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

317 results found

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, ISSN: 1355-6037

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

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

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. 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

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

Liu K-D, Acharjee A, Hinz C, Liggi S, Murgia A, Denes J, Gulston MK, Wang X, Chu Y, West JA, Glen RC, Roberts LD, Murray AJ, Griffin JLet al., 2020, Consequences of lipid remodeling of adipocyte membranes being functionally distinct from lipid storage in obesity., Journal of Proteome Research, Vol: 19, Pages: 3919-3935, ISSN: 1535-3893

Obesity is a complex disorder where the genome interacts with diet and environmental factors to ultimately influence body mass, composition, and shape. Numerous studies have investigated how bulk lipid metabolism of adipose tissue changes with obesity and, in particular, how the composition of triglycerides (TGs) changes with increased adipocyte expansion. However, reflecting the analytical challenge posed by examining non-TG lipids in extracts dominated by TGs, the glycerophospholipid composition of cell membranes has been seldom investigated. Phospholipids (PLs) contribute to a variety of cellular processes including maintaining organelle functionality, providing an optimized environment for membrane-associated proteins, and acting as pools for metabolites (e.g. choline for one-carbon metabolism and for methylation of DNA). We have conducted a comprehensive lipidomic study of white adipose tissue in mice which become obese either through genetic modification (ob/ob), diet (high fat diet), or a combination of the two, using both solid phase extraction and ion mobility to increase coverage of the lipidome. Composition changes in seven classes of lipids (free fatty acids, diglycerides, TGs, phosphatidylcholines, lyso-phosphatidylcholines, phosphatidylethanolamines, and phosphatidylserines) correlated with perturbations in one-carbon metabolism and transcriptional changes in adipose tissue. We demonstrate that changes in TGs that dominate the overall lipid composition of white adipose tissue are distinct from diet-induced alterations of PLs, the predominant components of the cell membranes. PLs correlate better with transcriptional and one-carbon metabolism changes within the cell, suggesting that the compositional changes that occur in cell membranes during adipocyte expansion have far-reaching functional consequences. Data are available at MetaboLights under the submission number: MTBLS1775.

Journal article

Piedrafita G, Varma S, Castro C, Messner C, Szyrwiel L, Griffin J, Ralser Met al., 2020, Single amino acid-promoted reactions link a non-enzymatic chemical network to the early evolution of enzymatic pentose phosphate pathway, Publisher: bioRxiv

How metabolic pathways emerged in early evolution remains largely unknown. Recently discovered chemical networks driven by iron and sulfur resemble reaction sequences found within glycolysis, gluconeogenesis, the oxidative and reductive Krebs cycle, the Wood Ljungdahl as well as the S-adenosylmethionine pathways, components of the core cellular metabolic network. These findings suggest that the evolution of central metabolism was primed by environmental chemical reactions, implying that non-enzymatic reaction networks served as a “template” in the evolution of enzymatic activities. We speculated that the turning point for this transition would depend on the catalytic properties of the simplest structural components of proteins, single amino acids. Here, we systematically combine constituents of Fe(II)-driven non-enzymatic reactions resembling glycolysis and pentose phosphate pathway (PPP), with single proteinogenic amino acids. Multiple reaction rates are enhanced by amino acids. In particular, cysteine is able to replace (and/or complement) the metal ion Fe(II) in driving the non-enzymatic formation of the RNA-backbone metabolite ribose 5-phosphate from 6-phosphogluconate, a rate-limiting reaction of the oxidative PPP. In the presence of both Fe(II) and cysteine, a complex is formed, enabling the non-enzymatic reaction to proceed at a wide range of temperatures. At mundane temperatures, this ‘minimal enzyme-like complex’ achieves a much higher specificity in the formation of ribose 5-phosphate than the Fe(II)-driven reaction at high temperatures. Hence, simple amino acids can accelerate key steps within metal-promoted metabolism-like chemical networks. Our results imply a stepwise scenario, in which environmental chemical networks served as primers in the early evolution of the metabolic network structure.

