Imperial College London

ProfessorJulianGriffin

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Chair in Biological Chemistry
 
 
 
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Contact

 

+44 (0)20 7594 3220julian.griffin

 
 
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Location

 

Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

339 results found

O'Brien KA, McNally BD, Sowton AP, Murgia A, Armitage J, Thomas LW, Krause FN, Maddalena LA, Francis I, Kavanagh S, Williams DP, Ashcroft M, Griffin JL, Lyon JJ, Murray AJet al., 2021, Enhanced hepatic respiratory capacity and altered lipid metabolism support metabolic homeostasis during short-term hypoxic stress, BMC BIOLOGY, Vol: 19

Journal article

Piedrafita G, Varma SJ, Castro C, Messner CB, Szyrwiel L, Griffin JL, Ralser Met al., 2021, Cysteine and iron accelerate the formation of ribose-5-phosphate, providing insights into the evolutionary origins of the metabolic network structure, PLoS Biology, Vol: 19, ISSN: 1544-9173

AU The:structure Pleaseconfirmthatallheadinglevelsarerepresentedcorrectly of the metabolic network is highly conserved, but : we know little about its evolutionary origins. Key for explaining the early evolution of metabolism is solving a chicken–egg dilemma, which describes that enzymes are made from the very same molecules they produce. The recent discovery of several nonenzymatic reaction sequences that topologically resemble central metabolism has provided experimental support for a “metabolism first” theory, in which at least part of the extant metabolic network emerged on the basis of nonenzymatic reactions. But how could evolution kick-start on the basis of a metal catalyzed reaction sequence, and how could the structure of nonenzymatic reaction sequences be imprinted on the metabolic network to remain conserved for billions of years? We performed an in vitro screening where we add the simplest components of metabolic enzymes, proteinogenic amino acids, to a nonenzymatic, iron-driven reaction network that resembles glycolysis and the pentose phosphate pathway (PPP). We observe that the presence of the amino acids enhanced several of the nonenzymatic reactions. Particular attention was triggered by a reaction that resembles a rate-limiting step in the oxidative PPP. A prebiotically available, proteinogenic amino acid cysteine accelerated the formation of RNA nucleoside precursor ribose-5-phosphate from 6-phosphogluconate. We report that iron and cysteine interact and have additive effects on the reaction rate so that ribose-5-phosphate forms at high specificity under mild, metabolism typical temperature and environmental conditions. We speculate that accelerating effects of amino acids on rate-limiting nonenzymatic reactions could have facilitated a stepwise enzymatization of nonenzymatic reaction sequences, imprinting their structure on the evolving metabolic network.

Journal article

Vilca-Melendez S, Uthaug M, Griffin J, 2021, 1H nuclear magnetic resonance: a future approach to the metabolic profiling of psychedelics in human biofluids?, Frontiers in Psychiatry Psychpharmacology, ISSN: 1664-0640

While psychedelics may have therapeutic potential for treating mental health disorders such as depression, further research is needed to better understand their biological effects and mechanisms of action when considering the development of future novel therapy approaches. Psychedelic research could potentially benefit from the integration of metabonomics by proton nuclear magnetic resonance (1H NMR) spectroscopy, an analytical chemistry-based approach that can measure the breakdown of drugs into their metabolites and their metabolic consequences from various biofluids. We have performed a systematic review of the literature to assess the use of 1H NMR spectroscopy-based metabolomics as a tool in psychedelic research.After exploring previously published literature where 1H NMR had analysed psychedelic substances including psilocin, lysergic acid diethylamide (LSD), LSD derivatives, N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and bufotenin, we found that the main use of 1H NMR to date has been for the structural elucidation and analytical characterisation of psychedelic molecules and that no papers used 1H NMR in the metabolic profiling of biofluids, thus exposing a current research gap and the underuse of 1H NMR. The efficacy of 1H NMR spectroscopy was also compared to mass spectrometry, where both metabonomics techniques have previously shown to be appropriate for biofluid analysis in other applications. Additionally, potential future directions for psychedelic research were identified as real-time NMR, in vivo 1H nuclear magnetic resonance spectroscopy (MRS) and 1H NMR studies of the gut microbiome. Further psychedelic studies need to be conducted that incorporate the use of 1H NMR spectroscopy in the analysis of metabolites both in the peripheral biofluids and CNS to determine whether it will be an effective future approach for clinical and naturalistic research.

