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O C T O B E R
feature
stor y
Immune Cell
Function and Fate
Regulated by
Metabolism
Upon exposure to foreign
antigens, relatively quiescent
cells of the immune system are
stimulated to undergo a highly
coordinated and scalable
response critical to combating
infection.
A
lthough initial activation events are
orchestrated by established physiological processes such as transcription and
post-translational modifications, growing
evidence demonstrates both an instructive
and responsive role for metabolic changes
in directing the proliferative potential,
differentiation, and function of immune
cells1, 2. The growing evidence for a
precisely engineered metabolic-immune
connection is also illuminating that, in
addition to traditional cell and molecular
biological approaches to understanding the
immune system, metabolism research also
is an important avenue to pursue to
complement and add to the understanding
of immunology with the ultimate goal of
facilitating treatments/modalities for immune
system modulation.
keep reading this story
REFERENCES
2 0 1 3
I S S U E
News & EVENTS
Press Release: DHMRI and Metabolon Announce Strategic
Partnership to Provide Expanded Metabolomics Capabilities
August 27th, 2013 | Read Press Release
Health Ingredients Congress
September 26 – 27th à Poitiers, France
10th International ISSX Meeting
September 29th – October 3rd Toronto, Canada
Cell Culture World Congress
September 30th – October 1st Boston, MA
Skin Forum Skin Metabolism
October 10 – 11th Valbonne, Nice France
HAPPI Anti-Aging Conference
October 29 – 30th Brunswick, NJ
Recent Advances in Fermentation Technology Conference
November 3 – 5th Marco Isle, Fl
publications in the news
An Integrated Clinico-Metabolomic Model Improves Prediction of
Death in Sepsis Langley et. al. | Science Translational Medicine, 2013
MORE INFO
The Mycobacterium Tuberculosis Regulatory Network and Hypoxia
Galagan, J. et. al. | Nature, 2013
MORE INFO
Leptin Engages a Hypothalamic Neurocircuitry to Permit Survival
in the Absence of Insulin Fujikawa, T. et. al. | Cell Metabolism, 2013
MORE INFO
Metabolomics Uncovers Dietary Omega-3 Fatty Acid-Derived
Metabolites Implicated in Anti-Nonciceptive Responses after
Experimental Spinal Cord Injury Figueroa, J. et. al. | Neuroscience, 2013
MORE INFO
october
the
path
forward
A Technical
Commentary by
Michael Milburn,
CSO
As we continue strive
to mine the genome
for clues that can assist in understanding
susceptibility to disease, selection of
better targets for combating disease,
and the biomarkers delineating
response, metabolism provides a key
source of data that can either lead or
strengthen this pursuit. That’s right –
metabolism. As metabolism research
continues to expand into areas
traditionally dominated by cell and
molecular biology approaches (e.g.
immunology research, see feature
article), it is becoming increasingly
clear that there are few areas in
biology that metabolism does not offer
a say in. Thus, despite the intense
interest in molecular biology the last
30 years, we are re-awakening to
the notion that, if one is interested in
understanding a biological phenomena,
it necessitates investigating the
metabolism of the system.
keep reading this story
Serum Metabolomics Indicate Altered Cellular
Energy Metabolism in Children with Cystic
Fibrosis
Joseloff, E. et. al. | Pediatric Pulmonology, 2013
VIEW SUMMARY
Listeria Monocytogenes Infection Causes
Metabolic Shifts in Drosophila Melanogastor
Chambers, M. et. al. | PloS One, 2012
VIEW SUMMARY
HuR is a Post-Transcriptional Regulator of Core
Metabolic Enzymes in Pancreatic Cancer
Burkhart, R. et. al. | RNA Biology, 2013
VIEW SUMMARY
Infectious Disease
Serum Metabolomics Indicate Altered
Cellular Energy Metabolism in Children
with Cystic Fibrosis
Joseloff, E. et. al.
Pediatric Pulmonology, 2013
VIEW SUMMARY
Metabolic Disturbances Associated with
Systemic Lupus Erythematosus
Wu, T. et. al. | PloS One, 2012
VIEW SUMMARY
Metabolomics Reveals Elevated Macromolecular
Degradation in Periodontal Disease
Barnes, V., et. al. | J Dent Res, 2012
VIEW SUMMARY
Exposure of Clinical MRSA Heterogeneous Strains
to β-Lactams Redirects Metabolism to Optimize
Energy Production through the TCA Cycle
Keaton, M. et. al. | PLoS One, 2013
VIEW SUMMARY
Metabolism/Cardiovascular Disease
Metabolite Profiling Reveals New Insights into the
Regulation of Serum Urate in Humans
Albrecht, E. et. al. | Metabolomics, 2013
The Transcription Factor Myc Controls
Metabolic Reprogramming upon T
Lymphocyte Activation
Wang, R. et. al. | Immunity, 2011
VIEW SUMMARY
Neuroscience/Neurology
VIEW SUMMARY
Detrimental Effects of Adenosine Signaling
in Sickle Cell Disease
Zhang, Y., et. al. | Nat Med, 2011
VIEW SUMMARY
Profile of Circulatory Metabolites in an Animal
Model of Multiple Sclerosis Using Global
Metabolomics
Mangalam, A. et. al.
Journal of Clinical and Cellular Immunology, 2013
VIEW SUMMARY
Reducing Endoplasmic Reticulum Stress
Through a Macrophage Lipid Chaperone
Alleviates Atherosclerosis
Erbay, E. et. al. | Nat Med, 2009
Lipidomics Reveals Early Metabolic Changes in
Subjects with Schizophrenia: Effects of Atypical
Antipsychotics
McEvoy, J. et. al. | PLoS One, 2013
VIEW SUMMARY
VIEW SUMMARY
Nutrition & Consumer Goods
3-Hydroxykynurenine and Other Parkinson’s
Disease Biomarkers Discovered by Metabolomic
Analysis
LeWitt, P. et. al. | Movement Disorders, 2013
Metabolic Profiling in Nutrition and
Metabolic Disorders
LeMieux, M. et. al.
Advances in Nutrition, 2013
VIEW SUMMARY
VIEW SUMMARY
A Diet Rich in High-Glucoraphanin
Broccoli Interacts with Genotype to Reduce
Discordance in Plasma Metabolite Profiles by
Modulating Mitochondrial Function
Armah, C. et. al. | The American Journal of
Clinical Nutrition, 2013
VIEW SUMMARY
Cancer/Oncology
For a complete list of publications,
please visit our website at
www.metabolon.com/news/Publications.aspx.
I S S U E
publications
Inflammation/Immunity
Unappreciated Power
of Metabolites for New
Insight into Signaling
Networks
2 0 1 3
Metabolomics Identifies Pyrimidine Starvation
as the Mechanism of 5-aminoimidazole4-carboxamide-1-beta-riboside (AlCAr)
Induced Apoptosis in Multiple Myeloma Cells
Bardeleben, C. et. al.