Working paper

Hall Z, Wilson CH, Burkhart DL, Ashmore T, Evan GI, Griffin JLet al., 2020, Myc linked to dysregulation of cholesterol transport and storage in non-small cell lung cancer., Journal of Lipid Research, Vol: 61, Pages: 1390-1399, ISSN: 0022-2275

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths. Whilst mutations in Kras and over-expression of Myc are commonly found in patients, the role of altered lipid metabolism in lung cancer and its interplay with oncogenic Myc is poorly understood. Here we use a transgenic mouse model of Kras-driven lung adenocarcinoma with reversible activation of Myc, in combination with surface analysis lipid profiling of lung tumours and transcriptomics, to study the effect of Myc activity on cholesterol homeostasis. Our findings reveal that activation of Myc leads to the accumulation of cholesteryl esters (CE), stored in lipid droplets. Subsequent Myc deactivation leads to further increases in CEs, in contrast to tumours in which Myc was never activated. Gene expression analysis linked cholesterol transport and storage pathways to Myc activity. Our results suggest that increased Myc activity is associated with increased cholesterol influx, reduced efflux and accumulation of CE-rich lipid droplets in lung tumours. Targeting cholesterol homeostasis is proposed as a promising avenue to explore for novel treatments of lung cancer, with diagnostic and stratification potential in human NSCLC.

Journal article

Piras C, Pibiri M, Leoni VP, Cabras F, Restivo A, Griffin JL, Fanos V, Mussap M, Zorcolo L, Atzori Let al., 2020, Urinary <sup>1</sup>H-NMR metabolic signature in subjects undergoing colonoscopy for colon cancer diagnosis, Applied Sciences (Switzerland), Vol: 10

© 2020 by the authors. Metabolomics represents a promising non-invasive approach that can be applied to identify biochemical changes in colorectal cancer patients (CRC) and is potentially useful for diagnosis and follow-up. Despite the literature regarding metabolomics CRC-specific profiles, discrimination between metabolic changes specifically related to CRC and intra-individual variability is still a problem to be solved. This was a preliminary case-control study, in which 1H-NMR spectroscopy combined with multivariate statistical analysis was used to profile urine metabolites in subjects undergoing colonoscopy for colon cancer diagnosis. To reduce intra-individual variability, metabolic profiles were evaluated in participants' urine samples, collected just before the colonoscopy and after a short-term dietary regimen required for the endoscopy procedure. Data obtained highlighted different urinary metabolic profiles between CRC and unaffected subjects (C). The metabolites altered in the CRC urine (acetoacetate, creatine, creatinine, histamine, phenylacetylglycine, and tryptophan) significantly correlated with colon cancer and discriminated with accuracy CRC patients from C patients (receiver operator characteristic (ROC) curve with an area under the curve (AUC) of 0.875; 95% CI: 0.667-1). These results confirm that urinary metabolomic analysis can be a valid tool to improve CRC diagnosis, prognosis, and response to therapy, representing a noninvasive approach that could precede more invasive tests.

Journal article

Vacca M, Leslie J, Virtue S, Lam BYH, Govaere O, Tiniakos D, Snow S, Davies S, Petkevicius K, Tong Z, Peirce V, Nielsen MJ, Ament Z, Li W, Kostrzewski T, Leeming DJ, Ratziu V, Allison MED, Anstee QM, Griffin JL, Oakley F, Vidal-Puig Aet al., 2020, Bone morphogenetic protein 8B promotes the progression of non-alcoholic steatohepatitis, Nature Metabolism, Vol: 2, Pages: 514-531, ISSN: 2522-5812

Non-alcoholic steatohepatitis (NASH) is characterized by lipotoxicity, inflammation and fibrosis, ultimately leading to end-stage liver disease. The molecular mechanisms promoting NASH are poorly understood, and treatment options are limited. Here, we demonstrate that hepatic expression of bone morphogenetic protein 8B (BMP8B), a member of the transforming growth factor beta (TGFβ)–BMP superfamily, increases proportionally to disease stage in people and animal models with NASH. BMP8B signals via both SMAD2/3 and SMAD1/5/9 branches of the TGFβ–BMP pathway in hepatic stellate cells (HSCs), promoting their proinflammatory phenotype. In vivo, the absence of BMP8B prevents HSC activation, reduces inflammation and affects the wound-healing responses, thereby limiting NASH progression. Evidence is featured in primary human 3D microtissues modelling NASH, when challenged with recombinant BMP8. Our data show that BMP8B is a major contributor to NASH progression. Owing to the near absence of BMP8B in healthy livers, inhibition of BMP8B may represent a promising new therapeutic avenue for NASH treatment.

