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Journal of Molecular Endocrinology Jan 2021Discovered as a b-ZIP transcription repressor 30 years ago, E4 promoter-binding protein 4 (E4BP4) has been shown to play critical roles in immunity, circadian rhythms,... (Review)
Review
Discovered as a b-ZIP transcription repressor 30 years ago, E4 promoter-binding protein 4 (E4BP4) has been shown to play critical roles in immunity, circadian rhythms, and cancer progression. Recent research has highlighted E4BP4 as a novel regulator of metabolisms in various tissues. In this review, we focus on the function and mechanisms of hepatic E4BP4 in regulating lipid and glucose homeostasis, bile metabolism, as well as xenobiotic metabolism. Finally, E4BP4-specific targets will be discussed for the prevention and treatment of metabolic disorders.
Topics: Animals; Basic-Leucine Zipper Transcription Factors; Bile Acids and Salts; Cell Nucleus; Energy Metabolism; Glucose; Humans; Insulin; Lipid Metabolism; Liver
PubMed: 33434146
DOI: 10.1530/JME-20-0239 -
EMBO Reports Jul 2021In eukaryotic cells, DNA is tightly packed with the help of histone proteins into chromatin. Chromatin architecture can be modified by various post-translational... (Review)
Review
In eukaryotic cells, DNA is tightly packed with the help of histone proteins into chromatin. Chromatin architecture can be modified by various post-translational modifications of histone proteins. For almost 60 years now, studies on histone lysine acetylation have unraveled the contribution of this acylation to an open chromatin state with increased DNA accessibility, permissive for gene expression. Additional complexity emerged from the discovery of other types of histone lysine acylations. The acyl group donors are products of cellular metabolism, and distinct histone acylations can link the metabolic state of a cell with chromatin architecture and contribute to cellular adaptation through changes in gene expression. Currently, various technical challenges limit our full understanding of the actual impact of most histone acylations on chromatin dynamics and of their biological relevance. In this review, we summarize the state of the art and provide an overview of approaches to overcome these challenges. We further discuss the concept of subnuclear metabolic niches that could regulate local CoA availability and thus couple cellular metabolisms with the epigenome.
Topics: Acetylation; Acylation; Chromatin; Histones; Protein Processing, Post-Translational
PubMed: 34159701
DOI: 10.15252/embr.202152774 -
Annual Review of Physiology Feb 2019The lung is often overlooked as a metabolically active organ, yet biochemical studies have long demonstrated that glucose utilization surpasses that of many other... (Review)
Review
The lung is often overlooked as a metabolically active organ, yet biochemical studies have long demonstrated that glucose utilization surpasses that of many other organs, including the heart, kidney, and brain. For most cells in the lung, energy consumption is relegated to performing common cellular tasks, like mRNA transcription and protein translation. However, certain lung cell populations engage in more specialized types of energy-consuming behaviors, such as the beating of cilia or the production of surfactant. While many extrapulmonary diseases are now linked to abnormalities in cellular metabolism, the pulmonary community has only recently embraced the concept of metabolic dysfunction as a driver of respiratory pathology. Herein, we provide an overview of the major metabolic pathways in the lung and discuss how cells sense and adapt to low-energy states. Moreover, we review some of the emerging evidence that links alterations in cellular metabolism to the pathobiology of several common respiratory diseases.
Topics: Animals; Energy Metabolism; Glycolysis; Humans; Lung; Lung Diseases; Mitochondria; Oxidative Phosphorylation
PubMed: 30485759
DOI: 10.1146/annurev-physiol-020518-114640 -
Molecular Metabolism Aug 2020ATP-dependent chromatin remodelers are evolutionarily conserved complexes that alter nucleosome positioning to influence many DNA-templated processes, such as... (Review)
Review
BACKGROUND
ATP-dependent chromatin remodelers are evolutionarily conserved complexes that alter nucleosome positioning to influence many DNA-templated processes, such as replication, repair, and transcription. In particular, chromatin remodeling can dynamically regulate gene expression by altering accessibility of chromatin to transcription factors.
SCOPE OF REVIEW
This review provides an overview of the importance of chromatin remodelers in the regulation of metabolic gene expression. Particular emphasis is placed on the INO80 and SWI/SNF (BAF/PBAF) chromatin remodelers in both yeast and mammals. This review details discoveries from the initial identification of chromatin remodelers in Saccharomyces cerevisiae to recent discoveries in the metabolic requirements of developing embryonic tissues in mammals.