Journal article

Dearlove DJ, Holdsworth D, Kirk T, Hodson L, Charidemou E, Kvalheim E, Stubbs B, Beevers A, Griffin JL, Evans R, Robertson J, Clarke K, Cox PJet al., 2021, β-Hydroxybutyrate Oxidation in Exercise Is Impaired by Low-Carbohydrate and High-Fat Availability, Frontiers in Medicine, Vol: 8

Purpose: In this study, we determined ketone oxidation rates in athletes under metabolic conditions of high and low carbohydrate (CHO) and fat availability. Methods: Six healthy male athletes completed 1 h of bicycle ergometer exercise at 75% maximal power (WMax) on three occasions. Prior to exercise, participants consumed 573 mg·kg bw−1 of a ketone ester (KE) containing a 13C label. To manipulate CHO availability, athletes undertook glycogen depleting exercise followed by isocaloric high-CHO or very-low-CHO diets. To manipulate fat availability, participants were given a continuous infusion of lipid during two visits. Using stable isotope methodology, β-hydroxybutyrate (βHB) oxidation rates were therefore investigated under the following metabolic conditions: (i) high CHO + normal fat (KE+CHO); (ii) high CHO + high fat KE+CHO+FAT); and (iii) low CHO + high fat (KE+FAT). Results: Pre-exercise intramuscular glycogen (IMGLY) was approximately halved in the KE+FAT vs. KE+CHO and KE+CHO+FAT conditions (both p < 0.05). Blood free fatty acids (FFA) and intramuscular long-chain acylcarnitines were significantly greater in the KE+FAT vs. other conditions and in the KE+CHO+FAT vs. KE+CHO conditions before exercise. Following ingestion of the 13C labeled KE, blood βHB levels increased to ≈4.5 mM before exercise in all conditions. βHB oxidation was modestly greater in the KE+CHO vs. KE+FAT conditions (mean diff. = 0.09 g·min−1, p = 0.03; d = 0.3), tended to be greater in the KE+CHO+FAT vs. KE+FAT conditions (mean diff. = 0.07 g·min−1; p = 0.1; d = 0.3) and were the same in the KE+CHO vs. KE+CHO+FAT conditions (p < 0.05; d < 0.1). A moderate positive correlation between pre-exercise IMGLY and βHB oxidation rates during exercise was present (p = 0.04; r = 0.5). Post-exercise intramuscular βHB abundance was markedly elevated in the KE+FAT vs. KE+CHO and KE+CHO+FAT conditions (both, p < 0.001; d

Journal article

Jarvis LB, Rainbow DB, Coppard V, Howlett SK, Georgieva Z, Davies JL, Mullay HK, Hester J, Ashmore T, Van Den Bosch A, Grist JT, Coles AJ, Mousa HS, Pluchino S, Mahbubani KT, Griffin JL, Saeb-Parsy K, Issa F, Peruzzotti-Jametti L, Wicker LS, Jones JLet al., 2021, Therapeutically expanded human regulatory T-cells are super-suppressive due to HIF1A induced expression of CD73., Commun Biol, Vol: 4

The adoptive transfer of regulatory T-cells (Tregs) is a promising therapeutic approach in transplantation and autoimmunity. However, because large cell numbers are needed to achieve a therapeutic effect, in vitro expansion is required. By comparing their function, phenotype and transcriptomic profile against ex vivo Tregs, we demonstrate that expanded human Tregs switch their metabolism to aerobic glycolysis and show enhanced suppressive function through hypoxia-inducible factor 1-alpha (HIF1A) driven acquisition of CD73 expression. In conjunction with CD39, CD73 expression enables expanded Tregs to convert ATP to immunosuppressive adenosine. We conclude that for maximum therapeutic benefit, Treg expansion protocols should be optimised for CD39/CD73 co-expression.

Journal article

Lana-Elola E, Cater H, Watson-Scales S, Greenaway S, Müller-Winkler J, Gibbins D, Nemes M, Slender A, Hough T, Keskivali-Bond P, Scudamore CL, Herbert E, Banks GT, Mobbs H, Canonica T, Tosh J, Noy S, Llorian M, Nolan PM, Griffin JL, Good M, Simon M, Mallon A-M, Wells S, Fisher EMC, Tybulewicz VLJet al., 2021, Comprehensive phenotypic analysis of the Dp1Tyb mouse strain reveals a broad range of Down syndrome-related phenotypes., Dis Model Mech, Vol: 14

Down syndrome (DS), trisomy 21, results in many complex phenotypes including cognitive deficits, heart defects and craniofacial alterations. Phenotypes arise from an extra copy of human chromosome 21 (Hsa21) genes. However, these dosage-sensitive causative genes remain unknown. Animal models enable identification of genes and pathological mechanisms. The Dp1Tyb mouse model of DS has an extra copy of 63% of Hsa21-orthologous mouse genes. In order to establish whether this model recapitulates DS phenotypes, we comprehensively phenotyped Dp1Tyb mice using 28 tests of different physiological systems and found that 468 out of 1800 parameters were significantly altered. We show that Dp1Tyb mice have wide-ranging DS-like phenotypes, including aberrant erythropoiesis and megakaryopoiesis, reduced bone density, craniofacial changes, altered cardiac function, a pre-diabetic state, and deficits in memory, locomotion, hearing and sleep. Thus, Dp1Tyb mice are an excellent model for investigating complex DS phenotype-genotype relationships for this common disorder.

