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Article ; Online: N-arachidonylglycine is a caloric state-dependent circulating metabolite which regulates human CD4+T cell responsiveness

Allison M. Meadows / Kim Han / Komudi Singh / Antonio Murgia / Ben D. McNally / James A. West / Rebecca D. Huffstutler / Tiffany M. Powell-Wiley / Yvonne Baumer / Julian L. Griffin / Michael N. Sack

iScience, Vol 26, Iss 5, Pp 106578- (2023)

2023

Abstract: Summary: Caloric deprivation interventions such as intermittent fasting and caloric restriction ameliorate metabolic and inflammatory disease. As a human model of caloric deprivation, a 24-h fast blunts innate and adaptive immune cell responsiveness ... ...

Abstract	Summary: Caloric deprivation interventions such as intermittent fasting and caloric restriction ameliorate metabolic and inflammatory disease. As a human model of caloric deprivation, a 24-h fast blunts innate and adaptive immune cell responsiveness relative to the refed state. Isolated serum at these time points confers these same immunomodulatory effects on transformed cell lines. To identify serum mediators orchestrating this, metabolomic and lipidomic analysis was performed on serum extracted after a 24-h fast and re-feeding. Bioinformatic integration with concurrent peripheral blood mononuclear cells RNA-seq analysis implicated key metabolite-sensing GPCRs in fasting-mediated immunomodulation. The putative GPR18 ligand N-arachidonylglycine (NAGly) was elevated during fasting and attenuated CD4+T cell responsiveness via GPR18 MTORC1 signaling. In parallel, NAGly reduced inflammatory Th1 and Th17 cytokines levels in CD4+T cells isolated from obese subjects, identifying a fasting-responsive metabolic intermediate that may contribute to the regulation of nutrient-level dependent inflammation associated with metabolic disease.
Keywords	Human metabolism ; Immunology ; Lipidomics ; Metabolomics ; Transcriptomics ; Science ; Q
Language	English
Publishing date	2023-05-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Author Correction

Anna S. Dickson / Tekle Pauzaite / Esther Arnaiz / Brian M. Ortmann / James A. West / Norbert Volkmar / Anthony W. Martinelli / Zhaoqi Li / Niek Wit / Dennis Vitkup / Arthur Kaser / Paul J. Lehner / James A. Nathan

Nature Communications, Vol 14, Iss 1, Pp 1-

A HIF independent oxygen-sensitive pathway for controlling cholesterol synthesis

2023 Volume 1

Keywords	Science ; Q
Language	English
Publishing date	2023-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A HIF independent oxygen-sensitive pathway for controlling cholesterol synthesis

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 16

Abstract: Abstract Cholesterol biosynthesis is a highly regulated, oxygen-dependent pathway, vital for cell membrane integrity and growth. In fungi, the dependency on oxygen for sterol production has resulted in a shared transcriptional response, resembling prolyl ...

Abstract	Abstract Cholesterol biosynthesis is a highly regulated, oxygen-dependent pathway, vital for cell membrane integrity and growth. In fungi, the dependency on oxygen for sterol production has resulted in a shared transcriptional response, resembling prolyl hydroxylation of Hypoxia Inducible Factors (HIFs) in metazoans. Whether an analogous metazoan pathway exists is unknown. Here, we identify Sterol Regulatory Element Binding Protein 2 (SREBP2), the key transcription factor driving sterol production in mammals, as an oxygen-sensitive regulator of cholesterol synthesis. SREBP2 degradation in hypoxia overrides the normal sterol-sensing response, and is HIF independent. We identify MARCHF6, through its NADPH-mediated activation in hypoxia, as the main ubiquitin ligase controlling SREBP2 stability. Hypoxia-mediated degradation of SREBP2 protects cells from statin-induced cell death by forcing cells to rely on exogenous cholesterol uptake, explaining why many solid organ tumours become auxotrophic for cholesterol. Our findings therefore uncover an oxygen-sensitive pathway for governing cholesterol synthesis through regulated SREBP2-dependent protein degradation.
Keywords	Science ; Q
Language	English
Publishing date	2023-08-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A Review of Odd-Chain Fatty Acid Metabolism and the Role of Pentadecanoic Acid (C15:0) and Heptadecanoic Acid (C17:0) in Health and Disease