Molecular Cancer Therapeutics, 2013
Respiratory
Serum Metabolomics Indicate Altered Cellular
Energy Metabolism in Children with Cystic Fibrosis
Joseloff, E. et. al. | Pediatric Pulmonology, 2013
VIEW SUMMARY
Technology
Metabolomics in Epidemiology: Sources of
Variability in Metabolite Measurements and
Implications
Sampson. J et. al. | Cancer Epidemiology,
Biomarkers & Prevention, 2013
VIEW SUMMARY
VIEW SUMMARY
A bimonthly publication of:
© Copyright Metabolon, Inc. 2013
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F eature
stor y — continued
Immune Cell Function and Fate Regulated by Metabolism
Highlighting this, the following brief synopsis discusses recent findings
that show the impact of intracellular metabolism and metabolite
availability on immune cell fate and the effect these cells can have on
systemic metabolism.
consumption due to enhanced nuclear receptor PGC1 and PPARδ
expression that facilitates fatty acid oxidation and mitochondrial
respiration10, 11. Thus, metabolic pathway choice supports the function
of these distinct pro- and anti-inflammatory macrophage subsets.
Although it has long been appreciated that metabolites are key
elements of immune cell signaling and functional execution (e.g.,
histamine, eicosanoids, leukotrienes and prostaglandins), recent results
have also illuminated that fundamental metabolic pathways (e.g.
glycolysis) are central to primary functions across both innate and
adaptive immunity.
Similar to macrophages, the choice between glycolytic and oxidative
metabolism has a critical impact on the adaptive immune response.
Naïve quiescent T cells can be stimulated by macrophages and
dendritic cells in response to cognate antigen recognition. This initial
event triggers a cascade of signaling networks that coordinate the
expansion and differentiation of T cells to combat pathogens, tumors,
and confer immunological memory. Considering the specificity of
these processes, T cell subsets predominantly consist of effector,
helper, memory, and regulatory types that promote inflammation
and cytotoxicity, assist humoral immunity, prevent reinfection, and
regulate the immune response respectively. Similar to M1 and M2
macrophages, inflammatory T effector cells upregulate glycolytic
metabolism to support rapid cell division and acquire cytolytic
capacity, while immune suppressive T regulatory cells and memory
cells are characterized by an enhanced rate of fatty acid oxidation.
Furthermore, these metabolic phenotypes are a requirement for fate
considering genetic and pharmacological enhancement of fatty acid
metabolism can increase T regulatory and memory cell development,
while limiting the development and function of effector T cells12, 13.
Thus, metabolic manipulation may be critical in the design of future
vaccine and autoimmune therapeutic strategies.
The innate and adaptive branches of the immune system function in
concert to generate a productive response. Consisting of granulocytes,
macrophages, and dendritic cells; the innate immune response is
dependent upon genetically encoded (“innate”) pathogen pattern
recognition receptors and serves as the first line of defense against
infection. Adaptive immune T and B lymphocytes provide pathogen
and tumor specificity and are stimulated by innate cells following
antigen presentation. As opposed to the broad non-targeted response
of innate cells, these lymphocytes “adapt” to initial infection to confer
immunological memory that protects the host from reinfection by the
same pathogen. Given their distinct roles in the immune system,
specific metabolic features are tailored to the precise function of each
of these cell types as described below.
Granulocytes such as neutrophils are relatively short-lived cells that
often produce an oxidative burst (release of free radical species) to
promote pathogen clearance and release metabolic regulators of
inflammation such as histamine and eicosanoids. Consequently, these
cells are often characterized by a highly glycolytic phenotype to
rapidly support changes in growth and function3. In contrast to the
relative simplicity of neutrophils, macrophages exhibit a more complex
role in the regulation of both pro- and anti-inflammatory processes
compared to granulocytes. Specifically, classical M1 macrophages
produce the cytokine IL-12 to facilitate effector T cell responses, TNFα
to induce inflammation and tissue damage, and anti-microbial nitric
oxide (NO). Alternatively activated M2 macrophages can suppress
inflammation, promote tissue repair, and regulate adaptive immunity4.
These differing roles in innate immunity are predicated by metabolic
pathway choices. For example, M1 macrophages upregulate
inducible nitric oxide synthase (iNOS) and consequently utilize
arginine for the production of inflammatory NO. In contrast, M2 cells
increase arginase 1 expression to inhibit NO synthesis and support
polyamine and hydroxyproline generation for wound healing5. M1
cells also exhibit a high rate of arachidonic acid processing for the
generation of inflammatory eicosanoids such as leukotrienes and
prostaglandins and utilize a glycolytic Warburg metabolism proposed
to be partially mediated by elevated NO capable of nitrosylating and
inactivating iron-sulfur containing electron transport proteins6-8. Indeed,
a well-established connection between increased NO and reduced
respiratory rate is reported in the literature9. In opposition, M2
macrophages have a high basal rate of mitochondrial oxygen
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Aside from pathogen clearance, immune cells can also have a
profound impact on host systemic metabolism. For example, lean
adipose and liver tissue possess M2 macrophages and T regulatory
cells that promote insulin sensitivity by inhibiting M1 macrophage from
releasing inflammatory cytokines and chemokines that can stimulate
aberrant JNK and IKK signaling typically upregulated in insulinresistance skeletal muscle and other tissues14-16. Indeed, an abundance
of M1 macrophages are often found in the tissues of obese
individuals. Similarly, dendritic cells can regulate the gut microbiome
via the production of the vitamin A metabolite retinoic acid (RA)17. RA
can promote T regulatory cell development to control immune
tolerance to symbiotic bacteria and facilitate the production of IgA
antibodies to maintain intestinal barrier integrity18.
Despite the insight that these discoveries have provided regarding
how metabolic pathway choices affect immune cell fate and contribute
to systemic metabolism, understanding the extent of these regulatory
networks and their implications in various diseases remains to be
determined. Recent advancements in hypothesis-generating, unbiased
metabolomics approaches have laid the foundation for answering
these questions and coupled with the power of computational tools for
not only analyzing these datasets, but marrying them with microarray,
genomic, and/or proteomic datasets, holds the potential to facilitate
the development of medical and therapeutic breakthroughs.
REFERENCES
F eature
stor y — R E F E R E N C E S
References
1. Pearce, E.L. & Pearce, E.J. Metabolic pathways in immune
cell activation and quiescence. Immunity 38, 633-43
(2013).
10. Vats, D. et al. Oxidative metabolism and PGC-1beta
attenuate macrophage-mediated inflammation. Cell Metab
4, 13-24 (2006).
2. MacIver, N.J., Michalek, R.D. & Rathmell, J.C. Metabolic
regulation of T lymphocytes. Annu Rev Immunol 31, 259-83
(2013).
11. Thomas, G.D. et al. The biology of nematode- and
IL4Ralpha-dependent murine macrophage polarization in
vivo as defined by RNA-Seq and targeted lipidomics. Blood
120, e93-e104 (2012).
3. Dale, D.C., Boxer, L. & Liles, W.C. The phagocytes:
neutrophils and monocytes. Blood 112, 935-45 (2008).