Journal article

Sowton AP, Padmanabhan N, Tunster SJ, McNally BD, Murgia A, Yusuf A, Griffin JL, Murray AJ, Watson EDet al., 2020, Mtrr hypomorphic mutation alters liver morphology, metabolism and fuel storage in mice, Molecular Genetics and Metabolism Reports, Vol: 23, Pages: 1-10, ISSN: 2214-4269

Nonalcoholic fatty liver disease (NAFLD) is associated with dietary folate deficiency and mutations in genes required for one‑carbon metabolism. However, the mechanism through which this occurs is unclear. To improve our understanding of this link, we investigated liver morphology, metabolism and fuel storage in adult mice with a hypomorphic mutation in the gene methionine synthase reductase (Mtrrgt). MTRR enzyme is a key regulator of the methionine and folate cycles. The Mtrrgt mutation in mice was previously shown to disrupt one‑carbon metabolism and cause a wide-spectrum of developmental phenotypes and late adult-onset macrocytic anaemia. Here, we showed that livers of Mtrrgt/gt female mice were enlarged compared to control C57Bl/6J livers. Histological analysis of these livers revealed eosinophilic hepatocytes with decreased glycogen content, which was associated with down-regulation of genes involved in glycogen synthesis (e.g., Ugp2 and Gsk3a genes). While female Mtrrgt/gt livers showed evidence of reduced β-oxidation of fatty acids, there were no other associated changes in the lipidome in female or male Mtrrgt/gt livers compared with controls. Defects in glycogen storage and lipid metabolism often associate with disruption of mitochondrial electron transfer system activity. However, defects in mitochondrial function were not detected in Mtrrgt/gt livers as determined by high-resolution respirometry analysis. Overall, we demonstrated that adult Mtrrgt/gt female mice showed abnormal liver morphology that differed from the NAFLD phenotype and that was accompanied by subtle changes in their hepatic metabolism and fuel storage.

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., 2020, Lipid remodelling in hepatocyte proliferation and hepatocellular carcinoma, Hepatology, 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

Kwok A, Zvetkova I, Virtue S, Luijten I, Huang-Doran I, Tomlinson P, Bulger DA, West J, Murfitt S, Griffin J, Alam R, Hart D, Knox R, Voshol P, Vidal-Puig A, Jensen J, O'Rahilly S, Semple RKet al., 2020, Truncation of Pik3r1 causes severe insulin resistance uncoupled from obesity and dyslipidaemia by increased energy expenditure., Molecular Metabolism, Vol: 40, Pages: 101020-101020, ISSN: 2212-8778

OBJECTIVE: Insulin signalling via phosphoinositide 3-kinase (PI3K) requires PIK3R1-encoded regulatory subunits. C-terminal PIK3R1 mutations cause SHORT syndrome, as well as lipodystrophy and insulin resistance (IR), surprisingly without fatty liver or metabolic dyslipidaemia. We sought to investigate this discordance. METHODS: The human pathogenic Pik3r1 Y657∗ mutation was knocked into mice by homologous recombination. Growth, body composition, bioenergetic and metabolic profiles were investigated on chow and high-fat diet (HFD). We examined adipose and liver histology, and assessed liver responses to fasting and refeeding transcriptomically. RESULTS: Like humans with SHORT syndrome, Pik3r1WT/Y657∗ mice were small with severe IR, and adipose expansion on HFD was markedly reduced. Also as in humans, plasma lipid concentrations were low, and insulin-stimulated hepatic lipogenesis was not increased despite hyperinsulinemia. At odds with lipodystrophy, however, no adipocyte hypertrophy nor adipose inflammation was found. Liver lipogenic gene expression was not significantly altered, and unbiased transcriptomics showed only minor changes, including evidence of reduced endoplasmic reticulum stress in the fed state and diminished Rictor-dependent transcription on fasting. Increased energy expenditure, which was not explained by hyperglycaemia nor intestinal malabsorption, provided an alternative explanation for the uncoupling of IR from dyslipidaemia. CONCLUSIONS: Pik3r1 dysfunction in mice phenocopies the IR and reduced adiposity without lipotoxicity of human SHORT syndrome. Decreased adiposity may not reflect bona fide lipodystrophy, but rather, increased energy expenditure, and we suggest that further study of brown adipose tissue in both humans and mice is warranted.

