Download Insight into Metabolic Reprogramming in Tumor Cells

A U G U S T
feature
stor y
Insight into
Metabolic
Reprogramming
in Tumor Cells
A tumor cell may acquire as
many as 100 mutations in the
course of neoplastic initiation and
progression. In our genomics
centric world, we tend to
associate those mutational events
with alterations in signal
transduction pathways which
regulate cell cycle progression.
C
hanges in signal transduction pathways
can result from activating mutations in
proto-oncogenes, loss of tumor suppressor
function, or over-expression of proliferating
enabling gene products (e.g. tyrosine
kinase receptors). In addition to the requirement to circumvent cell cycle checkpoints,
proliferating tumor cells must enable
mechanisms to support biosynthesis resulting
in a doubling of cell mass. This requires a
metabolic reprogramming directed by many
of the same mutational events and altered
signal transduction pathways more typically
associated with cell cycle regulation.
keep reading this story
2 0 1 3
I S S U E
News & EVENTS
Press Release: IMDEA Food and Metabolon, Inc. Announce Strategic
Collaboration to Advance Nutrition-based Personalized Medicine
July 9, 2013 | Read Press Release
Publication makes cover and gets media attention:
A Bloodspot-based Diagnostic Test for Fibromyalgia
Syndrome and Related Disorders
June 20, 2013 | MORE INFO
Metabolomics in Pneumonia and Sepsis: an Analysis of the GenIMS
Cohort Study Seymour, C. et al | Intensive Care Medicine, 2013
MORE INFO
publications
Cancer/Oncology
Integrated Metabolite and Gene Expression Profiles Identify Lipid Biomarkers Associated
with Progression of Hepatocellular Carcinoma and Patient Outcomes
Budhu, A., S. Roessler, et al. | Gastroenterology, 2013
VIEW SUMMARY
Phosphoglycerate Mutase 1 Coordinates Glycolysis and Biosynthesis to Promote
Tumor Growth
Hitosugi, T., L. Zhou, et al. | Cancer Cell, 2012
VIEW SUMMARY
The Downregulation of miR-125b in Chronic Lymphocytic Leukemias Leads to Metabolic
Adaptation of Cells to a Transformed State
Tili, E., J.J. Michaille, et al. | Blood, 2012
VIEW SUMMARY
Metabolomic Profiles Delineate Potential Role for Sarcosine in Prostate Cancer Progression
Sreekumar, A., L. M. Poisson, et al. | Nature, 2009
VIEW SUMMARY
The Small Molecule GMX1778 is a Potent Inhibitor of NAD+ Biosynthesis: Strategy for
Enhanced Therapy in Nicotinic Acid Phosphoribosyltransferase 1-Deficient Tumors
Watson, M., A. Roulston, et al. | Molecular Cell Biology, 2009
VIEW SUMMARY
Inhibition of Nonsense-Mediated RNA Decay Activates Autophagy
Wengrod, J. et al. | Molecular Cellular Biology, 2013
VIEW SUMMARY
REFERENCES
Metabolic Alterations in Mammary Cancer Prevention by Withaferin A in a Clinically
Relevant Mouse Model
Hahm, E. et al. | Journal of the National Cancer Institute, 2013
VIEW SUMMARY
A U G U S T
t h e
pat h
for w ard
A Technical
Commentary by
Michael Milburn,
CSO
Oncology treatments
have typically
occupied two extreme ends of a
spectrum, either consisting of radiation
and chemotherapy regiments that can
be regarded as a “sledgehammer” or
the precise targeting of oncogenic
activators via a “silver-bullet”
approach. Both have produced
success, but dose limiting toxicities
reside on one end of this spectrum
while evasiveness and resistance
reside on the other.
In addition to some profound success
stories (e.g. vemurafenib, trastuzumab),
the silver bullet approach has illuminated
much about cancer biology—showing
us that there is a large amount of
redundancy and crosstalk in pathways
such as RAF/MEK/ERK or those
initiated by receptor tyrosine kinases.
Heterogeneity of Tumor-Induced Gene
Expression Changes in the Human
Metabolic Network
Hu, J. et al. | Nature Biotechnology, 2013
VIEW SUMMARY
Metabolic Alterations in Lung CancerAssociated Fibroblasts Correlated with
Increased Glycolytic Metabolism of the Tumor
Chaudhri, V. et al.