4. Murray, P.J. & Wynn, T.A. Protective and pathogenic
functions of macrophage subsets. Nat Rev Immunol 11,
723-37 (2011).
5. Stout, R.D. Editorial: macrophage functional phenotypes: no
alternatives in dermal wound healing? J Leukoc Biol 87,
19-21 (2010).
6. Greene, E.R., Huang, S., Serhan, C.N. & Panigrahy, D.
Regulation of inflammation in cancer by eicosanoids.
Prostaglandins Other Lipid Mediat 96, 27-36 (2011).
7. Beltran, B., Mathur, A., Duchen, M.R., Erusalimsky, J.D. &
Moncada, S. The effect of nitric oxide on cell respiration: A
key to understanding its role in cell survival or death. Proc
Natl Acad Sci U S A 97, 14602-7 (2000).
8. Cleeter, M.W., Cooper, J.M., Darley-Usmar, V.M.,
Moncada, S. & Schapira, A.H. Reversible inhibition of
cytochrome c oxidase, the terminal enzyme of the
mitochondrial respiratory chain, by nitric oxide. Implications
for neurodegenerative diseases. FEBS Lett 345, 50-4
(1994).
9. Rees, D.D., Monkhouse, J.E., Cambridge, D. & Moncada,
S. Nitric oxide and the haemodynamic profile of endotoxin
shock in the conscious mouse. Br J Pharmacol 124, 540-6
(1998).
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12. Michalek, R.D. et al. Cutting edge: distinct glycolytic and
lipid oxidative metabolic programs are essential for effector
and regulatory CD4+ T cell subsets. J Immunol 186,
3299-303 (2011).
13. Pearce, E.L. et al. Enhancing CD8 T-cell memory by
modulating fatty acid metabolism. Nature 460, 103-7
(2009).
14. Feuerer, M. et al. Lean, but not obese, fat is enriched for a
unique population of regulatory T cells that affect metabolic
parameters. Nat Med 15, 930-9 (2009).
15. Olefsky, J.M. & Glass, C.K. Macrophages, inflammation,
and insulin resistance. Annu Rev Physiol 72, 219-46
(2010).
16. Patel, P.S., Buras, E.D. & Balasubramanyam, A. The role of
the immune system in obesity and insulin resistance. J Obes
2013, 616193 (2013).
17. Coombes, J.L. et al. A functionally specialized population of
mucosal CD103+ DCs induces Foxp3+ regulatory T cells
via a TGF-beta and retinoic acid-dependent mechanism. J
Exp Med 204, 1757-64 (2007).
18. Mora, J.R. et al. Generation of gut-homing IgA-secreting B
cells by intestinal dendritic cells. Science 314, 1157-60
(2006).
P R E S S
R E L E A S E
Press Release: DHMRI and Metabolon Announce
Strategic Partnership to Provide Expanded
Metabolomics Capabilities
KANNAPOLIS & RESEARCH TRIANGLE PARK, N.C. (August 27,
About the David H. Murdock Research Institute
2013)–The David H. Murdock Research Institute (DHMRI) at the
The David H. Murdock Research Institute (DHMRI) is a not-for-profit,
North Carolina Research Campus and Metabolon, Inc., announced research institute committed to the improvement of human life.
today that they have entered into a strategic agreement to align
DHMRI provides collaborators groundbreaking research and
metabolomics research services. Metabolon is a pioneering leader development solutions at the intersection of human health, nutrition
in discovery metabolomics and specializes in rapidly assessing
and agriculture through investigations in genomics, proteomics,
metabolism in biological samples to quickly identify prospective
metabolomics, NMR, light microscopy and cell biology. DHMRI
biomarkers and to understand metabolic effects of treatments,
combines collaboration and customized solutions with a
interventions, nutritionals, etc. The agreement complements DHMRI’s multidisciplinary, systems biology approach to find answers to
mass spectrometry and NMR-based metabolomics services through advance research and product development. To learn more,
access to Metabolon’s industry-leading high-throughput biomarker
please visit www.dhmri.org or contact [email protected].
discovery and profiling platform which provides an extensive,
untargeted, broad metabolite survey of more than 4000
About Metabolon
biochemicals.
Metabolon, Inc. is a world leader in the field of metabolomics
by pioneering and patenting the industry’s leading biochemical
“This agreement leverages the strengths of our organizations to best
biomarker discovery and profiling platform. It has developed the
serve DHMRI collaborators to understand metabolism and ultimately
technology to quickly identify and measure the biochemicals in a
answer key research questions and deliver healthy food products
biological sample through its proprietary global processing method.
for consumers. We have worked extensively in food science and
Metabolon has a broad pipeline of diagnostic products in the
nutrition and recognize that our combined resources are indeed
fields of obesity-related conditions and cancer. Quantose™ is the
complementary. DHMRI is a center of excellence in nutrition
first diagnostic test developed by Metabolon using its technology.
research and we are delighted to do our part to meet their growing
Metabolon’s expertise is embraced by a wide range of
needs,” says Chris Bernard, Senior Vice President of Sales &
pharmaceutical, biotechnology, food and agricultural companies.
Marketing for Metabolon.
Metabolytics, its biomarker discovery and analysis business, has
completed
over 3,000 client studies with more than 550 customers.
DHMRI is an established not-for-profit research institute that provides
For more information about Metabolon, please visit www.
flexible, client-focused research services to academia, government
metabolon.com or contact Matt Zaske at 919-595-2200 or
and industry collaborators. This agreement, consistent with the
[email protected].
DHMRI’s collaborative approach to scientific inquiry, provides
partners with additional resources for metabolomics. Metabolon’s
global metabolomic approach can pinpoint active pathways which Media Contact:
Mackenzie Mills, SpecOps Communications
can be further interrogated by targeted and or customized
212.518.7721
Ph. | 913.558.2492 Cell
approaches offered by the DHMRI Metabolomics team.
www.SpecOpsComm.com | @SpecOpsComm
“We are excited to broaden the breadth of services offered by the
Benjamin D. Machon, David H Murdock Research Institute
DHMRI to our collaborators. The benefits stemming from the
704.250.2600 Ph. | www.dhmri.org
collective knowledge of our organizations will be readily realized
by researchers, companies and consumers,” said Steve Lommel
Ph.D., Interim President, David H. Murdock Research Institute.
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An Integrated Clinico-Metabolomic Model
Improves Prediction of Death in Sepsis
Langley et. al. | Science Translational Medicine, 2013
Metabolon results led to:
• Biomarkers for identifying sepsis patients who merit intensive treatment due to
risk of death
Key metabolomic observations:
• Fatty acid transport and b-oxidation, gluconeogenesis, and the citric acid
cycle alterations
Synopsis
Differentiating mild infections from life-threatening ones is a complex decision
that is made millions of times a year in U.S. emergency rooms. Should a
patient be sent home with antibiotics and chicken soup? Or should the patient
be hospitalized for intensive treatment? Sepsis—a serious infection that is
associated with a generalized inflammatory response—is one of the leading
causes of death. In two prospective clinical studies reported by Langley et. al.,
patients arriving at four urban emergency departments with symptoms of sepsis
were evaluated clinically and by analysis of their plasma proteome and
metabolome. Survivors and nonsurvivors at 28 days were compared, and a
molecular signature was detected that appeared to differentiate these outcomes–
even as early as the time of hospital arrival. The signature was part of a large
set of differences between these groups, showing that better energy-producing
fatty acid catabolism was associated with survival of the fittest in sepsis. A test
developed from the signature was able to predict sepsis survival and nonsurvival
reproducibly and better than current methods. This test could aid in improving the
accuracy of emergency room decisions regarding treatment of patients at risk of
sepsis.
