Metabolism and metabolomics in studying human health and ageing

Transcription

1 Metabolism and metabolomics in studying human health and ageing Dr Warwick (Rick) Dunn School of Biosciences, Phenome Centre Birmingham and Institute of Metabolism and Systems Research, University of Birmingham, UK

2 The next 25 minutes Why do we study metabolites in human health, disease and ageing? The role of metabolomics in research and translation the path to personalised/stratified medicine Case studies from Birmingham and beyond Large-scale (epidemiological) studies: HUSERMET study Pathophysiology: PCI intervention (planned AMI) Prognostic biomarkers and interventions: Burn trauma Endocrinology and glucocorticoids Ageing and exercise Reverse genetics: using metabolomics to understand the phenotype of genotypes

3 Why do we want to study metabolites?

4 What are metabolites? Small molecular weight organic and inorganic biochemicals generally have a molecular weight less than 1500Da Typically, not proteins or peptides a few exceptions e.g. glutathione is a tripeptide but has a metabolic function The building blocks for larger biochemicals proteins, RNA, DNA

5 PHENOTYPE = Gene x environment x lifestyle interaction CAN APPLY TO STUDY THE EFFECT OF THE LONGITUDINAL EXPOSOME

6 Metabolomics is all about INTERACTIONS

7 Experimental strategies METABOLIC PROFILING or NON-TARGETED ANALYSIS TARGETED OR SEMI-TARGETED ANALYSIS (semi)-quantitative (global) detection of a wide range of metabolites NMR or GC-MS/LC-MS Data acquisition without a priori knowledge of biologically interesting metabolites Metabolite identification required post data acquisition Discovery/hypothesis generating Quantification of a smaller number of (related) metabolites for targeted = generally less than 20 semi-targeted = low 100s LC-MS/MS Metabolite identity already known no further metabolite identification required Hypothesis testing

8 Metabolomics can be applied in different approaches Discovery Prognostic and diagnostic biomarkers Molecular pathophysiology Targets for interventions (drug, diet, exercise) Side effects of interventions Responders vs non-responders Translation Biomarkers Intervention Responders/non-responders

9 Objectives of Phenome Centre Birmingham To provide capacity and capabilities for human metabolic phenotyping studies with academia, industry and government partners, e.g. NHS To help translate the UK s vision for Precision Medicine Untargeted and targeted assays for biofluids, cells and tissues Full collaborative fee-forservice, from expt al design to data collection to data analysis and interpretation

10 We are all (metabolically) different: the path to personalised and stratified medicine

11 The metabolic phenotype is highly variable and can be applied in stratification and personalisation

12 How can metabolomics be applied to improve prognosis, diagnosis and treatment?

13 The Husermet project Gender 2-aminomalonic acid higher in women and this is a marker of atherosclerotic plaques CVD risk equal in men and postmenopausal women Age citrate levels were age and genderdependant aromatic amino acids were age and gender-dependant BMI the majority of amino acids showed a decrease with BMI three strong changes in valine, tyrosine and phenylalanine which are associated with insulin resistance and type 2 diabetes onset Blood pressure: lactate increased and acetate decreased with blood pressure (see right)

14 Metabolic changes during planned acute myocardial infarction Patients undergoing transient coronary artery occlusion (median time = 30 seconds) Similar physiology to a heart attack Metabolic changes observed in arachidonic acid metabolism tryptophan metabolism lysophosphocholines oxidation products of heme proylhydroxyproline sphingosine-1-phosphate C 8 and C 10 acyl carnitines hypoxanthine (ATP cycling) LysoPC(20:4)

15 SIFTI study: burn trauma METABOLISM IS A KEY PROCESS FOLLOWING A BURN TRAUMA HYPERMETABOLISM IS OBSERVED ACROSS MANY DIFFERENT METABOLIC CLASSES PREDICTION OF OUTCOME IS PROGRESSING

16 Insulin and glucocortocoid metabolism Glucocorticoids (e.g. cortisol) Regulation of glucose and lipid metabolism Cardiovascular functions Anti-inflammatory effects Heavy use in pharmacology Importantly, 1-2% of developed world are treated with cortisol for adrenal insufficiency which can lead to dangerously high cortisol levels Cushing s syndrome occurs as a result of high cortisol levels

17 As insulin concentration increases it negates the effects of cortisol on global metabolism S1P High cortisol levels promote increased sphingosine-1-phosphate (S1P) levels in blood S1P is linked to insulin secretion and obesity S1P is a potential regulator of cortisol biosynthesis and appears to be regulated by cortisol

18 5-alpha reductase targeting drugs influence global metabolism in different ways in fasted and fed state J. Clin Endo., 2016, 101,

19 Comparison of PCOS vs. controls (fasted)

20 Reverse genetics Nat. Genet., 2014, 46,

21 Summary Metabolites have many important roles to play in human health, disease and ageing Metabolomics is applied for discovery and translation prognostic and diagnostic biomarkers, stratification and molecular pathophysiology We have the capacity in the UK to study large population cohorts (e.g. Phenome Centre Birmingham) Multiple examples of where metabolomics has been applied in human health disease and ageing

22 Acknowledgements Dunn group and Phenome Centre Birmingham: Riccardo Di Guida, Elliott Palmer, Will Allwood, Will Nash, Giovanny Rodriguez-Blanco, Andrew Chetwynd, Donna O Neill, Cate Winder, Lukas Najdekr, Andrew Southam HUSERMET: Douglas Kell, Roy Goodacre, David Broadhurst and many others AMI: Mamas Mamas, Ludwig neyses, Sanoj Chacko and many others SIFTI: Janet Lord, Christopher Wearn, Naiem Moiemen and many others Institute of Metabolism and Systems Research: Wiebke Arlt, Mick O Reilly Oxford Centre for Diabetes, Endocrinology, and Metabolism: Jeremy Tomlinson, Laura Gathercole, Jonathan Hazlehurst