Journal article

Legler J, Zalko D, Jourdan F, Jacobs M, Fromenty B, Balaguer P, Bourguet W, Munic Kos V, Nadal A, Beausoleil C, Cristobal S, Remy S, Ermler S, Margiotta-Casaluci L, Griffin JL, Blumberg B, Chesné C, Hoffmann S, Andersson PL, Kamstra JHet al., 2020, The GOLIATH Project: Towards an Internationally Harmonised Approach for Testing Metabolism Disrupting Compounds., International Journal of Molecular Sciences, Vol: 21, ISSN: 1422-0067

The purpose of this project report is to introduce the European "GOLIATH" project, a new research project which addresses one of the most urgent regulatory needs in the testing of endocrine-disrupting chemicals (EDCs), namely the lack of methods for testing EDCs that disrupt metabolism and metabolic functions. These chemicals collectively referred to as "metabolism disrupting compounds" (MDCs) are natural and anthropogenic chemicals that can promote metabolic changes that can ultimately result in obesity, diabetes, and/or fatty liver in humans. This project report introduces the main approaches of the project and provides a focused review of the evidence of metabolic disruption for selected EDCs. GOLIATH will generate the world's first integrated approach to testing and assessment (IATA) specifically tailored to MDCs. GOLIATH will focus on the main cellular targets of metabolic disruption-hepatocytes, pancreatic endocrine cells, myocytes and adipocytes-and using an adverse outcome pathway (AOP) framework will provide key information on MDC-related mode of action by incorporating multi-omic analyses and translating results from in silico, in vitro, and in vivo models and assays to adverse metabolic health outcomes in humans at real-life exposures. Given the importance of international acceptance of the developed test methods for regulatory use, GOLIATH will link with ongoing initiatives of the Organisation for Economic Development (OECD) for test method (pre-)validation, IATA, and AOP development.

Journal article

Griffin JL, 2020, In memory of Michael J. O. Wakelam (1955-2020): a pioneer in lipid signalling and lipidomics., Metabolomics, Vol: 16, Pages: 60-60, ISSN: 1573-3882

Journal article

McNally BD, Moran A, Watt NT, Ashmore T, Whitehead A, Murfitt SA, Kearney MT, Cubbon RM, Murray AJ, Griffin JL, Roberts LDet al., 2020, Inorganic nitrate promotes glucose uptake and oxidative catabolism in white adipose tissue through the XOR-catalyzed nitric oxide pathway, Diabetes, Vol: 69, Pages: 893-901, ISSN: 0012-1797

An aging global population combined with sedentary lifestyles and unhealthy diets has contributed to an increasing incidence of obesity and type 2 diabetes. These metabolic disorders are associated with perturbations to nitric oxide (NO) signaling and impaired glucose metabolism. Dietary inorganic nitrate, found in high concentration in green leafy vegetables, can be converted to NO in vivo and demonstrates antidiabetic and antiobesity properties in rodents. Alongside tissues including skeletal muscle and liver, white adipose tissue is also an important physiological site of glucose disposal. However, the distinct molecular mechanisms governing the effect of nitrate on adipose tissue glucose metabolism and the contribution of this tissue to the glucose-tolerant phenotype remain to be determined. Using a metabolomic and stable-isotope labeling approach, combined with transcriptional analysis, we found that nitrate increases glucose uptake and oxidative catabolism in primary adipocytes and white adipose tissue of nitrate-treated rats. Mechanistically, we determined that nitrate induces these phenotypic changes in primary adipocytes through the xanthine oxidoreductase-catalyzed reduction of nitrate to NO and independently of peroxisome proliferator-activated receptor-α. The nitrate-mediated enhancement of glucose uptake and catabolism in white adipose tissue may be a key contributor to the antidiabetic effects of this anion.

Journal article

Tong TYN, Koulman A, Griffin JL, Wareham NJ, Forouhi NG, Imamura Fet al., 2020, A combination of metabolites predicts adherence to the Mediterranean diet pattern and its associations with insulin sensitivity and lipid homeostasis in the general population: The Fenland Study, United Kingdom, The Journal of Nutrition, Vol: 150, Pages: 568-578, ISSN: 0022-3166