For more information, visit here.
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The Mycobacterium Tuberculosis Regulatory
Network and Hypoxia
Galagan, J. et. al. | Nature, 2013
Abstract
We have taken the first steps towards a complete reconstruction of the
Mycobacterium tuberculosis regulatory network based on ChIP-Seq and
combined this reconstruction with system-wide profiling of messenger RNAs,
proteins, metabolites and lipids during hypoxia and re-aeration. Adaptations to
hypoxia are thought to have a prominent role in M. tuberculosis pathogenesis.
Using ChIP-Seq combined with expression data from the induction of the
same factors, we have reconstructed a draft regulatory network based on 50
transcription factors. This network model revealed a direct interconnection
between the hypoxic response, lipid catabolism, lipid anabolism and the
production of cell wall lipids. As a validation of this model, in response to
oxygen availability we observe substantial alterations in lipid content and
changes in gene expression and metabolites in corresponding metabolic
pathways. The regulatory network reveals transcription factors underlying
these changes, allows us to computationally predict expression changes,
and indicates that Rv0081 is a regulatory hub.
For more information, visit here.
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Leptin Engages a Hypothalamic Neurocircuitry to
Permit Survival in the Absence of Insulin
Fujikawa, T. et. al. | Cell Metabolism, 2013
Abstract
The dogma that life without insulin is incompatible has recently been challenged
by results showing the viability of insulin-deficient rodents undergoing leptin
monotherapy. Yet, the mechanisms underlying these actions of leptin are
unknown. Here, the metabolic outcomes of intracerebroventricular (i.c.v.)
administration of leptin in mice devoid of insulin and lacking or re-expressing
leptin receptors (LEPRs) only in selected neuronal groups were assessed. Our
results demonstrate that concomitant re-expression of LEPRs only in hypothalamic
g-aminobutyric acid (GABA) and pro-opiomelanocortin (POMC) neurons is
sufficient to fully mediate the lifesaving and antidiabetic actions of leptin in insulin
deficiency. Our analyses indicate that enhanced glucose uptake by brown
adipose tissue and soleus muscle, as well as improved hepatic metabolism,
underlies these effects of leptin. Collectively, our data elucidate a hypothalamicdependent pathway enabling life without insulin and hence pave the way for
developing better treatments for diseases of insulin deficiency.
For more information, visit here.
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Metabolomics Uncovers Dietary Omega-3 Fatty
Acid-Derived Metabolites Implicated in AntiNonciceptive Responses after Experimental Spinal
Cord Injury
Figueroa, J. et. al. | Nueroscience, 2013
Abstract
Chronic neuropathic pain is a frequent comorbidity following spinal cord injury
(SCI) and often fails to respond to conventional pain management strategies.
Preventive administration of docosahexaenoic acid (DHA) or consumption of
a diet rich in omega-3 polyunsaturated fatty acids (O3PUFAs) confers potent
prophylaxis against SCI and improves functional recovery. The present study
examines whether this novel dietary strategy provides significant antinociceptive
benefits in rats experiencing SCI-induced pain. Rats were fed control chow
or chow enriched with O3PUFAs for 8 weeks before being subjected to
sham or cord contusion surgeries, continuing the same diets after surgery for
another 8 more weeks. The paw sensitivity to noxious heat was quantified
for at least 8 weeks post-SCI using the Hargreaves test. We found that SCI
rats consuming the preventive O3PUFA-enriched diet exhibited a significant
reduction in thermal hyperalgesia compared to those consuming the normal diet.
Functional neurometabolomic profiling revealed a distinctive deregulation in
the metabolism of endocannabinoids (eCB) and related N-acyl ethanolamines
(NAEs) at 8 weeks post-SCI. We found that O3PUFAs consumption led to a
robust accumulation of novel NAE precursors, including the glycerophosphocontaining docosahexaenoyl ethanolamine (DHEA), docosapentaenoyl
ethanolamine (DPEA), and eicosapentaenoyl ethanolamine (EPEA). The tissue
levels of these metabolites were significantly correlated with the antihyperalgesic
phenotype. In addition, rats consuming the O3PUFA-rich diet showed reduced
sprouting of nociceptive fibers containing CGRP and dorsal horn neuron p38
MAPK expression, well-established biomarkers of pain. The spinal cord levels
of inositols were positively correlated with thermal hyperalgesia, supporting
their role as biomarkers of chronic neuropathic pain. Notably, the O3PUFA-rich
dietary intervention reduced the levels of these metabolites. Collectively, these
results demonstrate the prophylactic value of dietary O3PUFA against SCImediated chronic pain.
For more information, visit here.
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the
path
forward — continued
Unappreciated Power of Metabolites for New Insight
into Signaling Networks
A Technical Commentary by Michael Milburn, CSO
Obviously, to many, this is not a new concept as this
understanding formed the basis of almost a century of
metabolic investigation from the likes of Krebs, Warburg,
Cori, and Pasteur.
Until recently, technologies that could fully exploit the
information embedded within metabolites did not exist. But,
now, metabolomics offers a more effective means for
surveying metabolism and has confronted us with reminders
of many of the lessons learned in the past. Perhaps the best
current example of this is in the area of the regulation of
metabolism where metabolite concentrations have been
shown to be pivotal inputs for directing signaling and
metabolic enzymes (e.g. histone acetylases/deacetylases,
sirtuins, AMPK, mTOR, DNA methyltransferases)1.
Although regulation of metabolic enzymes by either
covalent modification or allostery has a deep history, many
new findings are extending this deep history and starting to
connect these principles to more advanced aspects of
biological regulation. This includes the field highlighted in
our feature article this month–immunology.
Recent work by Chang et al.2 offers an explanation how
metabolism influences immune cell fate by suggesting that
metabolic substrate availability can govern non-metabolic
functions for enzymes. Specifically, the authors demonstrate
that T cells can utilize glycerate as an alternative fuel source
to glucose for proliferation, but not inflammatory cytokine
production. Instead, glycerate utilization limits glycolysis
and results in a decline in the GAPDH substrate
glyceraldehydes 3-phosphate. Consequently, GAPDH
acquires a non-metabolic function by interacting with the
3’UTR of IFNγ mRNA and inhibiting translation. Thus,
effector T cell mediated inflammation is compromised.
