3-Hydroxybutyric acid (Synonyms: 3-Hydroxybutyric Acid, NSC 3806, βOHB)

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 H3_K9 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.