Journal article

Knatko E, Castro C, Higgins M, Zhang Y, Honda T, Henderson CJ, Wolf CR, Griffin JL, Dinkova-Kostova ATet al., 2021, Nrf2 activation does not affect adenoma development in a mouse model of colorectal cancer, COMMUNICATIONS BIOLOGY, Vol: 4

Journal article

Harshfield EL, Fauman EB, Stacey D, Paul DS, Ziemek D, Ong RMY, Danesh J, Butterworth AS, Rasheed A, Sattar T, Zameer-Ul-Asar, Saleem I, Hina Z, Ishtiaq U, Qamar N, Mallick NH, Yaqub Z, Saghir T, Rizvi SNH, Memon A, Ishaq M, Rasheed SZ, Memon F-U-R, Jalal A, Abbas S, Frossard P, Saleheen D, Wood AM, Griffin JL, Koulman Aet al., 2021, Genome-wide analysis of blood lipid metabolites in over 5000 South Asians reveals biological insights at cardiometabolic disease loci., BMC Med, Vol: 19

BACKGROUND: Genetic, lifestyle, and environmental factors can lead to perturbations in circulating lipid levels and increase the risk of cardiovascular and metabolic diseases. However, how changes in individual lipid species contribute to disease risk is often unclear. Moreover, little is known about the role of lipids on cardiovascular disease in Pakistan, a population historically underrepresented in cardiovascular studies. METHODS: We characterised the genetic architecture of the human blood lipidome in 5662 hospital controls from the Pakistan Risk of Myocardial Infarction Study (PROMIS) and 13,814 healthy British blood donors from the INTERVAL study. We applied a candidate causal gene prioritisation tool to link the genetic variants associated with each lipid to the most likely causal genes, and Gaussian Graphical Modelling network analysis to identify and illustrate relationships between lipids and genetic loci. RESULTS: We identified 253 genetic associations with 181 lipids measured using direct infusion high-resolution mass spectrometry in PROMIS, and 502 genetic associations with 244 lipids in INTERVAL. Our analyses revealed new biological insights at genetic loci associated with cardiometabolic diseases, including novel lipid associations at the LPL, MBOAT7, LIPC, APOE-C1-C2-C4, SGPP1, and SPTLC3 loci. CONCLUSIONS: Our findings, generated using a distinctive lipidomics platform in an understudied South Asian population, strengthen and expand the knowledge base of the genetic determinants of lipids and their association with cardiometabolic disease-related loci.

Journal article

Lindsay RT, Dieckmann S, Krzyzanska D, Manetta-Jones D, West JA, Castro C, Griffin JL, Murray AJet al., 2021, β-hydroxybutyrate accumulates in the rat heart during low-flow ischaemia with implications for functional recovery., Elife, Vol: 10

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.

Journal article

Belcastro L, Ferreira CS, Saraiva MA, Mucci DB, Murgia A, Lai C, Vigor C, Oger C, Galano J-M, Pinto GDA, Griffin JL, Torres AG, Durand T, Burton GJ, Sardinha FLC, El-Bacha Tet al., 2021, Decreased Fatty Acid Transporter FABP1 and Increased Isoprostanes and Neuroprostanes in the Human Term Placenta: Implications for Inflammation and Birth Weight in Maternal Pre-Gestational Obesity., Nutrients, Vol: 13

The rise in prevalence of obesity in women of reproductive age in developed and developing countries might propagate intergenerational cycles of detrimental effects on metabolic health. Placental lipid metabolism is disrupted by maternal obesity, which possibly affects the life-long health of the offspring. Here, we investigated placental lipid metabolism in women with pre-gestational obesity as a sole pregnancy complication and compared it to placental responses of lean women. Open profile and targeted lipidomics were used to assess placental lipids and oxidised products of docosahexaenoic (DHA) and arachidonic acid (AA), respectively, neuroprostanes and isoprostanes. Despite no overall signs of lipid accumulation, DHA and AA levels in placentas from obese women were, respectively, 2.2 and 2.5 times higher than those from lean women. Additionally, a 2-fold increase in DHA-derived neuroprostanes and a 1.7-fold increase in AA-derived isoprostanes were seen in the obese group. These changes correlated with a 70% decrease in placental FABP1 protein. Multivariate analyses suggested that neuroprostanes and isoprostanes are associated with maternal and placental inflammation and with birth weight. These results might shed light on the molecular mechanisms associated with altered placental fatty acid metabolism in maternal pre-gestational obesity, placing these oxidised fatty acids as novel mediators of placental function.

