PHDs/CPT1B/VDAC1 axis regulates long-chain fatty acid oxidation in cardiomyocytes

Angelini, Aude; Saha, Pradip Kumar; Jain, Antrix; Jung, Sung Yun; Mynatt, Randall L.; Pi, Xinchun; Xie, Liang

doi:10.1016/j.celrep.2021.109767

Cited by 22 publications

(10 citation statements)

References 93 publications

(119 reference statements)

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“…As cardiomyocytes mature, the primary mechanism for ATP generation switches from glycolysis to beta fatty acid oxidation (β-FAOX) ( Lopaschuk and Jaswal, 2010 ), which is consistent with our observation that glycolysis genes [Acyl-CoA Synthetase Short Chain Family Member 2 (ACSS2), Glucose-6-Phosphate Isomerase (GPI), and Hexokinase 1 (HK1) ( Glycolysis, 2021 )] were highly expressed in the CM8 cluster (i.e., fetal cardiomyocytes) but not in CM9 (i.e., the CTL-P56–exclusive cluster), while genes involved in β-FAOX [ATP Binding Cassette Subfamily D Member 1 (ABCD1) ( van Roermund et al, 2011 ), Carnitine Palmitoyltransferase 1B (CPT1B) ( Angelini et al, 2021 ), and Hydroxyacyl-CoA Dehydrogenase Trifunctional Multienzyme Complex Subunits Alpha ( Miklas et al, 2019 ) and Beta ( Sekine et al, 2021 ) (HADHA and HADHB, respectively)] were downregulated in CM8 and upregulated in CM9 ( Figures 4A, B ). Sparse-model analysis indicated that glycolysis ( Glycolysis, 2021 ) was the dominant metabolic pathway in most other cardiomyocyte clusters.…”

Section: Resultsmentioning

confidence: 99%

Cardiomyocyte Cell-Cycle Regulation in Neonatal Large Mammals: Single Nucleus RNA-Sequencing Data Analysis via an Artificial-Intelligence–Based Pipeline

Nguyen

Wei²,

Nakada³

et al. 2022

Front. Bioeng. Biotechnol.

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Adult mammalian cardiomyocytes have very limited capacity to proliferate and repair the myocardial infarction. However, when apical resection (AR) was performed in pig hearts on postnatal day (P) 1 (ARP1) and acute myocardial infarction (MI) was induced on P28 (MIP28), the animals recovered with no evidence of myocardial scarring or decline in contractile performance. Furthermore, the repair process appeared to be driven by cardiomyocyte proliferation, but the regulatory molecules that govern the ARP1-induced enhancement of myocardial recovery remain unclear. Single-nucleus RNA sequencing (snRNA-seq) data collected from fetal pig hearts and the hearts of pigs that underwent ARP1, MIP28, both ARP1 and MI, or neither myocardial injury were evaluated via autoencoder, cluster analysis, sparse learning, and semisupervised learning. Ten clusters of cardiomyocytes (CM1–CM10) were identified across all experimental groups and time points. CM1 was only observed in ARP1 hearts on P28 and was enriched for the expression of T-box transcription factors 5 and 20 (TBX5 and TBX20, respectively), Erb-B2 receptor tyrosine kinase 4 (ERBB4), and G Protein-Coupled Receptor Kinase 5 (GRK5), as well as genes associated with the proliferation and growth of cardiac muscle. CM1 cardiomyocytes also highly expressed genes for glycolysis while lowly expressed genes for adrenergic signaling, which suggested that CM1 were immature cardiomyocytes. Thus, we have identified a cluster of cardiomyocytes, CM1, in neonatal pig hearts that appeared to be generated in response to AR injury on P1 and may have been primed for activation of CM cell-cycle activation and proliferation by the upregulation of TBX5, TBX20, ERBB4, and GRK5.

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Section: Resultsmentioning

confidence: 99%

Cardiomyocyte Cell-Cycle Regulation in Neonatal Large Mammals: Single Nucleus RNA-Sequencing Data Analysis via an Artificial-Intelligence–Based Pipeline

Nguyen

Wei²,

Nakada³

et al. 2022

Front. Bioeng. Biotechnol.

