BDK inhibition acts as a catabolic switch to mimic fasting and improve metabolism in mice

Bollinger, Eliza; Peloquin, Matthew; Libera, Jenna; Albuquerque, Bina; Pashos, Evanthia; Shipstone, Arun; Hadjipanayis, Angela; Sun, Zenghui; Xing, Gang; Clasquin, Michelle; Stansfield, John C.; Tierney, Brendan; Gernhardt, Steven; Siddall, C. Parker; Greizer, Timothy; Geoly, Frank J.; Vargas, Sarah R.; Gao, Lily C.; Williams, Gail M.; Marshall, Mackenzie; Rosado, Amy; Steppan, Claire M.; Filipski, Kevin J.; Zhang, Bei B.; Miller, Russell A.; Flach, Rachel J. Roth

doi:10.1016/j.molmet.2022.101611

Cited by 20 publications

(30 citation statements)

References 52 publications

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“…2 B and C. BT2 treatment markedly activated BCKDHA in liver ( Fig. S2 ) consistent with other studies [ 24 , 25 ], demonstrating the validity of BT2 treatment as liver is the most important organ of BCAA metabolism. At the same time, BT2 treatment significantly decreased plasma BCAA and BCKA levels, whereas BCAA intake further elevated plasma BCAA and BCKA levels compared with AS mice ( Fig.…”

Section: Resultssupporting

confidence: 90%

Elevated branched-chain amino acid promotes atherosclerosis progression by enhancing mitochondrial-to-nuclear H2O2-disulfide HMGB1 in macrophages

Zhao¹,

Zhou²,

Wang³

et al. 2023

Redox Biology

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Section: Resultssupporting

confidence: 90%

Elevated branched-chain amino acid promotes atherosclerosis progression by enhancing mitochondrial-to-nuclear H2O2-disulfide HMGB1 in macrophages

Zhao¹,

Zhou²,

Wang³

et al. 2023

Redox Biology

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“…Considering the potent effect of pharmacological inhibition of BCKDK on heart failure progression [4,28,34], our results with cardiac specific BCKDK inactivation model is quite puzzling, but consistent with the similar observation reported by Murashige et al [11]. One possibility is that pharmacological approach by administration of small molecule BT2 systemically changes both cardiac as well as systemic BCAA flux, leading to changes of glucose homeostasis and whole body metabolism as previously demonstrated [35]. Therefore, the cardiac protective effect post injury could be a combined effect of both cardiac and systemic changes in BCAA flux.…”

Section: Discussionsupporting

confidence: 91%

Cell-autonomous effect of cardiomyocyte branched-chain amino acid catabolism in heart failure in mice

Cao

Rau

et al. 2023

Acta Pharmacol Sin

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Parallel to major changes in fatty acid and glucose metabolism, defect in branched-chain amino acid (BCAA) catabolism has also been recognized as a metabolic hallmark and potential therapeutic target for heart failure. However, BCAA catabolic enzymes are ubiquitously expressed in all cell types and a systemic BCAA catabolic defect is also manifested in metabolic disorder associated with obesity and diabetes. Therefore, it remains to be determined the cell-autonomous impact of BCAA catabolic defect in cardiomyocytes in intact hearts independent from its potential global effects. In this study, we developed two mouse models. One is cardiomyocyte and temporal-specific inactivation of the E1α subunit (BCKDHA-cKO) of the branched-chain α-ketoacid dehydrogenase (BCKDH) complex, which blocks BCAA catabolism. Another model is cardiomyocyte specific inactivation of the BCKDH kinase (BCKDK-cKO), which promotes BCAA catabolism by constitutively activating BCKDH activity in adult cardiomyocytes. Functional and molecular characterizations showed E1α inactivation in cardiomyocytes was sufficient to induce loss of cardiac function, systolic chamber dilation and pathological transcriptome reprogramming. On the other hand, inactivation of BCKDK in intact heart does not have an impact on baseline cardiac function or cardiac dysfunction under pressure overload. Our results for the first time established the cardiomyocyte cell autonomous role of BCAA catabolism in cardiac physiology. These mouse lines will serve as valuable model systems to investigate the underlying mechanisms of BCAA catabolic defect induced heart failure and to provide potential insights for BCAA targeted therapy.

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“…The effects of pharmacologic MPCi on BCAAs may be more dramatic because they are not liver-specific and could enhance BCKA oxidation in other organs that have high rates of BCKA catabolism. Indeed, a recent study with BDK liver-specific knockout mice demonstrated that this was not sufficient to affect systemic BCAA concentrations, but that systematic BDK inhibition lowered BCAAs by enhancing oxidation in extrahepatic tissues [ 47 ]. In the rat study described herein, we did not find an effect of MPCi on BCKDH phosphorylation in heart, BAT, or skeletal muscle and only a trend towards reduced pBCKDH in liver.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial pyruvate carrier inhibition initiates metabolic crosstalk to stimulate branched chain amino acid catabolism

Ferguson¹,

Eichler²,

Yiew³

et al. 2023

Molecular Metabolism

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BDK inhibition acts as a catabolic switch to mimic fasting and improve metabolism in mice

Cited by 20 publications

References 52 publications

Elevated branched-chain amino acid promotes atherosclerosis progression by enhancing mitochondrial-to-nuclear H2O2-disulfide HMGB1 in macrophages

Elevated branched-chain amino acid promotes atherosclerosis progression by enhancing mitochondrial-to-nuclear H2O2-disulfide HMGB1 in macrophages

Cell-autonomous effect of cardiomyocyte branched-chain amino acid catabolism in heart failure in mice

Mitochondrial pyruvate carrier inhibition initiates metabolic crosstalk to stimulate branched chain amino acid catabolism

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