BACKGROUND: Cardiometabolic benefits of the Mediterranean diet have been recognized, but underlying mechanisms are not fully understood. OBJECTIVES: We aimed to investigate how the Mediterranean diet could influence circulating metabolites and how the metabolites could mediate the associations of the diet with cardiometabolic risk factors. METHODS: Among 10,806 participants (58.9% women, mean age = 48.4 y) in the Fenland Study (2004-2015) in the United Kingdom, we assessed dietary consumption with FFQs and conducted a targeted metabolomics assay for 175 plasma metabolites (acylcarnitines, amines, sphingolipids, and phospholipids). We examined cross-sectional associations of the Mediterranean diet score (MDS) and its major components with each metabolite, modeling multivariable-adjusted linear regression. We used the regression estimates to summarize metabolites associated with the MDS into a metabolite score as a marker of the diet. Subsequently, we assessed how much metabolite subclasses and the metabolite score would mediate the associations of the MDS with circulating lipids, homeostasis model assessment of insulin resistance (HOMA-IR), and other metabolic factors by comparing regression estimates upon adjustment for the metabolites. RESULTS: Sixty-six metabolites were significantly associated with the MDS (P ≤ 0.003, corrected for false discovery rate) (Spearman correlations, r: -0.28 to +0.28). The metabolite score was moderately correlated with the MDS (r = 0.43). Of MDS components, consumption of nuts, cereals, and meats contributed to variations in acylcarnitines; fruits, to amino acids and amines; and fish, to phospholipids. The metabolite score was estimated to explain 37.2% of the inverse association of the MDS with HOMA-IR (P for mediation < 0.05). The associations of the MDS with cardiometabolic factors were estimated to be mediated by acylcarnitines, sphingolipids, and phospholipids. CONCLUSIONS: Multiple m

Journal article

Perrotta S, Roberti D, Bencivenga D, Corsetto P, O'Brien KA, Caiazza M, Stampone E, Allison L, Fleck RA, Scianguetta S, Tartaglione I, Robbins PA, Casale M, West JA, Franzini-Armstrong C, Griffin JL, Rizzo AM, Sinisi AA, Murray AJ, Borriello A, Formenti F, Della Ragione Fet al., 2020, Effects of germline VHL deficiency on growth, metabolism, and mitochondria., New England Journal of Medicine, Vol: 382, Pages: 835-844, ISSN: 0028-4793

Mutations in VHL, which encodes von Hippel-Lindau tumor suppressor (VHL), are associated with divergent diseases. We describe a patient with marked erythrocytosis and prominent mitochondrial alterations associated with a severe germline VHL deficiency due to homozygosity for a novel synonymous mutation (c.222C→A, p.V74V). The condition is characterized by early systemic onset and differs from Chuvash polycythemia (c.598C→T) in that it is associated with a strongly reduced growth rate, persistent hypoglycemia, and limited exercise capacity. We report changes in gene expression that reprogram carbohydrate and lipid metabolism, impair muscle mitochondrial respiratory function, and uncouple oxygen consumption from ATP production. Moreover, we identified unusual intermitochondrial connecting ducts. Our findings add unexpected information on the importance of the VHL-hypoxia-inducible factor (HIF) axis to human phenotypes. (Funded by Associazione Italiana Ricerca sul Cancro and others.).

Journal article

Cader MZ, de Almeida Rodrigues RP, West JA, Sewell GW, Md-Ibrahim MN, Reikine S, Sirago G, Unger LW, Iglesias-Romero AB, Ramshorn K, Haag L-M, Saveljeva S, Ebel J-F, Rosenstiel P, Kaneider NC, Lee JC, Lawley TD, Bradley A, Dougan G, Modis Y, Griffin JL, Kaser Aet al., 2020, FAMIN is a multifunctional purine enzyme enabling the purine nucleotide cycle., Cell, Vol: 180, Pages: 815-815, ISSN: 0092-8674

Journal article

Cader MZ, Rodrigues RPDA, West JA, Sewell GW, Md-Ibrahim MN, Unger LW, Reikine S, Sirago G, Lawley TD, Bradley A, Dougan G, Modis Y, Griffin J, Kaser Aet al., 2020, FAMIN is a multifunctional purine enzyme enabling the purine nucleotide cycle, Cell, Vol: 180, Pages: 278-295.e23, ISSN: 0092-8674

Mutations in FAMIN cause arthritis and inflammatory bowel disease in early childhood, and a common genetic variant increases the risk for Crohn's disease and leprosy. We developed an unbiased liquid chromatography-mass spectrometry screen for enzymatic activity of this orphan protein. We report that FAMIN phosphorolytically cleaves adenosine into adenine and ribose-1-phosphate. Such activity was considered absent from eukaryotic metabolism. FAMIN and its prokaryotic orthologs additionally have adenosine deaminase, purine nucleoside phosphorylase, and S-methyl-5′-thioadenosine phosphorylase activity, hence, combine activities of the namesake enzymes of central purine metabolism. FAMIN enables in macrophages a purine nucleotide cycle (PNC) between adenosine and inosine monophosphate and adenylosuccinate, which consumes aspartate and releases fumarate in a manner involving fatty acid oxidation and ATP-citrate lyase activity. This macrophage PNC synchronizes mitochondrial activity with glycolysis by balancing electron transfer to mitochondria, thereby supporting glycolytic activity and promoting oxidative phosphorylation and mitochondrial H+ and phosphate recycling.