Benjamin Jenkins / James A. West / Albert Koulman

Molecules, Vol 20, Iss 2, Pp 2425-

2015 Volume 2444

Abstract: The role of C17:0 and C15:0 in human health has recently been reinforced following a number of important biological and nutritional observations. Historically, odd chain saturated fatty acids (OCS-FAs) were used as internal standards in GC-MS methods of ... ...

Abstract	The role of C17:0 and C15:0 in human health has recently been reinforced following a number of important biological and nutritional observations. Historically, odd chain saturated fatty acids (OCS-FAs) were used as internal standards in GC-MS methods of total fatty acids and LC-MS methods of intact lipids, as it was thought their concentrations were insignificant in humans. However, it has been thought that increased consumption of dairy products has an association with an increase in blood plasma OCS-FAs. However, there is currently no direct evidence but rather a casual association through epidemiology studies. Furthermore, a number of studies on cardiometabolic diseases have shown that plasma concentrations of OCS-FAs are associated with lower disease risk, although the mechanism responsible for this is debated. One possible mechanism for the endogenous production of OCS-FAs is α-oxidation, involving the activation, then hydroxylation of the α-carbon, followed by the removal of the terminal carboxyl group. Differentiation human adipocytes showed a distinct increase in the concentration of OCS-FAs, which was possibly caused through α-oxidation. Further evidence for an endogenous pathway, is in human plasma, where the ratio of C15:0 to C17:0 is approximately 1:2 which is contradictory to the expected levels of C15:0 to C17:0 roughly 2:1 as detected in dairy fat. We review the literature on the dietary consumption of OCS-FAs and their potential endogenous metabolism.
Keywords	odd chain fatty acids ; pentadecanoic ; heptadecanoic ; biomarker ; α-oxidation ; dairy ; Organic chemistry ; QD241-441
Subject code	610
Language	English
Publishing date	2015-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: β-hydroxybutyrate accumulates in the rat heart during low-flow ischaemia with implications for functional recovery

Ross T Lindsay / Sophie Dieckmann / Dominika Krzyzanska / Dominic Manetta-Jones / James A West / Cecilia Castro / Julian L Griffin / Andrew J Murray

eLife, Vol

2021 Volume 10

Abstract: Extrahepatic tissues which oxidise ketone bodies also have the capacity to accumulate them under particular conditions. We hypothesised that acetyl-coenzyme A (acetyl-CoA) accumulation and altered redox status during low-flow ischaemia would support ... ...

Abstract	Extrahepatic tissues which oxidise ketone bodies also have the capacity to accumulate them under particular conditions. We hypothesised that acetyl-coenzyme A (acetyl-CoA) accumulation and altered redox status during low-flow ischaemia would support ketone body production in the heart. Combining a Langendorff heart model of low-flow ischaemia/reperfusion with liquid chromatography coupled tandem mass spectrometry (LC-MS/MS), we show that β-hydroxybutyrate (β-OHB) accumulated in the ischaemic heart to 23.9 nmol/gww and was secreted into the coronary effluent. Sodium oxamate, a lactate dehydrogenase (LDH) inhibitor, increased ischaemic β-OHB levels 5.3-fold and slowed contractile recovery. Inhibition of β-hydroxy-β-methylglutaryl (HMG)-CoA synthase (HMGCS2) with hymeglusin lowered ischaemic β-OHB accumulation by 40%, despite increased flux through succinyl-CoA-3-oxaloacid CoA transferase (SCOT), resulting in greater contractile recovery. Hymeglusin also protected cardiac mitochondrial respiratory capacity during ischaemia/reperfusion. In conclusion, net ketone generation occurs in the heart under conditions of low-flow ischaemia. The process is driven by flux through both HMGCS2 and SCOT, and impacts on cardiac functional recovery from ischaemia/reperfusion.
Keywords	Heart ; Langendorff ; cardiomyocyte ; Ischaemia ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Integration of metabolomics, lipidomics and clinical data using a machine learning method

