From these observations, we speculated that endogenous D-BHB which was dramatically increased by food deprivation, plays an important role in the attenuation of hypersensitivity symptoms through suppression of mast cell activation.
Increases in intracellular calcium activity are critical for the rapid exocytotic response of mast cells. The signaling pathway leading to exocytosis of mast cells has been well characterized [
33]. Interestingly, mast cells delivered from 24 hours of food deprivation and a ketogenic diet showed a decrease in mast cell [Ca2+]i mobilization induced by exposure to compound 48/80. Furthermore, in vitro D-BHB treatment with mast cells delivered from a control diet rat also suppressed degranulation and [Ca2+]i mobilization (Figure
4). G protein coupled receptor-mediated activation of phospholipase C and the associated production of inositol 1,4,5-trisphosphate induces release of Ca2+ from stores in the endoplasmic reticulum and Golgi apparatus through Ca2+-conducting IP3-receptors. Compound 48/80 is also known to initiate mast cell degranulation through direct activation of G proteins, which was proposed to mimic receptor signaling [
34,
35]. Thus, we speculate that D-BHB might have inhibited downstream of G-protein coupled intracellular signaling pathway, which leads to stabilization of mast cell membranes against degranulation stimuli. Further study is necessary to determine the cellular and molecular mechanism(s) underlying the stabilization of mast cells by D-BHB.