β-Hydroxybutyrate induces histone H3 β-hydroxybutyrylation and attenuates diabetic brain microvascular endothelial hyperpermeability.

Although the main ketone body β-hydroxybutyrate (BHB) exerts multiple protective roles in the brain, it remains unclear whether BHB can up-regulate tight junction proteins and antagonize brain microvascular endothelial hyperpermeability in diabetes. In this study, type 2 diabetic db/db mice and high glucose-stimulated bEnd3 cells were treated with BHB. The brain microvascular permeability, the generation and localization of tight junction proteins Claudin-5 and zonula occludens-1 (ZO-1), the content and distribution of global lysine β-hydroxybutyrylation (Kbhb) and the content of histone H3-Kbhb were evaluated. The results firstly showed that BHB up-regulated the generation of Claudin-5 and ZO-1, promoted their co-localization, attenuated brain microvascular hyperpermeability and at least partially alleviated behavioral deficits in db/db mice. Meanwhile, BHB was confirmed to reverse the high glucose-induced paracellular hyperpermeability and the down-regulation of Claudin-5 and ZO-1 in brain microvascular endothelial bEnd3 cells. Mechanistically, global Kbhb levels were markedly elevated by BHB treatment but not by high glucose stimulation in bEnd3 cells. Then subcellular distribution showed that the BHB-induced Kbhb was predominantly enriched in the nucleus. Furthermore, the content of histone H3-Kbhb was increased significantly for BHB treatments in bEnd3 cells. In conclusion, BHB could induce histone H3-Kbhb and up-regulate the tight junction proteins Claudin-5 and ZO-1 in high glucose-stimulated brain microvascular endothelial cells, thereby attenuating microvascular hyperpermeability in db/db mice.