Journal article

Aikaterini I, Emmanuel M, Karaman I, Elliott F, Griffin J, Tzoulaki I, Elliott Pet al., 2021, Metabolic phenotyping and cardiovascular disease: Overview of evidence from epidemiological settings, Heart, Vol: 107, Pages: 1123-1129, ISSN: 1355-6037

Metabolomics, the comprehensive measurement of low-molecular-weight molecules in biological fluids used for metabolic phenotyping, has emerged as a promising tool to better understand pathways underlying cardiovascular disease (CVD) and to improve cardiovascular risk stratification. Here, we present the main methodologies for metabolic phenotyping, the methodological steps to analyse these data in epidemiological settings and the associated challenges. We discuss evidence from epidemiological studies linking metabolites to coronary heart disease and stroke. These studies indicate the systemic nature of CVD and identify associated metabolic pathways such as gut microbial cometabolism, branched-chain amino acids, glycerophospholipid and cholesterol metabolism, as well as activation of inflammatory processes. Integration of metabolomic with genomic data can provide new evidence for involved biochemical pathways and potential for causality using Mendelian randomisation. The clinical utility of metabolic biomarkers for cardiovascular risk stratification in healthy individuals has not yet been established. As sample sizes with high-dimensional molecular data increase in epidemiological settings, integration of metabolomic data across studies and platforms with other molecular data will lead to new understanding of the metabolic processes underlying CVD and contribute to identification of potentially novel preventive and pharmacological targets. Metabolic phenotyping offers a powerful tool in the characterisation of the molecular signatures of CVD, paving the way to new mechanistic understanding and therapies, as well as improving risk prediction of CVD patients. However, there are still challenges to face in order to contribute to clinically important improvements in CVD.

Journal article

Azzu V, Vacca M, Kamzolas I, Hall Z, Leslie J, Carobbio S, Virtue S, Davies SE, Lukasik A, Dale M, Bohlooly-Y M, Acharjee A, Lindén D, Bidault G, Petsalaki E, Griffin JL, Oakley F, Allison MED, Vidal-Puig Aet al., 2021, Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression, Molecular Metabolism, Vol: 48, Pages: 1-10, ISSN: 2212-8778

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is a silent pandemic associated with obesity and the metabolic syndrome, and also increases cardiovascular- and cirrhosis-related morbidity and mortality. A complete understanding of adaptive compensatory metabolic programmes that modulate non-alcoholic steatohepatitis (NASH) progression is lacking. METHODS AND RESULTS: Transcriptomic analysis of liver biopsies in patients with NASH revealed that NASH progression is associated with rewiring of metabolic pathways, including upregulation of de novo lipid/cholesterol synthesis and fatty acid remodelling. The modulation of these metabolic programmes was achieved by activating sterol regulatory element-binding protein (SREBP) transcriptional networks; however, it is still debated whether, in the context of NASH, activation of SREBPs acts as a pathogenic driver of lipotoxicity, or rather promotes the biosynthesis of protective lipids that buffer excessive lipid accumulation, preventing inflammation and fibrosis. To elucidate the pathophysiological role of SCAP/SREBP in NASH and wound-healing response, we used an Insig1 deficient (with hyper-efficient SREBPs) murine model challenged with a NASH-inducing diet. Despite enhanced lipid and cholesterol biosynthesis, Insig1 KO mice had similar systemic metabolism and insulin sensitivity to Het/WT littermates. Moreover, activating SREBPs resulted in remodelling the lipidome, decreased hepatocellular damage, and improved wound-healing responses. CONCLUSIONS: Our study provides actionable knowledge about the pathways and mechanisms involved in NAFLD pathogenesis, which may prove useful for developing new therapeutic strategies. Our results also suggest that the SCAP/SREBP/INSIG1 trio governs transcriptional programmes aimed at protecting the liver from lipotoxic insults in NASH.

Journal article

Newberry EP, Hall Z, Xie Y, Molitor EA, Bayguinov PO, Strout GW, Fitzpatrick JAJ, Brunt EM, Griffin JL, Davidson NOet al., 2021, Liver-Specific Deletion of Mouse Tm6sf2 Promotes Steatosis, Fibrosis, and Hepatocellular Cancer, Liver Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD), Publisher: WILEY, Pages: 1203-1219, ISSN: 0270-9139

Conference paper

Garcia-Segura ME, Durainayagam BR, Liggi S, Graça G, Jimenez B, Dehghan A, Tzoulaki I, Karaman I, Elliott P, Griffin JLet al., 2021, Pathway-based integration of multi-omics data reveals lipidomics alterations validated in an Alzheimer’s Disease mouse model and risk loci carriers

