Qiao Ya-Nan, Li Lei, Hu Song-Hua, Yang Yuan-Xin, Ma Zhen-Zhen, Huang Lin, An Yan-Peng, Yuan Yi-Yuan, Lin Yan, Xu Wei, Li Yao, Lin Peng-Cheng, Cao Jing, Zhao Jian-Yuan, Zhao Shi-Min
The Obstetrics & Gynaecology Hospital of Fudan University, State Key Laboratory of Genetic Engineering, Shanghai Key Laboratory of Metabolic Remodelling and Health, Institutes of Biomedical Sciences, and Children's Hospital of Fudan University, Fudan University, Shanghai, China.
Department of Anatomy, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
Cell Discov. 2024 Feb 13;10(1):17. doi: 10.1038/s41421-023-00636-x.
Ketogenic diet (KD) alleviates refractory epilepsy and reduces seizures in children. However, the metabolic/cell biologic mechanisms by which the KD exerts its antiepileptic efficacy remain elusive. Herein, we report that KD-produced β-hydroxybutyric acid (BHB) augments brain gamma-aminobutyric acid (GABA) and the GABA/glutamate ratio to inhibit epilepsy. The KD ameliorated pentetrazol-induced epilepsy in mice. Mechanistically, KD-produced BHB, but not other ketone bodies, inhibited HDAC1/HDAC2, increased H3K27 acetylation, and transcriptionally upregulated SIRT4 and glutamate decarboxylase 1 (GAD1). BHB-induced SIRT4 de-carbamylated and inactivated glutamate dehydrogenase to preserve glutamate for GABA synthesis, and GAD1 upregulation increased mouse brain GABA/glutamate ratio to inhibit neuron excitation. BHB administration in mice inhibited epilepsy induced by pentetrazol. BHB-mediated relief of epilepsy required high GABA level and GABA/glutamate ratio. These results identified BHB as the major antiepileptic metabolite of the KD and suggested that BHB may serve as an alternative and less toxic antiepileptic agent than KD.
生酮饮食（KD）可缓解儿童难治性癫痫并减少癫痫发作。然而，KD发挥其抗癫痫疗效的代谢/细胞生物学机制仍不清楚。在此，我们报告KD产生的β-羟基丁酸（BHB）可增加脑γ-氨基丁酸（GABA）及GABA/谷氨酸比值以抑制癫痫。KD改善了小鼠戊四氮诱导的癫痫。机制上，KD产生的BHB而非其他酮体，抑制组蛋白去乙酰化酶1/组蛋白去乙酰化酶2（HDAC1/HDAC2），增加H3K27乙酰化，并转录上调沉默调节蛋白4（SIRT4）和谷氨酸脱羧酶1（GAD1）。BHB诱导SIRT4使谷氨酸脱氢酶脱氨甲酰化并使其失活，以保留谷氨酸用于GABA合成，且GAD1上调增加小鼠脑GABA/谷氨酸比值以抑制神经元兴奋。给小鼠注射BHB可抑制戊四氮诱导的癫痫。BHB介导的癫痫缓解需要高GABA水平和GABA/谷氨酸比值。这些结果确定BHB是KD的主要抗癫痫代谢物，并表明BHB可能作为一种比KD毒性更小的替代性抗癫痫药物。
