ArticleNature communications2022
The mitochondrial β-oxidation enzyme HADHA restrains hepatic glucagon response by promoting β-hydroxybutyrate production.
Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 42 papers, 1 of them a synthesis that pooled it.
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Who cites it
42 citing papers in PubMed, 1 synthesis or guideline pooled it, 64 citations in OpenAlex.
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- A tryptophan metabolism-related gene signature predicts prognosis and immune features in cutaneous melanoma.Frontiers in immunology · 2026Article
- Immunocytes Play a Crucial Role as Mediators in the Protective Effects of D-β-Hydroxybutyrate Dehydrogenase 1 against Type 2 Diabetes Mellitus: A Mendelian Randomization StudyEndocrine, metabolic & immune disorders drug targets · 2026Article
- Longitudinal associations between PMFrontiers in cellular and infection microbiology · 2026Article
- ACSS2 coupled with KAT7 regulates histone β-hydroxybutyrylation to enhance transcription.Science advances · 2025Article
- Mild hypothermia attenuates hepatic ischemia-reperfusion injury by regulating FoxO1/PPARα pathway.Scientific reports · 2025Article
- Gut Microbiota Dysbiosis Remodels the Lysine Acetylome of the Mouse Cecum in Early Life.Biology · 2025Article
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- Metformin hydrochloride improves hepatic glucolipid metabolism in diabetes progression through SIRT5-mediated ECHA desuccinylation.Scientific reports · 2025Article
- Carabrone Attenuates Metabolic Dysfunction-Associated Steatohepatitis by Targeting STAT3 in Mice.MedComm · 2025Article
Corrections and comments
- Erratum issued
Authors and funding
11 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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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