<jats:title>Abstract</jats:title><jats:p>Alzheimer’s Disease (AD) is a highly prevalent neurodegenerative disorder. Despite increasing evidence of important metabolic dysregulation in AD, the underlying metabolic changes that may impact amyloid plaque formation are not understood, particularly for late onset AD. This study analyzed genome-wide association studies (GWAS), transcriptomics and proteomics data obtained from several data repositories to obtain differentially expressed (DE) multi-omics elements in mouse models of AD. We characterized the metabolic modulation in these datasets using gene ontology, and transcription factor, pathway and cell-type enrichment analysis. A predicted lipid signature was extracted from genome-scale metabolic networks (GSMN) and subsequently validated in a lipidomic dataset derived from cortical tissue of ABCA7-null mice, a mouse model of one of the genes associated with late onset AD. Moreover, a metabolome-wide association study (MWAS) was performed to further characterize the association between dysregulated lipid metabolism in human blood serum and AD.</jats:p><jats:p>We found 203 DE transcripts, 164 DE proteins and 58 DE GWAS-derived mouse orthologs associated with significantly enriched metabolic biological processes. Lipid and bioenergetics metabolic pathways were significantly over-represented across the AD multi-omics datasets. Microglia and astrocytes were significantly enriched in the lipid-predominant AD-metabolic transcriptome. We also extracted a predicted lipid signature that was validated and robustly modelled class separation in the ABCA7 mice cortical lipidome, with 11 of these lipid species exhibiting statistically significant modulations. MWAS revealed 298 AD single nucleotide polymorphisms (SNP)-metabolite associations, of which 70% corresponded to lipid classes.</jats:p><jats:p>These results support the importance of lipid metabolism dysregulation in AD and highl

Journal article

Gallagher K, Catesson A, Griffin JL, Holmes E, Williams HRTet al., 2021, Metabolomic analysis in inflammatory bowel disease: a systematic review, Journal of Crohns & Colitis, Vol: 15, Pages: 813-826, ISSN: 1873-9946

BACKGROUND AND AIMS: The inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis, are chronic, idiopathic gastrointestinal (GI) diseases. Whilst their precise etiology is unknown, it is thought to involve a complex interaction between genetic predisposition and an abnormal host immune response to environmental exposures, likely microbial. Microbial dysbiosis has frequently been documented in IBD. Metabolomics (the study of small molecular intermediates and end products of metabolism in biological samples) provides a unique opportunity to characterize disease-associated metabolic changes and may be of particular use in quantifying gut microbial metabolism. Numerous metabolomic studies have been undertaken in inflammatory bowel disease populations, identifying consistent alterations in a range of molecules across several biological matrices. This systematic review aims to summarize these findings. METHODS: A comprehensive, systematic search was carried out using Medline and EMBASE. All studies were reviewed by two authors independently using predefined exclusion criteria. A total of sixty-four relevant papers were quality assessed and included in the review. RESULTS: Consistent metabolic perturbations were identified, including increases in levels of branched chain amino acids and lipid classes across stool, serum, plasma and tissue biopsy samples, and reduced levels of microbially modified metabolites in both urine (such as hippurate) and stool (such as secondary bile acids). CONCLUSIONS: This review provides a summary of metabolomic research in IBD to date, highlighting underlying themes of perturbed gut microbial metabolism and mammalian-microbial co-metabolism associated with disease status.

Journal article

McKenna HT, O'Brien KA, Fernandez BO, Minnion M, Tod A, McNally BD, West JA, Griffin JL, Grocott MP, Mythen MG, Feelisch M, Murray AJ, Martin DSet al., 2021, Divergent trajectories of cellular bioenergetics, intermediary metabolism and systemic redox status in survivors and non-survivors of critical illness., Redox Biol, Vol: 41

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

Journal article

Whitehead A, Krause FN, Moran A, MacCannell ADV, Scragg JL, McNally BD, Boateng E, Murfitt SA, Virtue S, Wright J, Garnham J, Davies GR, Dodgson J, Schneider JE, Murray AJ, Church C, Vidal-Puig A, Witte KK, Griffin JL, Roberts LDet al., 2021, Brown and beige adipose tissue regulate systemic metabolism through a metabolite interorgan signaling axis., Nat Commun, Vol: 12

Brown and beige adipose tissue are emerging as distinct endocrine organs. These tissues are functionally associated with skeletal muscle, adipose tissue metabolism and systemic energy expenditure, suggesting an interorgan signaling network. Using metabolomics, we identify 3-methyl-2-oxovaleric acid, 5-oxoproline, and β-hydroxyisobutyric acid as small molecule metabokines synthesized in browning adipocytes and secreted via monocarboxylate transporters. 3-methyl-2-oxovaleric acid, 5-oxoproline and β-hydroxyisobutyric acid induce a brown adipocyte-specific phenotype in white adipocytes and mitochondrial oxidative energy metabolism in skeletal myocytes both in vitro and in vivo. 3-methyl-2-oxovaleric acid and 5-oxoproline signal through cAMP-PKA-p38 MAPK and β-hydroxyisobutyric acid via mTOR. In humans, plasma and adipose tissue 3-methyl-2-oxovaleric acid, 5-oxoproline and β-hydroxyisobutyric acid concentrations correlate with markers of adipose browning and inversely associate with body mass index. These metabolites reduce adiposity, increase energy expenditure and improve glucose and insulin homeostasis in mouse models of obesity and diabetes. Our findings identify beige adipose-brown adipose-muscle physiological metabokine crosstalk.