Molecular Cancer Research, 2013
VIEW SUMMARY
Metabolism/Cardiovascular Disease
Survival Response to Increased Ceramide
Involves Metabolic Adaptation through Novel
Regulators of Glycolysis and Lipolysis
Nirala, N. et al. | PLoS Genetics, 2013
VIEW SUMMARY
Metabolomic Signatures in Lipid-Loaded
HepaRGs Reveal Pathways Involved in
Steatotic Progression- Strain-Specific Red
Blood Cell Storage, Metabolism, and
Eicosanoid Generation in a Mouse Model
Brown, M. et al. | Obesity, 2013
For a complete list of publications,
please visit our website at
www.metabolon.com/news/Publications.aspx.
Paraoxonase-1 Deficiency is Associated with
Severe Liver Steatosis in Mice Fed a High-fat
High-cholesterol Diet: A Metabolomic Approach
Garcia-Heredia, A. et al.
Journal of Proteome Research, 2013
VIEW SUMMARY
Nutrition & Consumer Goods
The Role of Adipocyte XBP1 in Metabolic
Regulation during Lactation
Gregor, M. et al. | Cell Reports, 2013
VIEW SUMMARY
Metabolomic Analysis of Sun Exposed Skin
Randhawa, M. et al.
Molecular BioSystems, 2013
VIEW SUMMARY
Lacritin Rescues Stressed Epithelia Via Rapid
FOX03 Associated Autophagy That Restores
Metabolism
Wang, N. et al.
The Journal of Biological Chemistry, 2013
VIEW SUMMARY
Infectious Disease
Plasma Metabolomics Identifies Lipid
Abnormalities Linked to Markers of
Inflammation, Microbial Translocation, and
Hepatic Function in HIV Patients Receiving
Protease Inhibitors
Cassol, E. et al.
BMC Infectious Diseases, 2013
VIEW SUMMARY
Metabolomics and Incident Hypertension
Among Blacks: the Atherosclerosis Risk in
Communities Study
Zheng, et al. | Hypertension, 2013
VIEW SUMMARY
VIEW SUMMARY
Associations between Metabolomic
Compounds and Incident Heart Failure among
African-Americans: The Atherosclerosis Risk
in Communities (ARIC) Study
Zheng, Y. et al.
American Journal of Epidemiology, 2013
Bioprocessing
VIEW SUMMARY
Application of Combined Omics Platforms to
Accelerate Biomedical Discovery in Diabesity
Kurland, I. et al.
Annals of the NY Academy of Sciences, 2013
VIEW SUMMARY
keep reading this story
I S S U E
publications —continued
Cancer/Oncology
Is it Time to Go “All-in”
on Leveraging Metabolic
Reprogramming of
Cancer?
2 0 1 3
Pharmacological Inhibition to Examine the
Role of DGAT1 in Dietary Lipid Absorption in
Rodents and Humans
Maciejewski, B. et al.
Gastrointestinal and Liver Physiology: American
Journal of Physiology, 2013
VIEW SUMMARY
Glycogen Synthesis is a Required Component of
the Nitrogen Stress Response in Synechococcus
Elongatus PCC 7942
Hickman, J. et al. | Algal Research, 2013
VIEW SUMMARY
Plant
Mobilization of Lipids and Fortification of Cell
Wall and Cuticle are Important in Host Defense
Against Hessian Fly
Khajuria, C. et al. | BMC Genomics, 2013
VIEW SUMMARY
Aging
Metabolomic Markers Reveal Novel Pathways
of Ageing and Early Development in Human
Populations
Menni, C. et al.
International Journal of Epidemiology, 2013
VIEW SUMMARY
A bimonthly publication of:
© Copyright Metabolon, Inc. 2013
+1.919.572.1711
| www.metabolon.com | [email protected]
F eature
stor y — continued
Insight into Metabolic Reprogramming in Tumor Cells
It is now appreciated that activation of oncogenes and loss of
tumor suppressors contribute to a reprogramming of cellular
metabolism which supports: 1) sufficient ATP and reducing
equivalents to support energetic needs; 2) increases in nutrient
uptake and biosynthesis; 3) survival of tumor cells in less than
optimal growth conditions and 4) management of cellular redox
conditions. This brief synopsis will touch on some highlights
described in recent reviews [1–5] and address the role of
discovery metabolic profiling in providing essential insight into cell
metabolism’s critical role in tumorigenesis.