Journal article

Griffin JL, Liggi S, Hall Z, 2020, CHAPTER 2: Multivariate Statistics in Lipidomics, New Developments in Mass Spectrometry, Pages: 25-48, ISBN: 9781788011600

© The Royal Society of Chemistry 2020. In lipidomics the aim is to measure the concentration of every lipid above the limit of detection in a biofluid or tissue extract. By its very nature this produces large multivariate datasets where standard univariate statistical tools are inappropriate because of the problems of multiple testing and multiple co-variants. To address this there is increasing interest in the use of multivariate statistics and machine learning approaches to process the datasets obtained. In this chapter we will examine why multivariate statistical tools are often more appropriate than their univariate counterparts, and introduce some common unsupervised and supervised approaches used in lipidomics, including principal components analysis, hierarchical cluster analysis, partial least squares discriminate analysis and machine learning approaches such as random forests. The application of multivariate statistics will then be demonstrated in applications that produce one-dimensional (direct infusion mass spectrometry), two-dimensional (liquid chromatography mass spectrometry) and three-dimensional (mass spectrometry imaging, liquid chromatography ion mobility mass spectrometry) datasets as part of their lipidomic workflows.

Book chapter

Griffin JL, 2020, Twenty years of metabonomics: so what has metabonomics done for toxicology?, Xenobiotica: the fate of foreign compounds in biological systems, Vol: 50, Pages: 110-114, ISSN: 0049-8254

In 1999 the journal Xenobiotica published a perspective article detailing the new concept of metabonomics and its application to toxicology. The approach was to apply analytical chemistry techniques, and in particular 1 H NMR spectroscopy, to profile biofluids and tissues to assess the metabolic effects of xenobiotics. Metabonomics has been shown to be sensitive not only to organ specific toxicity but also provides information on the cells, tissues and mechanisms involved, as well as their interactions with the host's sex, age, diet and environment. This review assesses the impact of metabonomics on drug toxicology over the past twenty years and its future prospects. These applications include:Pharmacometabonomics - the prediction of drug effects through the analysis of predose, biofluid metabolite profiles, which reflect both genetic and environmental influences on physiology.The microbiomes role in toxicology - understanding how xenobiotics can be modified by the microbiome dramatically changing their impact on the host.Development of expert systems for toxicity prediction.Data fusion of different omics to better understand the underlying mechanisms of drug toxicity.Metabonomics and exposome - understanding how multiple environmental toxicants might interact with the host organism to produce their overall phenotype. While there has been huge growth in the use of metabonomics within toxicology these applications are set to increase as the tools become more sensitive and robust, as well as the increased use of both experimental and in silico databases to aid prediction of toxicology.

Journal article

Lindsay RT, Demetriou D, Manetta-Jones D, West JA, Murray AJ, Griffin JLet al., 2019, A model for determining cardiac mitochondrial substrate utilisation using stable 13C-labelled metabolites, Metabolomics, Vol: 15, ISSN: 1573-3882

INTRODUCTION: Relative oxidation of different metabolic substrates in the heart varies both physiologically and pathologically, in order to meet metabolic demands under different circumstances. 13C labelled substrates have become a key tool for studying substrate use-yet an accurate model is required to analyse the complex data produced as these substrates become incorporated into the Krebs cycle. OBJECTIVES: We aimed to generate a network model for the quantitative analysis of Krebs cycle intermediate isotopologue distributions measured by mass spectrometry, to determine the 13C labelled proportion of acetyl-CoA entering the Krebs cycle. METHODS: A model was generated, and validated ex vivo using isotopic distributions measured from isolated hearts perfused with buffer containing 11 mM glucose in total, with varying fractions of universally labelled with 13C. The model was then employed to determine the relative oxidation of glucose and triacylglycerol by hearts perfused with 11 mM glucose and 0.4 mM equivalent Intralipid (a triacylglycerol mixture). RESULTS: The contribution of glucose to Krebs cycle oxidation was measured to be 79.1 ± 0.9%, independent of the fraction of buffer glucose which was U-13C labelled, or of which Krebs cycle intermediate was assessed. In the presence of Intralipid, glucose and triglyceride were determined to contribute 58 ± 3.6% and 35.6 ± 0.8% of acetyl-CoA entering the Krebs cycle, respectively. CONCLUSION: These results demonstrate the accuracy of a functional model of Krebs cycle metabolism, which can allow quantitative determination of the effects of therapeutics and pathology on cardiac substrate metabolism.

