2. Academic Validation
  3. The mitochondrial β-oxidation enzyme HADHA restrains hepatic glucagon response by promoting β-hydroxybutyrate production

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

  • Nat Commun. 2022 Jan 19;13(1):386. doi: 10.1038/s41467-022-28044-x.
An Pan 1,  Xiao-Meng Sun 1,  Feng-Qing Huang 1,  Jin-Feng Liu 2,  Yuan-Yuan Cai 1,  Xin Wu 1,  Raphael N Alolga 2,  Ping Li 1,  Bao-Lin Liu 1,  Qun Liu 3 4,  Lian-Wen Qi 5 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China.
  • 2 Clinical Metabolomics Center, China Pharmaceutical University, Nanjing, 211198, China.
  • 3 State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. liuquncpu@126.com.
  • 4 Clinical Metabolomics Center, China Pharmaceutical University, Nanjing, 211198, China. liuquncpu@126.com.
  • 5 State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China. Qilw@cpu.edu.cn.
  • 6 Clinical Metabolomics Center, China Pharmaceutical University, Nanjing, 211198, China. Qilw@cpu.edu.cn.
PMID: 35046401 DOI: 10.1038/s41467-022-28044-x
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.

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