The mitochondrial β-oxidation enzyme HADHA restrains hepatic glucagon response by promoting β-hydroxybutyrate production

Disordered hepatic glucagon response contributes to hyperglycemia in diabetes via gluconeogenesis. Here the authors report that the mitochondrial beta-oxidation enzyme HADHA promotes beta-hydroxybutyrate production, which negatively regulates hepatic gluconeogenesis during glucagon challenge by targeting HDAC7 in mice. Disordered hepatic glucagon response contributes to hyperglycemia in diabetes. The regulators involved in glucagon response are less understood. This work aims to investigate the roles of mitochondrial beta-oxidation enzyme HADHA and its downstream ketone bodies in hepatic glucagon response. Here we show that glucagon challenge impairs expression of HADHA. Liver-specific HADHA overexpression reversed hepatic gluconeogenesis in mice, while HADHA knockdown augmented glucagon response. Stable isotope tracing shows that HADHA promotes ketone body production via beta-oxidation. The ketone body beta-hydroxybutyrate (BHB) but not acetoacetate suppresses gluconeogenesis by selectively inhibiting HDAC7 activity via interaction with Glu543 site to facilitate FOXO1 nuclear exclusion. In HFD-fed mice, HADHA overexpression improved metabolic disorders, and these effects are abrogated by knockdown of BHB-producing enzyme. In conclusion, BHB is responsible for the inhibitory effect of HADHA on hepatic glucagon response, suggesting that HADHA activation or BHB elevation by pharmacological intervention hold promise in treating diabetes.

Automated summary

Disordered hepatic glucagon response is a contributing factor to hyperglycemia in diabetes. This study reveals that the mitochondrial beta-oxidation enzyme HADHA promotes the production of beta-hydroxybutyrate, which negatively regulates hepatic gluconeogenesis during glucagon challenge by targeting HDAC7. Activation of HADHA or elevation of beta-hydroxybutyrate levels through pharmacological intervention may hold promise in the treatment of diabetes.