Non-metabolic functions have also been previously
described for the hexokinase 2 and PKM2 as these
enzymes can regulate cytochrome c release and HDAC
removal respectively. Notably, these findings have broad
implications highlighting the importance of biochemical
substrate availability in dictating traditional and nonmetabolic signaling networks. Future studies may reveal
similar mechanisms in other cell types that potentially
regulate complex diseases such as cancer, obesity, and
heart disease. A hot off the press example is recent work by
Moellering and Cravatt showing how cells use an
intrinsically reactive glycolytic intermediate to modify lysine
residues as a means to regulate glycolysis and redirect
carbon to alternate pathways.3-4
Thus, these results continue to remind us that the basic unit
that all life evolved around–metabolism–is central to even
the most complex biological phenomena and the use of
metabolomics as a vehicle for gaining a comprehensive
fingerprint of the system under study will serve to integrate
and advance this understanding.
References
1. Wellen, K.E. & Thompson, C.B. A two-way street:
reciprocal regulation of metabolism and signalling. Nat Rev
Mol Cell Biol 13, 270-276 (2012).
3. Green, Douglas R. & Rathmell, Jeffrey. Sweet Nothings:
Sensing of Sugar Metabolites Controls T Cell Function. Cell
Metabolism 18, 7-8 (2013).
2. Chih-Hao Chang, et. al. Posttranscriptional Control of T Cell
Effector Function by Aerobic Glycolysis. Cell 153, 12391251 (2013).
4. Moellering, R. E. and Cravett, B. F. Functional Lysine
Modification by an Intrinsically Reactive Primary Glycolytic
Metabolite. Science 2, 549-553 (2013).
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Serum Metabolomics Indicate Altered Cellular
Energy Metabolism in Children with Cystic Fibrosis
Joseloff, E. et. al | Pediatric Pulmonology, 2013
Abstract
Background: Cystic fibrosis (CF) is a multi-system disease affecting multiple
organs and cells besides the respiratory system. Metabolomic profiling allows
simultaneous detection of biochemicals originating from cells, organs, or
exogenous origin that may be valuable for monitoring of disease severity or
in diagnosis.
Aim: We hypothesized that metabolomics using serum from children would
differentiate CF from non-CF lung disease subjects and would provide insight
into metabolism in CF.
Methods: Serum collected from children with CF (n ¼ 31) and 31 age and
gender matched children with other lung diseases was used for metabolomic
profiling by gas-and liquid-chromatography. Relative concentration of metabolites
was compared between the groups using partial least square discriminant analyses
(PLS-DA) and linear modeling.
Results: A clear separation of the two groups was seen in PLS-DA. Linear model
found that among the 459 detected metabolites 92 differed between CF and
non-CF. These included known biochemicals in lipid metabolism, oxidants, and
markers consistent with abnormalities in bile acid processing. Bacterial metabolites
were identified and differed between the groups indicating intestinal dysbiosis in
CF. As a novel finding several pathways were markedly different in CF, which
jointly point towards decreased activity in the b-oxidation of fatty acids. These
pathways include low ketone bodies, low medium chain carnitines, elevated
di-carboxylic acids and decreased 2-hydroxybutyrate from amino acid
metabolism in CF compared to non-CF.
Conclusion: Serum metabolomics discriminated CF from non-CF and show
altered cellular energy metabolism in CF potentially reflecting mitochondrial
dysfunction. Future studies are indicated to examine their relation to the underlying
CF defect and their use as biomarkers for disease severity or for cystic fibrosis
transmembrane regulator (CFTR) function in an era of CFTR modifying drugs.
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Listeria Monocytogenes Infection Causes
Metabolic Shifts in Drosophila Melanogaster
Chambers et. al. | PLoS One, 2012
Metabolon results led to:
• Important insights into how metabolism and innate immunity are coupled
• Novel pathways that offer possible avenues for manipulating the innate
immune response for combating infection
Key metabolomic observations:
• Wide-scale changes in energy metabolism with Listeria monocytogenes
infection
• Novel pathway changes with infection (uric acid metabolism)
Synopsis
Although immunity and metabolism are tightly linked, this connection is not
well understood and often unappreciated. Deeper understanding may allow
for more effective manipulation (through diet, environment or drugs) to improve
from infection. Thus, investigators used a model of innate immunity (lethal L.
monocytogenes infection of Drosophila melanogaster) to investigate metabolic
changes coupled to the event. Metabolomics revealed profound changes in
pathways of energy metabolism (beta-oxidation and glycolysis). In addition to
energy pathway changes, significant reductions in the anti-oxidant uric acid
were noted and uricase mutants were shown to be more resistant to infection by
some strains of bacteria and had improved survival upon wounding. This study
lays a foundation for further investigation of the metabolic-immune connection
with the ultimate goal of facilitating treatments/modalities for combating infection.
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Metabolic Disturbances Associated with Systemic
Lupus Erythematosus
Wu T et. al. | PLoS One, 2012
Metabolon results led to:
• New therapeutic targets
• New biomarkers
• A potential treatment via dietary correction
Key metabolomic observations:
• Major changes related to inflammation and oxidative stress
• Metabolic changes suggesting dysregulated energy metabolism
Synopsis
Systemic lupus erythematosus (SLE) is a highly diverse autoimmune disease.
Reliable and specific biomarkers hinder clinical management and the
development of new therapies. Metabolomic analysis of plasma from SLE
subjects discovered biomarkers with remarkably high sensitivity and specificity
compared to normal subjects or subjects with Rheumatoid arthritis (another
pro-inflammatory, chronic systemic autoimmune disease). These results were then
validated in an independent assay and cohort. Oxidized lipids were among the
top differentiating metabolites and they also correlated well with disease grade.
Many of the markers intuitively connect to the clinical features of the disease. For
example, it is likely that the lipid peroxidation markers are a combination of the
impaired beta-oxidation of fatty acids (and the reported lower energy status of
SLE subjects) and the oxidative stress associated with the disease.
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Metabolomics Reveals Elevated Macromolecular
Degradation in Periodontal Disease
Barnes, V., et. al | J Dent Res, 2012
Abstract
Periodontitis is a chronic inflammatory disease characterized by tissue
destruction. In the diseased oral environment, saliva has primarily been
considered to act as a protectant by lubricating the tissue, mineralizing the
bones, neutralizing the pH, and combating microbes. To understand the
metabolic role that saliva plays in the diseased state, we performed untargeted
metabolomic profiling of saliva from healthy and periodontitic individuals.
Several classes of biochemicals, including dipeptide, amino acid, carbohydrate,
lipids, and nucleotide metabolites, were altered, consistent with increased
macromolecular degradation of proteins, triacylglycerol, glycerolphospholipids,
polysaccharides, and polynucleotides in the individuals with periodontal
disease. These changes partially reflected the enhanced host-bacterial
interactions in the diseased state as supported by increased levels of bacterially
modified amino acids and creatine metabolite. More importantly, the increased
lipase, protease, and glycosidase activities associated with periodontitis
generated a more favorable energy environment for oral bacteria, potentially
exacerbating the disease state.