Journal article

McMurran CE, Guzman de la Fuente A, Penalva R, Ben Menachem-Zidon O, Dombrowski Y, Falconer J, Gonzalez GA, Zhao C, Krause FN, Young AMH, Griffin JL, Jones CA, Hollins C, Heimesaat MM, Fitzgerald DC, Franklin RJMet al., 2019, The microbiota regulates murine inflammatory responses to toxin-induced CNS demyelination but has minimal impact on remyelination, Proceedings of the National Academy of Sciences, Vol: 116, Pages: 25311-25321, ISSN: 0027-8424

The microbiota is now recognized as a key influence on the host immune response in the central nervous system (CNS). As such, there has been some progress toward therapies that modulate the microbiota with the aim of limiting immune-mediated demyelination, as occurs in multiple sclerosis. However, remyelination—the regeneration of myelin sheaths—also depends upon an immune response, and the effects that such interventions might have on remyelination have not yet been explored. Here, we show that the inflammatory response during CNS remyelination in mice is modulated by antibiotic or probiotic treatment, as well as in germ-free mice. We also explore the effect of these changes on oligodendrocyte progenitor cell differentiation, which is inhibited by antibiotics but unaffected by our other interventions. These results reveal that high combined doses of oral antibiotics impair oligodendrocyte progenitor cell responses during remyelination and further our understanding of how mammalian regeneration relates to the microbiota.

Journal article

Peachey LE, Castro C, Molena RA, Jenkins TP, Griffin JL, Cantacessi Cet al., 2019, Dysbiosis associated with acute helminth infections in herbivorous youngstock - observations and implications, Scientific Reports, Vol: 9, ISSN: 2045-2322

A plethora of data points towards a role of the gastrointestinal (GI) microbiota of neonatal and young vertebrates in supporting the development and regulation of the host immune system. However, knowledge of the impact that infections by GI helminths exert on the developing microbiota of juvenile hosts is, thus far, limited. This study investigates, for the first time, the associations between acute infections by GI helminths and the faecal microbial and metabolic profiles of a cohort of equine youngstock, prior to and following treatment with parasiticides (ivermectin). We observed that high versus low parasite burdens (measured via parasite egg counts in faecal samples) were associated with specific compositional alterations of the developing microbiome; in particular, the faecal microbiota of animals with heavy worm infection burdens was characterised by lower microbial richness, and alterations to the relative abundances of bacterial taxa with immune-modulatory functions. Amino acids and glucose were increased in faecal samples from the same cohort, which indicated the likely occurrence of intestinal malabsorption. These data support the hypothesis that GI helminth infections in young livestock are associated with significant alterations to the GI microbiota, which may impact on both metabolism and development of acquired immunity. This knowledge will direct future studies aimed to identify the long-term impact of infection-induced alterations of the GI microbiota in young livestock.

Journal article

Imanikia S, Sheng M, Castro C, Griffin JL, Taylor RCet al., 2019, XBP-1 remodels lipid metabolism to extend longevity, Cell Reports, Vol: 28, Pages: 581-589.e4, ISSN: 2211-1247

The endoplasmic reticulum unfolded protein response (UPRER) is a cellular stress response that maintains homeostasis within the secretory pathway, regulates glucose and lipid metabolism, and influences longevity. To ask whether this role in lifespan determination depends upon metabolic intermediaries, we metabotyped C. elegans expressing the active form of the UPRER transcription factor XBP-1, XBP-1s, and found many metabolic changes. These included reduced levels of triglycerides and increased levels of oleic acid (OA), a monounsaturated fatty acid associated with lifespan extension in C. elegans. Here, we show that constitutive XBP-1s expression increases the activity of lysosomal lipases and upregulates transcription of the Δ9 desaturase FAT-6, which is required for the full lifespan extension induced by XBP-1s. Dietary OA supplementation increases the lifespan of wild-type, but not xbp-1s-expressing animals and enhances proteostasis. These results suggest that modulation of lipid metabolism by XBP-1s contributes to its downstream effects on protein homeostasis and longevity.