Journal article

Savic D, Ball V, Curtis MK, Sousa Fialho MDL, Timm KN, Hauton D, West J, Griffin J, Heather LC, Tyler DJet al., 2021, L-Carnitine Stimulates In Vivo Carbohydrate Metabolism in the Type 1 Diabetic Heart as Demonstrated by Hyperpolarized MRI., Metabolites, Vol: 11, ISSN: 2218-1989

The diabetic heart is energetically and metabolically abnormal, with increased fatty acid oxidation and decreased glucose oxidation. One factor contributing to the metabolic dysfunction in diabetes may be abnormal handling of acetyl and acyl groups by the mitochondria. L-carnitine is responsible for their transfer across the mitochondrial membrane, therefore, supplementation with L-carnitine may provide a route to improve the metabolic state of the diabetic heart. The primary aim of this study was to use hyperpolarized magnetic resonance imaging (MRI) to investigate the effects of L-carnitine supplementation on the in vivo metabolism of [1-13C]pyruvate in diabetes. Male Wistar rats were injected with either vehicle or streptozotocin (55 mg/kg) to induce type-1 diabetes. Three weeks of daily i.p. treatment with either saline or L-carnitine (3 g/kg/day) was subsequently undertaken. In vivo cardiac function and metabolism were assessed with CINE and hyperpolarized MRI, respectively. L-carnitine supplementation prevented the progression of hyperglycemia, which was observed in untreated streptozotocin injected animals and led to reductions in plasma triglyceride and ß-hydroxybutyrate concentrations. Hyperpolarized MRI revealed that L-carnitine treatment elevated pyruvate dehydrogenase flux by 3-fold in the diabetic animals, potentially through increased buffering of excess acetyl-CoA units in the mitochondria. Improved functional recovery following ischemia was also observed in the L-carnitine treated diabetic animals.

Journal article

Hall Z, Chiarugi D, Charidemou E, Leslie J, Scott E, Pellegrinet L, Allison M, Mocciaro G, Anstee Q, Evan G, Hoare M, Vidal-Puig A, Oakley F, Vacca M, Griffin Jet al., 2021, Lipid remodelling in hepatocyte proliferation and hepatocellular carcinoma, Hepatology, Vol: 73, Pages: 1028-1044, ISSN: 0270-9139

Background & AimsHepatocytes undergo profound metabolic rewiring when primed to proliferate during compensatory regeneration and in hepatocellular carcinoma (HCC). However, the metabolic control of these processes is not fully understood. In order to capture the metabolic signature of proliferating hepatocytes, we applied state‐of‐the‐art systems biology approaches to models of liver regeneration, pharmacologically‐ and genetically‐activated cell proliferation, and HCC.Approach & ResultsIntegrating metabolomics, lipidomics and transcriptomics, we link changes in the lipidome of proliferating hepatocytes to altered metabolic pathways including lipogenesis, fatty acid desaturation, and generation of phosphatidylcholine (PC). We confirm this altered lipid signature in human HCC and show a positive correlation of monounsaturated‐PC with hallmarks of cell proliferation and hepatic carcinogenesis.ConclusionOverall, we demonstrate that specific lipid metabolic pathways are coherently altered when hepatocytes switch to proliferation. These represent a source of targets for the development of new therapeutic strategies and prognostic biomarkers of HCC.

Journal article

Newberry E, Hall ZL, Yan X, Molitor E, Bayguinov P, Strout G, Fitzpatrick J, Brunt E, Griffin J, Davidson Net al., 2021, Liver specific deletion of mouse Tm6sf2 promotes steatosis, fibrosis and hepatocellular cancer, Hepatology, Pages: 1-1, ISSN: 0270-9139

Background and AimsHuman TM6SF2 variant rs58542926 is associated with nonalcoholic fatty liver disease (NAFLD) and hepatocellular cancer (HCC). However, conflicting reports in germline Tm6sf2 knockout mice suggest no change or decreased VLDL secretion and either unchanged or increased hepatic steatosis, with no increased fibrosis. We generated liver specific Tm6Sf2 knockout mice (Tm6 LKO) to study VLDL secretion and the impact on development and progression of NAFLD.Approach and ResultsTwo independent lines of Tm6 LKO mice exhibited spontaneous hepatic steatosis. Targeted lipidomic analyses showed increased triglyceride (TG) species whose distribution and abundance phenocopied findings in mice with liver specific deletion of microsomal triglyceride transfer protein. VLDL TG secretion was reduced, with small, underlipidated particles and unchanged or increased APOB. Liver‐specific adeno‐associated viral (AAV8‐TBG) rescue using either wild type (WT) or mutant E167K‐Tm6 reduced hepatic steatosis and improved VLDL secretion. Tm6 LKO mice fed a high milk‐fat diet for 3 weeks exhibited increased steatosis and fibrosis and those phenotypes were further exacerbated when mice were fed fibrogenic, high fat/fructose diets for 20 weeks. In two models of HCC, either neonatal mice injected with streptozotocin (NASH/STAM) and high fat fed or with diethylnitrosamine (DEN) injection plus fibrogenic diet feeding, Tm6 LKO mice exhibited increased steatosis, greater tumor burden and increased tumor area versus Tm6 flox controls. Additionally, DEN‐injected and fibrogenic diet fed Tm6 LKO mice administered WT Tm6 or E167K‐mutant Tm6 AAV8 revealed significant tumor attenuation, with tumor burden inversely correlated with Tm6 protein levels.Conclusions: Liver‐specific Tm6sf2 deletion impairs VLDL secretion, promoting hepatic steatosis, fibrosis and accelerated development of HCC, which was mitigated with AAV8‐ mediated rescue.