MAJOR CONCLUSIONS
INO80 and SWI/SNF (BAF/PBAF) chromatin remodelers regulate the expression of energy metabolism pathways in S. cerevisiae and mammals in response to diverse nutrient environments. In particular, the INO80 complex organizes the temporal expression of gene expression in the metabolically synchronized S. cerevisiae system. INO80-mediated chromatin remodeling is also needed to constrain cell division during metabolically favorable conditions. Conversely, the BAF/PBAF remodeler regulates tissue-specific glycolytic metabolism and is disrupted in cancers that are dependent on glycolysis for proliferation. The role of chromatin remodeling in metabolic gene expression is downstream of the metabolic signaling pathways, such as the TOR pathway, a critical regulator of metabolic homeostasis. Furthermore, the INO80 and BAF/PBAF chromatin remodelers have both been shown to regulate heart development, the tissues of which have unique requirements for energy metabolism during development. Collectively, these results demonstrate that chromatin remodelers communicate metabolic status to chromatin and are a central component of homeostasis pathways that optimize cell fitness, organismal development, and prevent disease.
Topics: Animals; Chromatin; Chromatin Assembly and Disassembly; DNA-Binding Proteins; Gene Expression; Gene Expression Regulation; Metabolic Networks and Pathways; Metabolism; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Transcription Factors; Transcriptional Activation
PubMed: 32251664
DOI: 10.1016/j.molmet.2020.100973 -
Drug Metabolism and Disposition: the... Aug 2018Drug-induced cardiotoxicity may be modulated by endogenous arachidonic acid (AA)-derived metabolites known as epoxyeicosatrienoic acids (EETs) synthesized by cytochrome... (Review)
Review
Drug-induced cardiotoxicity may be modulated by endogenous arachidonic acid (AA)-derived metabolites known as epoxyeicosatrienoic acids (EETs) synthesized by cytochrome P450 2J2 (CYP2J2). The biologic effects of EETs, including their protective effects on inflammation and vasodilation, are diverse because, in part, of their ability to act on a variety of cell types. In addition, CYP2J2 metabolizes both exogenous and endogenous substrates and is involved in phase 1 metabolism of a variety of structurally diverse compounds, including some antihistamines, anticancer agents, and immunosuppressants. This review addresses current understanding of the role of CYP2J2 in the metabolism of xenobiotics and endogenous AA, focusing on the effects on the cardiovascular system. In particular, we have promoted here the hypothesis that CYP2J2 influences drug-induced cardiotoxicity through potentially conflicting effects on the production of protective EETs and the metabolism of drugs.
Topics: Animals; Cardiotoxicity; Cardiovascular System; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Humans; Inactivation, Metabolic; Metabolic Clearance Rate; Xenobiotics
PubMed: 29695613
DOI: 10.1124/dmd.117.078964 -
Nucleic Acids Research Jan 2021Drug-metabolizing enzymes (DMEs) are critical determinant of drug safety and efficacy, and the interactome of DMEs has attracted extensive attention. There are 3 major...
Drug-metabolizing enzymes (DMEs) are critical determinant of drug safety and efficacy, and the interactome of DMEs has attracted extensive attention. There are 3 major interaction types in an interactome: microbiome-DME interaction (MICBIO), xenobiotics-DME interaction (XEOTIC) and host protein-DME interaction (HOSPPI). The interaction data of each type are essential for drug metabolism, and the collective consideration of multiple types has implication for the future practice of precision medicine. However, no database was designed to systematically provide the data of all types of DME interactions. Here, a database of the Interactome of Drug-Metabolizing Enzymes (INTEDE) was therefore constructed to offer these interaction data. First, 1047 unique DMEs (448 host and 599 microbial) were confirmed, for the first time, using their metabolizing drugs. Second, for these newly confirmed DMEs, all types of their interactions (3359 MICBIOs between 225 microbial species and 185 DMEs; 47 778 XEOTICs between 4150 xenobiotics and 501 DMEs; 7849 HOSPPIs between 565 human proteins and 566 DMEs) were comprehensively collected and then provided, which enabled the crosstalk analysis among multiple types. Because of the huge amount of accumulated data, the INTEDE made it possible to generalize key features for revealing disease etiology and optimizing clinical treatment. INTEDE is freely accessible at: https://idrblab.org/intede/.