Journal article

Hinz C, Liggi S, Mocciaro G, Jung S, Induruwa I, Pereira M, Bryant CE, Meckelmann SW, O'Donnell VB, Farndale RW, Fjeldsted J, Griffin JLet al., 2019, A comprehensive UHPLC ion mobility quadrupole time-of-flight method for profiling and quantification of eicosanoids, other oxylipins, and fatty acids, Analytical Chemistry, Vol: 91, Pages: 8025-8035, ISSN: 0003-2700

Analysis of oxylipins by liquid chromatography mass spectrometry (LC/MS) is challenging because of the small mass range occupied by this diverse lipid class, the presence of numerous structural isomers, and their low abundance in biological samples. Although highly sensitive LC/MS/MS methods are commonly used, further separation is achievable by using drift tube ion mobility coupled with high-resolution mass spectrometry (DTIM-MS). Herein, we present a combined analytical and computational method for the identification of oxylipins and fatty acids. We use a reversed-phase LC/DTIM-MS workflow able to profile and quantify (based on chromatographic peak area) the oxylipin and fatty acid content of biological samples while simultaneously acquiring full scan and product ion spectra. The information regarding accurate mass, collision-cross-section values in nitrogen (DTCCSN2), and retention times of the species found are compared to an internal library of lipid standards as well as the LIPID MAPS Structure Database by using specifically developed processing tools. Features detected within the DTCCSN2 and m/z ranges of the analyzed standards are flagged as oxylipin-like species, which can be further characterized using drift-time alignment of product and precursor ions distinctive of DTIM-MS. This not only helps identification by reducing the number of annotations from LIPID MAPS but also guides discovery studies of potentially novel species. Testing the methodology on Salmonella enterica serovar Typhimurium-infected murine bone-marrow-derived macrophages and thrombin activated human platelets yields results in agreement with literature. This workflow has also annotated features as potentially novel oxylipins, confirming its ability in providing further insights into lipid analysis of biological samples.

Journal article

Charidemou E, Ashmore T, Li X, McNally BD, West JA, Liggi S, Harvey M, Orford E, Griffin JLet al., 2019, A randomized 3-way crossover study indicates that high-protein feeding induces de novo lipogenesis in healthy humans, JCI insight, Vol: 4, Pages: 1-21, ISSN: 2379-3708

BACKGROUND. Dietary changes have led to the growing prevalence of type 2 diabetes andnonalcoholic fatty liver disease. A hallmark of both disorders is hepatic lipid accumulation, derivedin part from increased de novo lipogenesis. Despite the popularity of high-protein diets for weightloss, the effect of dietary protein on de novo lipogenesis is poorly studied. We aimed to characterizethe effect of dietary protein on de novo lipid synthesis.METHODS. We use a 3-way crossover interventional study in healthy males to determine theeffect of high-protein feeding on de novo lipogenesis, combined with in vitro models to determinethe lipogenic effects of specific amino acids. The primary outcome was a change in de novolipogenesis–associated triglycerides in response to protein feeding.RESULTS. We demonstrate that high-protein feeding, rich in glutamate, increases de novolipogenesis–associated triglycerides in plasma (1.5-fold compared with control; P < 0.0001) andliver-derived very low-density lipoprotein particles (1.8-fold; P < 0.0001) in samples from humansubjects (n = 9 per group). In hepatocytes, we show that glutamate-derived carbon is incorporatedinto triglycerides via palmitate. In addition, supplementation with glutamate, glutamine, andleucine, but not lysine, increased triglyceride synthesis and decreased glucose uptake. Glutamate,glutamine, and leucine increased activation of protein kinase B, suggesting that induction of denovo lipogenesis occurs via the insulin signaling cascade.CONCLUSION. These findings provide mechanistic insight into how select amino acids induce denovo lipogenesis and insulin resistance, suggesting that high-protein feeding to tackle diabetes andobesity requires greater consideration.FUNDING. The research was supported by UK Medical Research Council grants MR/P011705/1, MC_UP_A090_1006 and MR/P01836X/1. JLG is supported by the Imperial Biomedical Research Centre,National Institute for Health Research (NIHR).

Journal article

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