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The Transcription Factor Myc Controls Metabolic
Reprogramming upon T Lymphocyte Activation
Wang, R. et. al. | Immunity, 2011
Abstract
To fulfill the bioenergetic and biosynthetic demand of proliferation, T
cells reprogram their metabolic pathways from fatty acid β-oxidation and
pyruvate oxidation via the TCA cycle to the glycolytic, pentose-phosphate,
and glutaminolytic pathways. Two of the top-ranked candidate transcription
factors potentially responsible for the activation-induced T cell metabolic
transcriptome, HIF1α and Myc, were induced upon T cell activation, but only
the acute deletion of Myc markedly inhibited activation-induced glycolysis and
glutaminolysis in T cells. Glutamine deprivation compromised activation-induced
T cell growth and proliferation, and this was partially replaced by nucleotides
and polyamines, implicating glutamine as an important source for biosynthetic
precursors in active T cells. Metabolic tracer analysis revealed a Myc-dependent
metabolic pathway linking glutaminolysis to the biosynthesis of polyamines.
Therefore, a Myc-dependent global metabolic transcriptome drives metabolic
reprogramming in activated, primary T lymphocytes. This may represent a
general mechanism for metabolic reprogramming under patho-physiological
conditions.
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Detrimental Effects of Adenosine Signaling in
Sickle Cell Disease
Zhang et al. | Nature Medicine, 2011
Metabolon results led to:
• A novel therapeutic target
• A novel biomarkers that also translate to humans
• Mechanistic understanding of signaling events that induce sickle cell disease
Key metabolomic observations:
• Adenosine was markedly increased in the SCD mouse and human subjects
suggesting disease involvement
• Adenosine leads to the release of a specific red blood cell metabolite that
lower oxygen affinity for hemoglobin, promoting sicklingand tissue damage.
Synopsis
Despite precise genetic understanding of sickle cell disease (SCD) and decades
of study, therapies are limited. In a mouse model of SCD, metabolomics
identified adenosine as a disease potentiator and led to the identification of the
adenosine 2B receptor (A2BR) as a novel therapeutic target. Specifically,
antagonism of the A2BR attenuated SCD. Metabolomic analysis revealed
signaling events downstream of the A2BR that promote SCD (PKA, 2,3-DPG).
These results are translatable since adenosine and 2,3-DPG were discovered to
be increased in humans with SCD. Finally, the results have impact in current
drugs targeting the inflammatory arm of SCD through agonismof a different
adenosine receptor (the A2AR). Thus, given the dual nature of adenosine
receptor activation in SCD, agonists to the A2AR may need to be exquisitely
selective across the receptor sub-classes.
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Reducing Endoplasmic Reticulum Stress Through
a Macrophage Lipid Chaperone Alleviates
Atherosclerosis
Erbayet al. | Nature Medicine, 2009
Metabolon results led to:
• Characterization of the mechanism of action
• Validation of potential target
Key metabolomic observations:
• Characterization of the mechanisms underlying lipid chaperone activation to
macrophage ER stress
• Reveal the lipid chaperone aP2 and steroylCoAdesaturase-1 (SCD-1) as
potential targets to combat macrophage ER stress and minimize atherosclerosis
Synopsis
Activation of the ER stress is characteristic of lipid-laden macrophages in
atherosclerotic lesions and is proposed to have a role in plaque vulnerability and
acute cardiac death. It has been proposed that lipid chaperones may be a link
between toxic lipids and organelle stress in macrophages. Lipidomic analysis
implicated regulation of de novo lipogenesis and desaturation, a rate-limiting
step catalyzed by SCD-1, as a potential mechanism underlying chaperone
driven changes in lipid composition in macrophage thus affecting lipid toxic
potential. Further chaperone mediated regulation of SCD-1 activity was causally
linked to lipid-induced ER stress responses in macrophage. Overall, this study
shows that de novo fatty acid synthesis and desaturation can be highly beneficial
if not essential for defending ER function when macrophages are exposed to
toxic lipids and it highlights how examining lipids as a class was able to identify
novel targets.
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Metabolic Profiling in Nutrition and Metabolic
Disorders
LeMieux, M. et. al. | Advances in Nutrition, 2013
Abstract
Nutrients exert potent effects on metabolism through a variety of regulatory
mechanisms, resulting in local and systemic changes in metabolite levels.
Numerous studies have focused on mechanisms by which nutrients and disease
states regulate metabolism at the gene or protein levels using genomic and
proteomic approaches, respectively. However, few studies have investigated
nutritional regulation of the whole metabolome. Thus, metabolomic approaches
have recently emerged to complement the genomics and proteomics research
and to help identify biologically meaningful metabolites and metabolic networks
that control cellular responses to genetic and environmental factors, including
diet, and to identify metabolic diseases that are influenced by genetic and
dietary factors. These large-scale studies expedite our ability to develop targeted
treatments. The goal of this symposium was to provide a forum to introduce the
metabolomics field to nutrition researchers. An overview of the state-of-the-art
metabolomic technologies used was provided. The impact of some specific
nutrients, disease states, or genetic variations and their interaction with the
metabolome was discussed by the speakers. Our objectives were as follows: 1)
to educate the audience about the use of metabolomics as an innovative tool for
linking changes in cell metabolites and genetic variations to nutrient metabolism,
energy balance, and the overlying effects on health and disease; 2) to
understand the concept of metabolomics and describe the analytical tools and
resources available in this area; 3) to introduce the potential application of
metabolomics in the field of nutrition research; and 4) to provide specific
nutrition-relevant metabolomics study examples in investigating regulation of the
metabolic network or metabolic changes resulting from disease states by dietary
factors. Adv. Nutr. 4: 548–550, 2013.
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A Diet Rich in High-Glucoraphanin Broccoli
Interacts with Genotype to Reduce Discordance
in Plasma Metabolite Profiles by Modulating
Mitochondrial Function
Armah, C. et. al. | The American Journal of Clinical Nutrition, 2013
Abstract
Background: Observational and experimental studies suggest that diets rich in
cruciferous vegetables and glucosinolates may reduce the risk of cancer and
cardiovascular disease (CVD).
Objective: We tested the hypothesis that a 12-wk dietary intervention with
high-glucoraphanin (HG) broccoli would modify biomarkers of CVD risk and
plasma metabolite profiles to a greater extent than interventions with standard
broccoli or peas.
Design: Subjects were randomly assigned to consume 400 g standard broccoli,
400 g HG broccoli, or 400 g peas each week for 12 wk, with no other
dietary restrictions. Biomarkers of CVD risk and 347 plasma metabolites were
quantified before and after the intervention.
Results: No significant differences in the effects of the diets on biomarkers of
CVD risk were found. Multivariate analyses of plasma metabolites identified 2
discrete phenotypic responses to diet in individuals within the HG broccoli arm,
differentiated by single nucleotide polymorphisms associated with the PAPOLG
gene. Univariate analysis showed effects of sex (P , 0.001), PAPOLG genotype
(P , 0.001), and PAPOLG genotype 3 diet (P , 0.001) on the plasma metabolic
profile. In the HG broccoli arm, the consequence of the intervention was to
reduce variation in lipid and amino acid metabolites, tricarboxylic acid (TCA)
cycle intermediates, and acylcarnitines between the 2 PAPOLG genotypes.
