3-Hydroxybutyric acid (D-β-hydroxybutyrate, BHB) is an endogenous and specific inhibitor of histone deacetylase (HDAC). The IC50 for inhibiting HDAC1, HDAC3 and HDAC4 is respectively 5.3, 2.4 and 4.5 mM[1]. 3-Hydroxybutyric acid is a ketone body that can interact with lipids and also reduce the interfacial viscosity of the DPPC monolayer [2]. 3-Hydroxybutyric acid blocks the NLRP3 inflammasome and does not undergo oxidation in the TCA cycle [3].
In vitro, histone H3K9 acetylation at the Foxo3a and Mt2 promoters increased after HEK293 cells were treated with 3-hydroxybutyrate (10 mM) for 24 hours [1]. After treating human monocytes for 24 hours, 3-hydroxybutyric acid (1-20 mM) dose-dependently inhibits the production of interleukin IL-1β and IL-18 mediated by the NLRP3 inflammasome [3]. 3-Hydroxybutyric acid (10 mM) treated mouse glial cells for 48 hours, which significantly promoted cell proliferation [4].
In vivo, 3-hydroxybutyrate (2mM or 5mM) administered to C57BL/6 mice via intracerebroventricular injection can reduce the binding of HDAC2 and HDAC3 to the pI promoter of Bdnf [5]. Intraperitoneal injection of 3-hydroxybutyric acid (5.0 mmol/kg) into suckling mice after hypoxia-ischemia treatment can reduce the number of TUNEL-positive cells in the brain area, reduce cerebral infarction, and thereby reduce brain damage [6].
References:
[1] Shimazu T , Hirschey M D , Newman J ,et al. Suppression of Oxidative Stress by β-Hydroxybutyrate, an Endogenous Histone Deacetylase Inhibitor[J]. Science, 2013, 339(6116):211-4.
[2] Hsu TT, et al. 3-Hydroxybutyric acid interacts with lipid monolayers at concentrations that impair consciousness[J]. Langmuir. 2013 Feb 12;29(6):1948-55.
[3] Youm Y H , Nguyen K Y , Grant R W ,et al. The ketone body β-hydroxybutyrate blocks the NLRP3 inflammasome-mediated inflammatory disease[J]. Nature Medicine, 2015.
[4] Xiao X Q , Zhao Y , Chen G Q .The effect of 3-hydroxybutyrate and its derivatives on the growth of glial cells[J].Biomaterials, 2007, 28(25):3608-3616.
[5]Sleiman S F , Jeffrey H , Rami A H ,et al. Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β-hydroxybutyrate[J].Elife, 2016.
[6]Lee B , Woo D C , Woo C W ,et al.Exogenous β-Hydroxybutyrate Treatment and Neuroprotection in a Suckling Rat Model of Hypoxic-Ischemic Encephalopathy[J].Dev Neurosci, 2018.
3-羟基丁酸（3-Hydroxybutyric acid，D-β-hydroxybutyrate，BHB）是一类组蛋白脱乙酰酶（HDAC）的内源性和特异性抑制剂，抑制HDAC1、HDAC3和HDAC4的IC50分别为5.3、2.4和4.5 mM[1]。3-羟基丁酸是一种酮体，能够与脂质相互作用，还会降低DPPC单分子层的界面粘度[2]。3-羟基丁酸阻断NLRP3炎症小体，且在TCA循环中不经历氧化[3]。
在体外，3-羟基丁酸 (10 mM)处理HEK293细胞24h后，Foxo3a 和 Mt2启动子处的组蛋白H3K9乙酰化增加[1]。3-羟基丁酸 (1-20 mM)处理人单核细胞24h后，剂量依赖性抑制NLRP3炎症小体介导的白细胞介素IL-1β和IL-18的产生[3]。3-羟基丁酸 (10 mM)处理小鼠神经胶质细胞48h，具有明显的促进细胞增殖的作用[4]。
在体内，3-羟基丁酸（2mM or 5mM）通过脑室内注射给予C57BL/6小鼠，可降低HDAC2和HDAC3对Bdnf 的pI启动子的结合[5]。3-羟基丁酸（5.0 mmol/kg）腹腔注射给予缺氧缺血处理后的乳鼠，可减少脑区TUNEL阳性细胞的数量，减少脑梗塞，从而减轻脑损伤[6]。