Animesh Acharjee / Zsuzsanna Ament / James A. West / Elizabeth Stanley / Julian L. Griffin

BMC Bioinformatics, Vol 17, Iss S15, Pp 37-

2016 Volume 49

Abstract: Abstract Background The recent pandemic of obesity and the metabolic syndrome (MetS) has led to the realisation that new drug targets are needed to either reduce obesity or the subsequent pathophysiological consequences associated with excess weight gain. ...

Abstract	Abstract Background The recent pandemic of obesity and the metabolic syndrome (MetS) has led to the realisation that new drug targets are needed to either reduce obesity or the subsequent pathophysiological consequences associated with excess weight gain. Certain nuclear hormone receptors (NRs) play a pivotal role in lipid and carbohydrate metabolism and have been highlighted as potential treatments for obesity. This realisation started a search for NR agonists in order to understand and successfully treat MetS and associated conditions such as insulin resistance, dyslipidaemia, hypertension, hypertriglyceridemia, obesity and cardiovascular disease. The most studied NRs for treating metabolic diseases are the peroxisome proliferator-activated receptors (PPARs), PPAR-α, PPAR-γ, and PPAR-δ. However, prolonged PPAR treatment in animal models has led to adverse side effects including increased risk of a number of cancers, but how these receptors change metabolism long term in terms of pathology, despite many beneficial effects shorter term, is not fully understood. In the current study, changes in male Sprague Dawley rat liver caused by dietary treatment with a PPAR-pan (PPAR-α, −γ, and –δ) agonist were profiled by classical toxicology (clinical chemistry) and high throughput metabolomics and lipidomics approaches using mass spectrometry. Results In order to integrate an extensive set of nine different multivariate metabolic and lipidomics datasets with classical toxicological parameters we developed a hypotheses free, data driven machine learning approach. From the data analysis, we examined how the nine datasets were able to model dose and clinical chemistry results, with the different datasets having very different information content. Conclusions We found lipidomics (Direct Infusion-Mass Spectrometry) data the most predictive for different dose responses. In addition, associations with the metabolic and lipidomic data with aspartate amino transaminase (AST), a hepatic leakage enzyme to assess organ damage, and ...
Keywords	Computer applications to medicine. Medical informatics ; R858-859.7 ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2016-11-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Divergent trajectories of cellular bioenergetics, intermediary metabolism and systemic redox status in survivors and non-survivors of critical illness

Helen T. McKenna / Katie A. O'Brien / Bernadette O. Fernandez / Magdalena Minnion / Adam Tod / Ben D. McNally / James A. West / Julian L. Griffin / Michael P. Grocott / Michael G. Mythen / Martin Feelisch / Andrew J. Murray / Daniel S. Martin

Redox Biology, Vol 41, Iss , Pp 101907- (2021)

2021

Abstract: Background: Numerous pathologies result in multiple-organ failure, which is thought to be a direct consequence of compromised cellular bioenergetic status. Neither the nature of this phenotype nor its relevance to survival are well understood, limiting ... ...