Conclusions: The metabolic changes observed with the HG broccoli diet are
consistent with a rebalancing of anaplerotic and cataplerotic reactions and
enhanced integration of fatty acid b-oxidation with TCA cycle activity. These
modifications may contribute to the reduction in cancer risk associated with diets
that are rich in cruciferous vegetables. This trial was registered at clinicaltrials.gov
as NCT01114399.
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Metabolomics Identifies PyrimidineStarvation
as the Mechanism of 5-Aminoimidazole-4Carboxamide-1-β-Riboside-Induced Apoptosis
in Multiple Myeloma Cells
Bardelebenet al. | Molecular Cancer Therapeutics, 2013
Metabolon results led to:
• Mechanism of action of a compound that induces apoptosis in multiple
myeloma cells
• A potential new target in multiple myeloma and a patient stratification strategy
Key metabolomic observations:
• Profound increase in the nucleotide precursor orotate
Synopsis
AICAr (5-aminoimidazole-4-carboxamide-1-b-riboside) has been studied as an
antitumor agent with the suspected mechanism of action (MOA) through AMPK
activation and mTOR inhibition. However, cytotoxic affects do not always
correlate with this putative MOA. Thus, investigators used a metabolomics
screen to elucidate the MOA and this screen revealed a >26 fold increase in
orotate, a precursor of de novo synthesis of pyrimidines. An array of follow-up
experimentation showed that inhibiting or rescuing steps governing pyrimidine
synthesis were clearly at the epicenter of the MOA of AICAr. This finding can be
coupled to the gene expression profiles of multiple myeloma (MM) patients that
reveal clones with deficiencies in this pathway suggesting that MM may be
particularly sensitive to pyrimidine starvation and thus, inhibitors to this pathway.
Hence, a metabolomics screen revealed a new target area (novel from the
putative target) that may be particularly promising against MM.
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HuR is a Post-Transcriptional Regulator of Core
Metabolic Enzymes in Pancreatic Cancer
Burkhart, R. et. al. | RNA Biology, 2013
Abstract
Cancer cell metabolism differs from normal cells, yet the regulatory mechanisms
responsible for these differences are incompletely understood, particularly in
response to acute changes in the tumor microenvironment. HuR, an RNA binding
protein, acts under acute stress to regulate core signaling pathways in cancer
through post-transcriptional regulation of mRNA targets. We demonstrate that
HuR regulates the metabolic phenotype in pancreatic cancer cells and is critical
for survival under acute glucose deprivation. Using three pancreatic cancer cell
line models, HuR-proficient cells demonstrated superior survival under glucose
deprivation when compared with isogenic cells with siRNA-silencing of HuR
expression (HuR-deficient cells). We found that HuR-proficient cells utilized
less glucose, but produced greater lactate, as compared with HuR-deficient
cells. Acute glucose deprivation was found to act as a potent stimulus for HuR
translocation from the nucleus to the cytoplasm, where HuR stabilizes its mRNA
targets. We performed a gene expression array on ribonucleoproteinimmuno
precipitated mRNAs bound to HuR and identified 11 novel HuR target transcripts
that encode enzymes central to glucose metabolism. Three (GPI, PRPS2 and
IDH1) were selected for validation studies, and confirmed as bona fide HuR
targets. These findings establish HuR as a critical regulator of pancreatic
cancer cell metabolism and survival under acute glucose deprivation. Further
explorations into HuR’s role in cancer cell metabolism should uncover novel
therapeutic targets that are critical for cancer cell survival in a metabolically
compromised tumor microenvironment.
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Exposure of Clinical MRSA Heterogeneous Strains
to β-Lactams Redirects Metabolism to Optimize
Energy Production through the TCA Cycle
Keaton et. al. | PLoS One, 2013
Metabolon results led to:
• Identification of key metabolic adaptation to resistance development
• Potential targets to prevent the acquisition of resistance or resistant strains
Key metabolomic observations:
• An increase in TCA cycle intermediates
• Changes in carbon sources that feed the TCA cycle (fatty acids, amino acids)
Synopsis
Methicillin-resistant Staphylococcus aureus (MRSA) is a severe threat in both
hospital and community-acquired infections so there is a continuing need to
expand our understanding of the cellular physiology that allow strains to adapt
and survive in the presence of beta-lactam antibiotics. To this end, metabolomics
and gene expression profiling were preformed on strains during resistance
development. Collectively, the data indicated that an upregulation of TCA cycle
activity was a key feature of adaptation (presumably for cell wall synthesis/
metabolism). The importance of this upregulation was confirmed when the fate of
strain adaptation was shown to follow the presence or absence of the TCA cycle
enzyme aconitase. These novel insights into the precise metabolic adaptations of
MRSA provide potential new targets for the design of new drugs against MRSA
infections.
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Metabolite Profiling Reveals New Insights into the
Regulation of Serum Urate in Humans
Albrecht, E. et. al. | Metabolomics, 2013
Abstract
Serum urate, the final breakdown product of purine metabolism, is causally
involved in the pathogenesis of gout, and implicated in cardiovascular
disease and type 2 diabetes. Serum urate levels highly differ between men
and women; however the underlying biological processes in its regulation
are still not completely understood and are assumed to result from a complex
interplay between genetic, environmental and lifestyle factors. In order to
describe the metabolic vicinity of serum urate, we analyzed 355 metabolites
in 1,764 individuals of the population based KORA F4 study and constructed
a metabolite network around serum urate using Gaussian Graphical Modeling
in a hypothesis-free approach. We subsequently investigated the effect of sex
and urate lowering medication on all 38 metabolites assigned to the network.
Within the resulting network three main clusters could be detected around urate,
including the well-known pathway of purine metabolism, as well as several
dipeptides, a group of essential amino acids, and a group of steroids. Of
the 38 assigned metabolites, 25 showed strong differences between sexes.
Association with uricostatic medication intake was not only confined to purine
metabolism but seen for seven metabolites within the network. Our findings
highlight pathways that are important in the regulation of serum urate and
suggest that dipeptides, amino acids, and steroid hormones are playing a
role in its regulation. The findings might have an impact on the development of
specific targets in the treatment and prevention of hyperuricemia.
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Profile of Circulatory Metabolites in an Animal
Model of Multiple Sclerosis Using Global
Metabolomics
Mangalam, A. et. al. | Journal of Clinical and Cellular Immunology, 2013
Abstract
Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease
of the CNS. Although, MS is well characterized in terms of the role played
by immune cells, cytokines and CNS pathology, nothing is known about the
metabolic alterations that occur during the disease process in circulation.
