Pyruvate Dehydrogenase Kinase 4: A Key Mediator for Metabolic Regulation of Liver Regeneration

Burdick, James F.; Sun, Zhao Li

doi:10.1002/hep4.1506

Cited by 2 publications

(1 citation statement)

References 7 publications

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“…24 New experimental evidence also supports an association between ADH1B and NAFLD severity, 25 and transgenic mouse data show that lower expression of CAT results in a higher likelihood of developing fatty liver and type-2 diabetes mellitus. 26 Furthermore, the visualization includes genes with biologically plausible roles in NAFLD etiology (SREBF1 is involved in lipogenesis in both adipose and liver tissue, which are in turn associated with NAFLD, 27 and PDK4 regulates insulin action and the metabolism of fatty acids, and plays a role in liver tissue regeneration 28 ). Other genes, including NFE2L2 and CD14, are to the best of our knowledge entirely novel and can therefore be thought of as new hypotheses generating to explore how PFOA and other toxicants can lead to NAFLD or pathologically similar diseases.…”

Section: ■ Resultsmentioning

confidence: 99%

Automating Predictive Toxicology Using ComptoxAI

Romano

Hao

Moore

et al. 2022

Chem. Res. Toxicol.

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ComptoxAI is a new data infrastructure for computational and artificial intelligence research in predictive toxicology. Here, we describe and showcase ComptoxAI’s graph-structured knowledge base in the context of three real-world use-cases, demonstrating that it can rapidly answer complex questions about toxicology that are infeasible using previous technologies and data resources. These use-cases each demonstrate a tool for information retrieval from the knowledge base being used to solve a specific task: The “shortest path” module is used to identify mechanistic links between perfluorooctanoic acid (PFOA) exposure and nonalcoholic fatty liver disease; the “expand network” module identifies communities that are linked to dioxin toxicity; and the quantitative structure–activity relationship (QSAR) dataset generator predicts pregnane X receptor agonism in a set of 4,021 pesticide ingredients. The contents of ComptoxAI’s source data are rigorously aggregated from a diverse array of public third-party databases, and ComptoxAI is designed as a free, public, and open-source toolkit to enable diverse classes of users including biomedical researchers, public health and regulatory officials, and the general public to predict toxicology of unknowns and modes of action.

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Section: ■ Resultsmentioning

confidence: 99%

Automating Predictive Toxicology Using ComptoxAI

Romano

Hao

Moore

et al. 2022

Chem. Res. Toxicol.

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Protein PDK4 Interacts with HMGCS2 to Facilitate High Glucoseinduced Myocardial Injuries

Liang

Tan

Bao³

et al. 2023

CMM

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Objectives: As a distinct type of cardiomyopathy, diabetic cardiomyopathy (DCM) is featured as diastolic or systolic cardiac dysfunction in diabetic patients. In order to broaden the understanding of molecular mechanisms in DCM, we intended to explore the mechanism of the interaction between PDK4 protein and Hmgcs2 in high glucose (HG)-induced myocardial damages. Methods: PDK4 and Hmgcs2 expression in the myocardium of diabetes mellitus (DM) model rats and HG-incubated cardiomyocyte line H9C2 were analyzed by western blot analysis. Echocardiography and TUNEL assay were utilized for respective assessment of cardiac structure and function and cardiomyocyte apoptosis in DM rats after silencing PDK4 or/and Hmgcs2. In vitro, the impact of PDK4 and Hmgcs2 on HG-induced cardiomyocyte injuries was identified with cell counting kit-8 and flow cytometry assays, along with detection of LDH release, Caspase-3/7 activities, and reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Moreover, a co-immunoprecipitation assay was utilized to test the interaction between PDK4 and Hmgcs2. Results: Both PDK4 and Hmgcs2 were highly expressed in the myocardial tissues of DM rats. Mechanistically, PDK4 interacted with Hmgcs2 to upregulate Hmgcs2 expression in HG-induced H9C2 cells. Silencing PDK4 improved cardiac function and reduced cardiomyocyte apoptosis in DM rats. In HG-induced H9C2 cells, PDK4 or Hmgcs2 silencing enhanced cell viability and reduced LDH release, Caspase-3/7 activities, cell apoptosis, and ROS and MDA levels, and these trends were further promoted by the simultaneous silencing of PDK4 and Hmgcs2. Conclusions: In summary, the silencing of PDK4 and Hmgcs2 alleviated HG-induced myocardial injuries through their interaction.

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Pyruvate Dehydrogenase Kinase 4: A Key Mediator for Metabolic Regulation of Liver Regeneration

Abstract: ReFeRenCes 1) Zhao Y, Tran M, Wang L, Shin DJ, Wu J. PDK4-deficiency reprograms intrahepatic glucose and lipid metabolism to facilitate liver regeneration in mice. Hepatol Commun 2020;4:504-517.

Cited by 2 publications

References 7 publications

Automating Predictive Toxicology Using ComptoxAI

Automating Predictive Toxicology Using ComptoxAI

Protein PDK4 Interacts with HMGCS2 to Facilitate High Glucoseinduced Myocardial Injuries

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