Abstract	Background: Numerous pathologies result in multiple-organ failure, which is thought to be a direct consequence of compromised cellular bioenergetic status. Neither the nature of this phenotype nor its relevance to survival are well understood, limiting the efficacy of modern life-support. Methods: To explore the hypothesis that survival from critical illness relates to changes in cellular bioenergetics, we combined assessment of mitochondrial respiration with metabolomic, lipidomic and redox profiling in skeletal muscle and blood, at multiple timepoints, in 21 critically ill patients and 12 reference patients. Results: We demonstrate an end-organ cellular phenotype in critical illness, characterized by preserved total energetic capacity, greater coupling efficiency and selectively lower capacity for complex I and fatty acid oxidation (FAO)-supported respiration in skeletal muscle, compared to health. In survivors, complex I capacity at 48 h was 27% lower than in non-survivors (p = 0.01), but tended to increase by day 7, with no such recovery observed in non-survivors. By day 7, survivors’ FAO enzyme activity was double that of non-survivors (p = 0.048), in whom plasma triacylglycerol accumulated. Increases in both cellular oxidative stress and reductive drive were evident in early critical illness compared to health. Initially, non-survivors demonstrated greater plasma total antioxidant capacity but ultimately higher lipid peroxidation compared to survivors. These alterations were mirrored by greater levels of circulating total free thiol and nitrosated species, consistent with greater reductive stress and vascular inflammation, in non-survivors compared to survivors. In contrast, no clear differences in systemic inflammatory markers were observed between the two groups. Conclusion: Critical illness is associated with rapid, specific and coordinated alterations in the cellular respiratory machinery, intermediary metabolism and redox response, with different trajectories in survivors and non-survivors. ...
Keywords	Critical illness ; Stress physiology ; Energy metabolism ; Mitochondria ; Redox signaling ; Oxidative stress ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
Subject code	610
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Cytosine-5 RNA methylation links protein synthesis to cell metabolism.

Nikoletta A Gkatza / Cecilia Castro / Robert F Harvey / Matthias Heiß / Martyna C Popis / Sandra Blanco / Susanne Bornelöv / Abdulrahim A Sajini / Joseph G Gleeson / Julian L Griffin / James A West / Stefanie Kellner / Anne E Willis / Sabine Dietmann / Michaela Frye

PLoS Biology, Vol 17, Iss 6, p e

2019 Volume 3000297

Abstract: Posttranscriptional modifications in transfer RNA (tRNA) are often critical for normal development because they adapt protein synthesis rates to a dynamically changing microenvironment. However, the precise cellular mechanisms linking the extrinsic ... ...

Abstract	Posttranscriptional modifications in transfer RNA (tRNA) are often critical for normal development because they adapt protein synthesis rates to a dynamically changing microenvironment. However, the precise cellular mechanisms linking the extrinsic stimulus to the intrinsic RNA modification pathways remain largely unclear. Here, we identified the cytosine-5 RNA methyltransferase NSUN2 as a sensor for external stress stimuli. Exposure to oxidative stress efficiently repressed NSUN2, causing a reduction of methylation at specific tRNA sites. Using metabolic profiling, we showed that loss of tRNA methylation captured cells in a distinct catabolic state. Mechanistically, loss of NSUN2 altered the biogenesis of tRNA-derived noncoding fragments (tRFs) in response to stress, leading to impaired regulation of protein synthesis. The intracellular accumulation of a specific subset of tRFs correlated with the dynamic repression of global protein synthesis. Finally, NSUN2-driven RNA methylation was functionally required to adapt cell cycle progression to the early stress response. In summary, we revealed that changes in tRNA methylation profiles were sufficient to specify cellular metabolic states and efficiently adapt protein synthesis rates to cell stress.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2019-06-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Metabolomics dataset of PPAR-pan treated rat liver

Zsuzsanna Ament / James A. West / Elizabeth Stanley / Xuefei Li / Tom Ashmore / Lee D. Roberts / Jayne Wright / Andrew W. Nicholls / Julian L. Griffin

Data in Brief, Vol 8, Iss , Pp 196-

2016 Volume 202

Abstract: This article contains mass spectrometry (MS) data investigating small molecule changes as an effect of a triple peroxisome proliferator-activated receptor (PPAR-pan) agonist GW625019 in the liver as described in the manuscript (Ament et al., 2016) [1]. ... ...