Topics: Bacteria; DNA Methylation; Databases, Factual; Drugs, Investigational; Enzymes; Fungi; Histones; Humans; Inactivation, Metabolic; Internet; Metabolic Clearance Rate; Microbiota; Prescription Drugs; Protein Processing, Post-Translational; RNA, Long Noncoding; Software; Xenobiotics
PubMed: 33045737
DOI: 10.1093/nar/gkaa755 -
Sleep & Breathing = Schlaf & Atmung Dec 2010Cells sense oxygen availability using not only the absolute value for cellular oxygen in regard to its energetic and metabolic functions, but also the gradient from the... (Review)
Review
Cells sense oxygen availability using not only the absolute value for cellular oxygen in regard to its energetic and metabolic functions, but also the gradient from the cell surface to the lowest levels in the mitochondria. Signals are used for regulatory purposes locally as well as in the generation of cellular, tissue, and humoral remodeling. Lowered oxygen availability (hypoxia) is theoretically important in the consideration of pharmacology because (1) hypoxia can alter cellular function and thereby the therapeutic effectiveness of the agent, (2) therapeutic agents may potentiate or protect against hypoxia-induced pathology, (3) hypoxic conditions may potentiate or mitigate drug-induced toxicity, (4) hypoxia may alter drug metabolism and thereby therapeutic effectiveness, and (5) therapeutic agents might alter the relative coupling of blood flow and energy metabolism in an organ. The prototypic biochemical effect of hypoxia is related to its known role as a cofactor in a number of enzymatic reactions, e.g., oxidases and oxygenases, which are affected independently from the bioenergetic effect of low oxygen on energetic functions. The cytochrome P-450 family of enzymes is another example. Here, there is a direct effect of oxygen availability on the conformation of the enzyme, thereby altering the metabolism of drug substrates. Indirectly, the NADH/NAD+ ratio is increased with 10% inspired oxygen, leading not only to reduced oxidation of ethanol but also to reduction of azo- and nitro-compounds to amines and disulfides to sulfhydryls. With chronic hypoxia, many of these processes are reversed, suggesting that hypoxia induces the drug-metabolizing systems. Support for this comes from observations that hypoxia can induce the hypoxic inducible factors which in turn alters transcription and function of some but not all cytochrome P-450 isoforms. Hypoxia is identified as a cofactor in cancer expression and metastatic potential. Thus, the effects of hypoxia play an important role in pharmacology, and the signaling pathways that are affected by hypoxia could become new targets for novel therapy or avenues for prevention.
Topics: Biological Availability; Biotransformation; Cell Hypoxia; Cytochrome P-450 Enzyme System; Cytochromes c; Energy Metabolism; Humans; Hypoxia; Inactivation, Metabolic; Metabolic Clearance Rate; Pharmacokinetics
PubMed: 20625934
DOI: 10.1007/s11325-010-0368-x -
Philosophical Transactions of the Royal... Sep 2015Across the diversity of life, organisms have evolved different strategies to thrive in hypoxic environments, and microbial eukaryotes (protists) are no exception.... (Review)
Review
Across the diversity of life, organisms have evolved different strategies to thrive in hypoxic environments, and microbial eukaryotes (protists) are no exception. Protists that experience hypoxia often possess metabolically distinct mitochondria called mitochondrion-related organelles (MROs). While there are some common metabolic features shared between the MROs of distantly related protists, these organelles have evolved independently multiple times across the breadth of eukaryotic diversity. Until recently, much of our knowledge regarding the metabolic potential of different MROs was limited to studies in parasitic lineages. Over the past decade, deep-sequencing studies of free-living anaerobic protists have revealed novel configurations of metabolic pathways that have been co-opted for life in low oxygen environments. Here, we provide recent examples of anaerobic metabolism in the MROs of free-living protists and their parasitic relatives. Additionally, we outline evolutionary scenarios to explain the origins of these anaerobic pathways in eukaryotes.
Topics: Anaerobiosis; Biological Evolution; Eukaryotic Cells; Gene Expression Regulation; Organelles; Oxygen Consumption
PubMed: 26323757
DOI: 10.1098/rstb.2014.0326 -
European Journal of Cell Biology 2022Metabolic alterations have been observed in many cancer types. The deregulated metabolism has thus become an emerging hallmark of the disease, where the metabolism is... (Review)
Review
Metabolic alterations have been observed in many cancer types. The deregulated metabolism has thus become an emerging hallmark of the disease, where the metabolism is frequently rewired to aerobic glycolysis. This has led to the concept of "metabolic reprogramming", which has therefore been extensively studied. Over the years, it has been characterized the enhancement of aerobic glycolysis, where key mutations in some of the enzymes of the TCA cycle, and the increased glucose uptake, are used by cancer cells to achieve a "metabolic phenotype" useful to gain a proliferation advantage. Many studies have highlighted in detail the signaling pathways and the molecular mechanisms responsible for the glycolytic switch. However, glycolysis is not the only metabolic process that cancer cells rely on. Oxidative Phosphorylation (OXPHOS), gluconeogenesis or the beta-oxidation of fatty acids (FAO) may be involved in the development and progression of several tumors. In some cases, these metabolisms are even more crucial than aerobic glycolysis for the tumor survival. This review will focus on the contribution of these alterations of metabolism to the development and survival of cancers. We will also analyze the molecular mechanisms by which the balance between these metabolic processes may be regulated, as well as some of the therapeutical approaches that can derive from their study.
Topics: Energy Metabolism; Fatty Acids; Glycolysis; Humans; Mitochondria; Neoplasms; Oxidative Phosphorylation
PubMed: 35453093
DOI: 10.1016/j.ejcb.2022.151225