝癌HepG2细胞和小鼠中FGF21表达的影响，并研究了组蛋白脱乙酰酶（HDACs）在β-OHB调节FGF21表达中的作用。结果显示，β-OHB显著上调HepG2细胞中FGF21基因表达并增加FGF21蛋白水平，同时抑制HDACs的活性。恩替诺特抑制HDACs上调了HepG2细胞中FGF21的表达，并消除了β-OHB刺激的FGF21表达。给小鼠腹腔注射β-OHB导致血清β-OHB升高和肝脏HDACs活性受到抑制。同时，与对照组相比，β-OHB处理的小鼠肝脏FGF21表达和血清FGF21水平显著增加。提示β-OHB通过抑制肝细胞中HDACs的活性上调FGF21表达。