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“…However, western blot analysis showed that only CPT1B was suppressed at the protein level by UA stimulation. CPT1B is the rate-limiting enzyme in cardiomyocytes that mediates FA transport into mitochondria for oxidation ( Wang et al, 2020 ; Angelini et al, 2021 ). Therefore, our results suggest that UA may induce FA metabolic disorders via CPT1B-mediated mitochondrial transport.…”

Section: Discussionmentioning

confidence: 99%

L-carnitine attenuated hyperuricemia-associated left ventricular remodeling through ameliorating cardiomyocytic lipid deposition

Yang

Lin²,

Zheng³

et al. 2023

Front. Pharmacol.

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Hyperuricemia (HUA) is associated with left ventricular remodeling (LVR) and thereby causes the initiation and development of a large number of cardiovascular diseases. LVR is typically accompanied by cardiomyocyte energy metabolic disorder. The energy supply of cardiomyocytes is provided by glucose and fatty acid (FA) metabolism. Currently, the effect of HUA on cardiomyocytic FA metabolism is unclear. In this study, we demonstrate that UA-induced cardiomyocyte injury is associated with cytoplasmic lipid deposition, which can be ameliorated by the FA metabolism-promoting drug L-carnitine (LC). UA suppresses carnitine palmitoyl transferase 1B (CPT1B), thereby inhibiting FA transport into the mitochondrial inner matrix for elimination. LC intervention can ameliorate HUA-associated left ventricular anterior wall thickening in mice. This study showed that FA transport dysfunction plays is a critical mechanism in both cardiomyocytic injury and HUA-associated LVR and promoting cytoplasmic FA transportation through pharmacological treatment by LC is a valid strategy to attenuate HUA-associated LVR.

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“…The dominant carnitine O-palmitoyltransferase (CPT) isoform in the heart is CPT1b. It is located on the outer mitochondrial membrane and catalyses carnitine conjugation of long-chain fatty acids, which facilitates mitochondrial transport and β-oxidation in cardiomyocytes [22]. In a rat diabetes model, CPT1b expression in myocardial tissues was significantly increased compared Liver and kidney Otsuka long-evans tokushima fatty rats, rats with induced insulin resistance Inhibit oxidative stress [30,31] with that in nondiabetic controls.…”

Section: Sglt2i and Myocardial Fat Metabolismmentioning

confidence: 99%

Insights into SGLT2 inhibitor treatment of diabetic cardiomyopathy: focus on the mechanisms

Huang

Luo

Liao

et al. 2023

Cardiovasc Diabetol

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Among the complications of diabetes, cardiovascular events and cardiac insufficiency are considered two of the most important causes of death. Experimental and clinical evidence supports the effectiveness of SGLT2i for improving cardiac dysfunction. SGLT2i treatment benefits metabolism, microcirculation, mitochondrial function, fibrosis, oxidative stress, endoplasmic reticulum stress, programmed cell death, autophagy, and the intestinal flora, which are involved in diabetic cardiomyopathy. This review summarizes the current knowledge of the mechanisms of SGLT2i for the treatment of diabetic cardiomyopathy. Graphical Abstract

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PHDs/CPT1B/VDAC1 axis regulates long-chain fatty acid oxidation in cardiomyocytes

Cited by 22 publications

References 93 publications

Cardiomyocyte Cell-Cycle Regulation in Neonatal Large Mammals: Single Nucleus RNA-Sequencing Data Analysis via an Artificial-Intelligence–Based Pipeline

Cardiomyocyte Cell-Cycle Regulation in Neonatal Large Mammals: Single Nucleus RNA-Sequencing Data Analysis via an Artificial-Intelligence–Based Pipeline

L-carnitine attenuated hyperuricemia-associated left ventricular remodeling through ameliorating cardiomyocytic lipid deposition

Insights into SGLT2 inhibitor treatment of diabetic cardiomyopathy: focus on the mechanisms

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