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

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.

SUBMITTER: Pan A

PROVIDER: S-EPMC8770464 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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

Pan An A Sun Xiao-Meng XM Huang Feng-Qing FQ Liu Jin-Feng JF Cai Yuan-Yuan YY Wu Xin X Alolga Raphael N RN Li Ping P Liu Bao-Lin BL Liu Qun Q Qi Lian-Wen LW

Nature communications 20220119 1

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 ...[more]

PMID: 35046401

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Project description:ObjectiveThroughout the last decade, interest has intensified in intermittent fasting, ketogenic diets, and exogenous ketone therapies as prospective health-promoting, therapeutic, and performance-enhancing agents. However, the regulatory roles of ketogenesis and ketone metabolism on liver homeostasis remain unclear. Therefore, we sought to develop a better understanding of the metabolic consequences of hepatic ketone body metabolism by focusing on the redox-dependent interconversion of acetoacetate (AcAc) and D-β-hydroxybutyrate (D-βOHB).MethodsUsing targeted and isotope tracing high-resolution liquid chromatography-mass spectrometry, dual stable isotope tracer nuclear magnetic resonance spectroscopy-based metabolic flux modeling, and complementary physiological approaches in novel cell type-specific knockout mice, we quantified the roles of hepatocyte D-β-hydroxybutyrate dehydrogenase (BDH1), a mitochondrial enzyme required for NAD+/NADH-dependent oxidation/reduction of ketone bodies.ResultsExogenously administered AcAc is reduced to D-βOHB, which increases hepatic NAD+/NADH ratio and reflects hepatic BDH1 activity. Livers of hepatocyte-specific BDH1-deficient mice did not produce D-βOHB, but owing to extrahepatic BDH1, these mice nonetheless remained capable of AcAc/D-βOHB interconversion. Compared to littermate controls, hepatocyte-specific BDH1 deficient mice exhibited diminished liver tricarboxylic acid (TCA) cycle flux and impaired gluconeogenesis, but normal hepatic energy charge overall. Glycemic recovery after acute insulin challenge was impaired in knockout mice, but they were not more susceptible to starvation-induced hypoglycemia.ConclusionsKetone bodies influence liver homeostasis. While liver BDH1 is not required for whole body equilibration of AcAc and D-βOHB, loss of the ability to interconvert these ketone bodies in hepatocytes results in impaired TCA cycle flux and glucose production. Therefore, through oxidation/reduction of ketone bodies, BDH1 is a significant contributor to hepatic mitochondrial redox, liver physiology, and organism-wide ketone body homeostasis.

Project description:Purpose: In this study, we determined ketone oxidation rates in athletes under metabolic conditions of high and low carbohydrate (CHO) and fat availability. Methods: Six healthy male athletes completed 1 h of bicycle ergometer exercise at 75% maximal power (WMax) on three occasions. Prior to exercise, participants consumed 573 mg·kg bw-1 of a ketone ester (KE) containing a 13C label. To manipulate CHO availability, athletes undertook glycogen depleting exercise followed by isocaloric high-CHO or very-low-CHO diets. To manipulate fat availability, participants were given a continuous infusion of lipid during two visits. Using stable isotope methodology, β-hydroxybutyrate (βHB) oxidation rates were therefore investigated under the following metabolic conditions: (i) high CHO + normal fat (KE+CHO); (ii) high CHO + high fat KE+CHO+FAT); and (iii) low CHO + high fat (KE+FAT). Results: Pre-exercise intramuscular glycogen (IMGLY) was approximately halved in the KE+FAT vs. KE+CHO and KE+CHO+FAT conditions (both p < 0.05). Blood free fatty acids (FFA) and intramuscular long-chain acylcarnitines were significantly greater in the KE+FAT vs. other conditions and in the KE+CHO+FAT vs. KE+CHO conditions before exercise. Following ingestion of the 13C labeled KE, blood βHB levels increased to ≈4.5 mM before exercise in all conditions. βHB oxidation was modestly greater in the KE+CHO vs. KE+FAT conditions (mean diff. = 0.09 g·min-1, p = 0.03; d = 0.3), tended to be greater in the KE+CHO+FAT vs. KE+FAT conditions (mean diff. = 0.07 g·min-1; p = 0.1; d = 0.3) and were the same in the KE+CHO vs. KE+CHO+FAT conditions (p < 0.05; d < 0.1). A moderate positive correlation between pre-exercise IMGLY and βHB oxidation rates during exercise was present (p = 0.04; r = 0.5). Post-exercise intramuscular βHB abundance was markedly elevated in the KE+FAT vs. KE+CHO and KE+CHO+FAT conditions (both, p < 0.001; d = 2.3). Conclusion: βHB oxidation rates during exercise are modestly impaired by low CHO availability, independent of circulating βHB levels.

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

Publications

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

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