Butyric Acid Influences How β-Hydroxybutyrate Modulates Fatty Acid Oxidation and Ketogenesis To Support Ketosis

Background: The ketogenic diet has been applied since the early 1900's for therapy.Although, the restrictive dietary application has proved to be effective in the treatment of neurologic disease we are seeing a more recent trend for the successful application of the ketogenic diet to treat metabolic disorders.The restrictive nature of the diet and the flu-like symptoms associated with its inception, however, make it intolerable for most patients.Objectives: Here we report the mechanism by which the combination of an exogenous ketone, β-hydroxybutyrate (BHB) and butyric acid (BA) supplement (BHB-BA) can help facilitate ketosis with moderate and more tolerable dietary restriction by inducing ketogenesis and fatty acid oxidation.Methods: HepG2 cell line was assayed for ketogenesis and fatty acid oxidation activity after treating the cells with equimolar dosing of BHB alone and BHB-BA in fed-and starved-conditions.HepG2, T98G, BV2 and HEK293 cells were analysed for Nrf2 expression through Western blotting after treatment with different BHB-BA concentrations.Results: The results support incremental fatty acid oxidation and ketogenesis by BHB-BA over equimolar dosing of BHB on its own.We also show that the BHB-BA complex up-regulates expression of Nrf2, a master regulator of endogenous antioxidant proteins such as hemeoxygenase-1, glutathione peroxidase, superoxide dismutase-1 and catalase, in a cell and dose specific manner. Conclusion:Although more research needs to be done to explore the full metabolic and signalling activities by BHB and BA, the reported results provide an indication of how the short chain fatty acid, BA, could synergise the effects of the exogenous ketone body, BHB, and support the elevation of ketone status independent of or as an addition to the ketogenic diet.