Fig. 8. Scheme of the role for HADHA in promoting BHB production to restrain hepatic gluconeogenesis.

In normal state, hepatic HADHA facilitates ketogenesis from fatty acid β-oxidation. BHB, a predominant ketone body which is dependent on upstream HADHA expression, plays a key role in regulating gluconeogenic genes and hepatic glucose production. Mechanism-wise, BHB can bind to HDAC7 and inhibit its activity, thus preserving FOXO1 acetylation and phosphorylation. In diabetes, excess glucagon impairs HADHA expression and inhibits downstream BHB production, thereby increasing FOXO1 transcriptional activity and hepatic gluconeogenesis via HDAC7 activation.