Journal article

Wylot M, Whittaker DTE, Wren SAC, Bothwell JH, Hughes L, Griffin JLet al., 2021, Monitoring apoptosis in intact cells by high-resolution magic angle spinning H-1 NMR spectroscopy, NMR IN BIOMEDICINE, Vol: 34, ISSN: 0952-3480

Journal article

Lotta LA, Pietzner M, Stewart ID, Wittemans LBL, Li C, Bonelli R, Raffler J, Biggs EK, Oliver-Williams C, Auyeung VPW, Luan J, Wheeler E, Paige E, Surendran P, Michelotti GA, Scott RA, Burgess S, Zuber V, Sanderson E, Koulman A, Imamura F, Forouhi NG, Khaw K-T, Griffin JL, Wood AM, Kastenmueller G, Danesh J, Butterworth AS, Gribble FM, Reimann F, Bahlo M, Fauman E, Wareham NJ, Langenberg Cet al., 2021, A cross-platform approach identifies genetic regulators of human metabolism and health, NATURE GENETICS, Vol: 53, ISSN: 1061-4036

Journal article

Tronci L, Serreli G, Piras C, Frau DV, Dettori T, Deiana M, Murgia F, Santoru ML, Spada M, Leoni VP, Griffin JL, Vanni R, Atzori L, Caria Pet al., 2021, Vitamin c cytotoxicity and its effects in redox homeostasis and energetic metabolism in papillary thyroid carcinoma cell lines, Antioxidants, Vol: 10

High-dose of vitamin C (L-ascorbic acid, ascorbate) exhibits anti-tumoral effects, primarily mediated by pro-oxidant mechanisms. This cytotoxic effect is thought to affect the reciprocal crosstalk between redox balance and cell metabolism in different cancer types. Vitamin C also inhibits the growth of papillary thyroid carcinoma (PTC) cells, although the metabolic and redox effects remain to be fully understood. To shed light on these aspects, PTC-derived cell lines harboring the most common genetic alterations characterizing this tumor were used. Cell viability, apoptosis, and the metabolome were explored by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide test (MTT), flow cytometry, and UHPLC/MS. Changes were observed in redox homeostasis, with increased reactive oxygen species (ROS) level and perturbation in antioxidants and electron carriers, leading to cell death by both apoptosis and necrosis. The oxidative stress contributed to the metabolic alterations in both glycolysis and TCA cycle. Our results confirm the pro-oxidant effect of vitamin C as relevant in triggering the cytotoxicity in PTC cells and suggest that inhibition of glycolysis and alteration of TCA cycle via NAD+ depletion can play an important role in this mechanism of PTC cancer cell death.

Journal article

Lecommandeur E, Cachón-González MB, Boddie S, McNally BD, Nicholls AW, Cox TM, Griffin JLet al., 2021, Decrease in myelin-associated lipids precedes neuronal loss and glial activation in the CNS of the sandhoff mouse as determined by metabolomics, Metabolites, Vol: 11, Pages: 1-16

Sandhoff disease (SD) is a lysosomal disease caused by mutations in the gene coding for the β subunit of β-hexosaminidase, leading to deficiency in the enzymes β-hexosaminidase (HEX) A and B. SD is characterised by an accumulation of gangliosides and related glycolipids, mainly in the central nervous system, and progressive neurodegeneration. The underlying cellular mechanisms leading to neurodegeneration and the contribution of inflammation in SD remain undefined. The aim of the present study was to measure global changes in metabolism over time that might reveal novel molecular pathways of disease. We used liquid chromatography-mass spectrometry and 1H Nuclear Magnetic Resonance spectroscopy to profile intact lipids and aqueous metabolites, respectively. We examined spinal cord and cerebrum from healthy and Hexb-/-mice, a mouse model of SD, at ages one, two, three and four months.We report decreased concentrations in lipids typical of the myelin sheath, galactosylceramides and plasmalogen-phosphatidylethanolamines, suggesting that reduced synthesis of myelin lipids is an early event in the development of disease pathology. Reduction in neuronal density is progressive, as demonstrated by decreased concentrations of N-acetylaspartate and amino acid neurotransmitters. Finally, microglial activation, indicated by increased amounts of myo-inositol correlates closely with the late symptomatic phases of the disease.