Recently, metabolic aberrations have been defined in various disease processes
either as contributing to the disease, as potential biomarkers, or as therapeutic
targets. Thus in an attempt to define the metabolic alterations that may be
associated with MS disease progression, we profiled the plasma metabolites
at the chronic phase of disease utilizing relapsing remitting experimental
autoimmune encephalomyelitis (RR-EAE) model in SJL mice. At the chronic
phase of the disease (day 45), untargeted global metabolomic profiling of
plasma collected from EAE diseased SJL and healthy mice was performed,
using a combination of high-throughput liquid-and-gas chromatography with
mass spectrometry. A total of 282 metabolites were identified, with significant
changes observed in 44 metabolites (32 up-regulated and 12 down-regulated),
that mapped to lipid, amino acid, nucleotide and xenobiotic metabolism
and distinguished EAE from healthy group [p<0.05, false discovery rate
(FDR)<0.23]. Mapping the differential metabolite signature to their respective
biochemical pathways using the Kyoto Encyclopedia of Genes and Genomics
(KEGG) database, we found six major pathways that were significantly altered
(containing concerted alterations) or impacted (containing alteration in key
junctions). These included bile acid biosynthesis, taurine metabolism, tryptophan
and histidine metabolism, linoleic acid and D-arginine metabolism pathways.
Overall, this study identified a 44 metabolite signature drawn from various
metabolic pathways which correlated well with severity of the EAE disease,
suggesting that these metabolic changes could be exploited as (1) biomarkers
for EAE/MS progression and (2) to design new treatment paradigms where
metabolic interventions could be combined with present and experimental
therapeutics to achieve better treatment of MS.
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Lipidomics Reveals Early Metabolic Changes in
Subjects with Schizophrenia: Effects of Atypical
Antipsychotics
McEvoy, J. et. al. | PLoS One, 2013
Abstract
There is a critical need for mapping early metabolic changes in schizophrenia
to capture failures in regulation of biochemical pathways and networks.
This information could provide valuable insights about disease mechanisms,
trajectory of disease progression, and diagnostic biomarkers. We used a
lipidomics platform to measure individual lipid species in 20 drug-naïve patients
with a first episode of schizophrenia (FE group), 20 patients with chronic
schizophrenia that had not adhered to prescribed medications (RE group), and
29 race-matched control subjects without schizophrenia. Lipid metabolic profiles
were evaluated and compared between study groups and within groups before
and after treatment with atypical antipsychotics, risperidone and aripiprazole.
Finally, we mapped lipid profiles to n3 and n6 fatty acid synthesis pathways
to elucidate which enzymes might be affected by disease and treatment.
Compared to controls, the FE group showed significant down-regulation of
several n3 polyunsaturated fatty acids (PUFAs), including 20:5n3, 22:5n3, and
22:6n3 within the phosphatidylcholine and phosphatidylethanolamine lipid
classes. Differences between FE and controls were only observed in the n3
class PUFAs; no differences where noted in n6 class PUFAs. The RE group was
not significantly different from controls, although some compositional differences
within PUFAs were noted. Drug treatment was able to correct the aberrant
PUFA levels noted in FE patients, but changes in re patients were not corrective.
Treatment caused increases in both n3 and n6 class lipids. These results
supported the hypothesis that phospholipid n3 fatty acid deficits are present
early in the course of schizophrenia and tend not to persist throughout its course.
These changes in lipid metabolism could indicate a metabolic vulnerability in
patients with schizophrenia that occurs early in development of the disease.
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3-Hydroxykynurenine and Other Parkinson’s
Disease Biomarkers Discovered by Metabolomic
Analysis
LeWitt, P. et. al. | Movement Disorders, 2013
Abstract
Parkinson’s disease (PD) biomarkers are needed to enhance therapeutics
research and to understand PD pathogenesis. Methods that simultaneously
measure hundreds of small molecular-weight compounds–metabolomic
analysis–“fingerprint” disease specific alterations in individual compounds or
metabolic pathways. Beyond a nontargeted search for PD biomarkers, we
hypothesized that PD cerebrospinal fluid would show increased formation of the
excitotoxin 3-hydroxykynurenine and diminished concentration of the antioxidant
glutathione. Cerebrospinal fluid was collected at <4 hours postmortem from 48
pathologically verified PD subjects and 57 comparably-aged controls. Assays
involved ultra-high-performance liquid and gas chromatography linked to mass
spectrometry. We used univariate techniques to determine fold-changes in
concentrations of biochemicals; false-discovery rates were calculated to exclude
spurious findings. Data was modeled using a Support Vector Machine for
analyzing compounds selected by Welch’s t test. Classification accuracy was
determined by cross-validation. Of 243 structurally-identified biochemicals,19
compounds differentiated PD from controls at a 20% false-discovery level. In
PD, mean 3-hydroxykynurenine concentration was increased by one-third,
and mean oxidized glutathione was decreased by 40% (for each, P<.01).
Four of the 19 compounds differentiating PD from controls were Nacetylated
amino acids, suggesting a generalized alteration in N-acetylation activity. The
Support Vector Machine classification model distinguished between groups
at 83% sensitivity and 91% specificity for the learning data, and at 65% and
79% from cross-validation. In this study, the first for metabolomic profiling of PD
cerebrospinal fluid, we found several novel biomarkers and offer new directions
for recognizing disease-specific biochemical indicators. The findings support
involvement of excitotoxicity and oxidative stress in the pathogenesis of PD.
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Metabolomics in Epidemiology: Sources of
Variability in Metabolite Measurements and
Implications
Sampson. J et. al. | Cancer Epidemiology, Biomarkers & Prevention, 2013
Abstract
Background: Metabolite levels within an individual vary over time. This withinindividual variability, coupled with technical variability, reduces the power for
epidemiologic studies to detect associations with disease. Here, the authors
assess the variability of a large subset of metabolites and evaluate the
implications for epidemiologic studies.
Methods: Using liquid chromatography/mass spectrometry (LC/MS) and gas
chromatography-mass spectroscopy (GC/MS) platforms, 385 metabolites were
measured in 60 women at baseline and year-one of the Shanghai Physical
Activity Study, and observed patterns were confirmed in the Prostate, Lung,
Colorectal, and Ovarian Cancer Screening study.
Results: Although the authors found high technical reliability (median intraclass
correlation ¼ 0.8), reliability over time within an individual was low. Taken
together, variability in the assay and variability within the individual accounted
for the majority of variability for 64% of metabolites. Given this, a metabolite
would need, on average, a relative risk of 3 (comparing upper and lower
quartiles of “usual” levels) or 2 (comparing quartiles of observed levels) to be
detected in 38%, 74%, and 97% of studies including 500, 1,000, and 5,000
individuals. Age, gender, and fasting status factors, which are often of less
interest in epidemiologic studies, were associated with 30%, 67%, and 34% of
metabolites, respectively, but the associations were weak and explained only a
small proportion of the total metabolite variability.
Conclusion: Metabolomics will require large, but feasible, sample sizes to
detect the moderate effect sizes typical for epidemiologic studies.
Impact: We offer guidelines for determining the sample sizes needed to conduct
metabolomic studies in epidemiology.
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