Abstract	This article contains mass spectrometry (MS) data investigating small molecule changes as an effect of a triple peroxisome proliferator-activated receptor (PPAR-pan) agonist GW625019 in the liver as described in the manuscript (Ament et al., 2016) [1]. Samples were measured using gas chromatography-mass spectrometry (GC–MS) for total fatty acid content, and liquid chromatography-mass spectrometry (LC–MS) to measure intact lipids, carnitines and selected aqueous metabolites and eicosanoids. Data files comprise of Excel (Microsoft, WA, USA) spreadsheets of identified metabolites and their area ratio values for total fatty acids, carnitines, aqueous metabolites, and eicosanoids where the intensity of the analytes were normalised to the intensity of the internal standard. In the case of open profiling intact lipid data, the Excel file contains area ratio values of retention time and mass to charge ratio pairs; again, the area ratio values were calculated by normalising to the intensity of the internal standard. It should be noted that several metabolic changes are potentially indirect (secondary, tertiary and ensuing changes). Keywords: Peroxisome proliferator activated receptors, PPAR, Metabolomics, Lipidomics, Mass spectrometry
Keywords	Computer applications to medicine. Medical informatics ; R858-859.7 ; Science (General) ; Q1-390
Language	English
Publishing date	2016-09-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Hypoxic regulation of hand1 controls the fetal-neonatal switch in cardiac metabolism.

Ross A Breckenridge / Izabela Piotrowska / Keat-Eng Ng / Timothy J Ragan / James A West / Surendra Kotecha / Norma Towers / Michael Bennett / Petra C Kienesberger / Ryszard T Smolenski / Hillary K Siddall / John L Offer / Mihaela M Mocanu / Derek M Yelon / Jason R B Dyck / Jules L Griffin / Andrey Y Abramov / Alex P Gould / Timothy J Mohun

PLoS Biology, Vol 11, Iss 9, p e

2013 Volume 1001666

Abstract: Cardiomyocytes are vulnerable to hypoxia in the adult, but adapted to hypoxia in utero. Current understanding of endogenous cardiac oxygen sensing pathways is limited. Myocardial oxygen consumption is determined by regulation of energy metabolism, which ... ...

Abstract	Cardiomyocytes are vulnerable to hypoxia in the adult, but adapted to hypoxia in utero. Current understanding of endogenous cardiac oxygen sensing pathways is limited. Myocardial oxygen consumption is determined by regulation of energy metabolism, which shifts from glycolysis to lipid oxidation soon after birth, and is reversed in failing adult hearts, accompanying re-expression of several "fetal" genes whose role in disease phenotypes remains unknown. Here we show that hypoxia-controlled expression of the transcription factor Hand1 determines oxygen consumption by inhibition of lipid metabolism in the fetal and adult cardiomyocyte, leading to downregulation of mitochondrial energy generation. Hand1 is under direct transcriptional control by HIF1α. Transgenic mice prolonging cardiac Hand1 expression die immediately following birth, failing to activate the neonatal lipid metabolising gene expression programme. Deletion of Hand1 in embryonic cardiomyocytes results in premature expression of these genes. Using metabolic flux analysis, we show that Hand1 expression controls cardiomyocyte oxygen consumption by direct transcriptional repression of lipid metabolising genes. This leads, in turn, to increased production of lactate from glucose, decreased lipid oxidation, reduced inner mitochondrial membrane potential, and mitochondrial ATP generation. We found that this pathway is active in adult cardiomyocytes. Up-regulation of Hand1 is protective in a mouse model of myocardial ischaemia. We propose that Hand1 is part of a novel regulatory pathway linking cardiac oxygen levels with oxygen consumption. Understanding hypoxia adaptation in the fetal heart may allow development of strategies to protect cardiomyocytes vulnerable to ischaemia, for example during cardiac ischaemia or surgery.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2013-09-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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