Journal article

Haim-Vilmovsky L, Henriksson J, Walker JA, Miao Z, Natan E, Kar G, Clare S, Barlow JL, Charidemou E, Mamanova L, Chen X, Proserpio V, Pramanik J, Woodhouse S, Protasio AV, Efremova M, Griffin JL, Berriman M, Dougan G, Fisher J, Marioni JC, McKenzie ANJ, Teichmann SAet al., 2021, Mapping Rora expression in resting and activated CD4+ T cells., PLoS One, Vol: 16

The transcription factor Rora has been shown to be important for the development of ILC2 and the regulation of ILC3, macrophages and Treg cells. Here we investigate the role of Rora across CD4+ T cells in general, but with an emphasis on Th2 cells, both in vitro as well as in the context of several in vivo type 2 infection models. We dissect the function of Rora using overexpression and a CD4-conditional Rora-knockout mouse, as well as a RORA-reporter mouse. We establish the importance of Rora in CD4+ T cells for controlling lung inflammation induced by Nippostrongylus brasiliensis infection, and have measured the effect on downstream genes using RNA-seq. Using a systematic stimulation screen of CD4+ T cells, coupled with RNA-seq, we identify upstream regulators of Rora, most importantly IL-33 and CCL7. Our data suggest that Rora is a negative regulator of the immune system, possibly through several downstream pathways, and is under control of the local microenvironment.

Journal article

Peto J, Hunter DJ, Riboli E, Griffin JLet al., 2020, Unnecessary obstacles to COVID-19 mass testing, LANCET, Vol: 396, Pages: 1633-1633, ISSN: 0140-6736

Journal article

Timm KN, Perera C, Ball V, Henry JA, Miller JJ, Kerr M, West JA, Sharma E, Broxholme J, Logan A, Savic D, Dodd MS, Griffin JL, Murphy MP, Heather LC, Tyler DJet al., 2020, Early detection of doxorubicin-induced cardiotoxicity in rats by its cardiac metabolic signature assessed with hyperpolarized MRI., Commun Biol, Vol: 3

Doxorubicin (DOX) is a widely used chemotherapeutic agent that can cause serious cardiotoxic side effects culminating in congestive heart failure (HF). There are currently no clinical imaging techniques or biomarkers available to detect DOX-cardiotoxicity before functional decline. Mitochondrial dysfunction is thought to be a key factor driving functional decline, though real-time metabolic fluxes have never been assessed in DOX-cardiotoxicity. Hyperpolarized magnetic resonance imaging (MRI) can assess real-time metabolic fluxes in vivo. Here we show that cardiac functional decline in a clinically relevant rat-model of DOX-HF is preceded by a change in oxidative mitochondrial carbohydrate metabolism, measured by hyperpolarized MRI. The decreased metabolic fluxes were predominantly due to mitochondrial loss and additional mitochondrial dysfunction, and not, as widely assumed hitherto, to oxidative stress. Since hyperpolarized MRI has been successfully translated into clinical trials this opens up the potential to test cancer patients receiving DOX for early signs of cardiotoxicity.

Journal article

Knatko EV, Tatham MH, Zhang Y, Castro C, Higgins M, Naidu SD, Leonardi C, de la Vega L, Honda T, Griffin JL, Hay RT, Dinkova-Kostova ATet al., 2020, Downregulation of Keap1 Confers Features of a Fasted Metabolic State, ISCIENCE, Vol: 23

Journal article

Evans AM, O'Donovan C, Playdon M, Beecher C, Beger RD, Bowden JA, Broadhurst D, Clish CB, Dasari S, Dunn WB, Griffin JL, Hartung T, Hsu P-C, Huan T, Jans J, Jones CM, Kachman M, Kleensang A, Lewis MR, Monge ME, Mosley JD, Taylor E, Tayyari F, Theodoridis G, Torta F, Ubhi BK, Vuckovic Det al., 2020, Dissemination and analysis of the quality assurance (QA) and quality control (QC) practices of LC-MS based untargeted metabolomics practitioners, METABOLOMICS, Vol: 16, ISSN: 1573-3882

Journal article

Hjelholt AJ, Charidemou E, Griffin JL, Pedersen SB, Gudiksen A, Pilegaard H, Jessen N, Moller N, Jorgensen JOLet al., 2020, Insulin resistance induced by growth hormone is linked to lipolysis and associated with suppressed pyruvate dehydrogenase activity in skeletal muscle: a 2x2 factorial, randomised, crossover study in human individuals, DIABETOLOGIA, Vol: 63, Pages: 2641-2653, ISSN: 0012-186X

Journal article

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