Abstract
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 β-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 β-oxidation. The ketone body β-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.
Highlights
Disordered hepatic glucagon response contributes to hyperglycemia in diabetes
The decreased level of HADHA was replicated in high-fat diet (HFD)fed mice and ob/ob mice compared with normal control (Supplementary Fig. 1c)
Since the mRNA of HADHA was not affected by glucagon (Supplementary Fig. 1d), we investigated whether glucagon impaired HADHA induction via post-transcriptional regulation
Summary
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 β-oxidation enzyme HADHA and its downstream ketone bodies in hepatic glucagon response. The ketone body β-hydroxybutyrate (BHB) but not acetoacetate suppresses gluconeogenesis by selectively inhibiting HDAC7 activity via interaction with Glu[543] 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. Fat mobilization increases hepatic fatty acid uptake, and mitochondrial β-oxidation provides acetyl-CoA. Loss of HMGCS2 in chow-fed mice causes mild hyperglycemia and increases hepatic gluconeogenesis[9]. These events indicate the potential role of fat oxidation and ketogenesis in hepatic glucose homeostasis. BHB is demonstrated to inhibit NLRP3 inflammasome-mediated inflammation[17]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