Other examples of oncogene mediated metabolic reprogramming
include the role of myc in increasing glutaminolysis, kras
enhancement of glucose utilization and mutant isocitrate
dehydrogenase modulating epigenetic programming through
production of 2-hydroxyglutarate. Additional tumor suppressors
whose loss impacts tumor cell metabolism include LKB, VHL and
the TCA cycle enzymes fumarate hydratase and succinate
dehydrogenase. Undoubtedly, many connections between tumor
genomic alterations and metabolic consequences have yet to
be uncovered.
Activation of the PI3-Kinase/AKT pathway is one of the most
common signal transduction alterations observed in tumor cells
and the pathway is one of the most heavily targeted in terms of
oncology drug discovery efforts. This pathway can be activated
by overexpression of tyrosine growth factor receptors such as Her2
or EGFR, or through loss of PTEN function allowing constitutive
activation of the pathway. AKT’s function in cell proliferation was
originally linked to its ability to phosphorylate p27Kip and p21
CIP/WAF, permitting cell cycle progression. It is now clear that
the PI3-Kinase/AKT pathway also contributes to: 1) increased
cellular glucose levels through upregulation of glucose transporter
expression and hexokinase activity, 2) increased fatty acid synthesis,
through increased expression of fatty acid synthase and activation
of ATP citrate lyase and 3) upregulation of protein and nucleotide
synthesis through activation of the mTor complex. While PI3Kinase/AKT activation serves many other functions, activating
fatty acid synthesis and protein translation are key steps toward
increasing the biomass of proliferating tumor cells.
The oncogenes and tumor suppressors described above represent
some of the most frequently altered gene products/signaling
pathways observed in tumor cells. It is now clear that oncogenes
and tumor suppressors can directly regulate metabolic pathways.
More importantly, we now know that measuring the resulting
metabolite changes can yield a better understanding of how
metabolic reprogramming might differentiate tumors, with regard to
their proliferative and metastatic potential. The power of discovery
metabolomics to reveal underlying signal transduction perturbations
that correlate with tumor progression and patient outcomes was
demonstrated in a study to identify hepatocellular (HCC) carcinoma
biomarkers [7]. Discovery metabolite profiling of aggressive HCC
tumors relative to normal hepatic tissue revealed that palmitic acid
saturation status may be associated with clinical outcome. Palmitic
acid is a substrate for stearoyl-CoA desaturase (SCD). Biological
network analysis, of an integrated metabolite and transcriptomic
data set, identified stearoyl-CoA desaturase as a biomarker for
aggressive HCC and linked its upregulation to the PI3-kinase
signaling pathway.
The tumor suppressor p53 is typically viewed as a transcription
factor and regulator of cell cycle progression and apoptosis.
Loss of p53 is now known to affect metabolic reprogramming
through upregulating glycolysis, downregulating oxidative
phosphorylation and negatively regulating AKT. Shifting from
oxidative phosphorylation to glycolysis as a means of generating
ATP is thought to preserve carbon for biosynthetic anabolic
processes of proliferating cells. An example of using global
metabolomics to understand the consequences of loss of p53 is
the elucidation of how phosphoglycerate mutase 1 (PGAM1)
coordinates glycolysis and biosynthesis in tumor cells [6]. PGAM1
is upregulated by the loss of p53. Global metabolite profiling of
lung cancer H12199 cells in which PGAM1 was stably knocked
down revealed that 3-phosphoglycerate (3-PG) was elevated in
knockdown cells relative to controls. Subsequent analysis
demonstrated that 3-PG elevation inhibits 6-phosphogluconate
dehydrogenase an enzyme that generates NADPH for use in
biosynthesis and redox management. Thus, loss of p53 may
enhance tumor cell biosynthesis and redox balance through
upregulation of PGAM1, demonstrating the connections which
can be uncovered in a discovery metabomics approach.
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In the past decade it has become quite evident that oncogene
signaling reprograms tumor cell metabolism to support growth and
survival. Since metabolic reprogramming is a critical component
of tumorigenesis, it is likely that different mutation strategies may be
selected, in tumor cell populations, to accomplish similar metabolic
goals. It may be advantageous to characterize tumors based on
their metabolic alterations and correlate these tumor “metabolic
classes” to clinical outcomes. Metabolic alterations may also
contribute to de novo or acquired drug resistance, by attenuating
downstream effects of therapeutics targeting specific signaling
pathways [8]. Tumor cell reliance on specific oncogene or tumor
suppressor-driven metabolic alterations may make them more
susceptible to therapeutic agents that target those metabolic
pathways. Understanding the manner in which therapeutics
targeting signal transduction pathways impact tumor cell
metabolism may lead to defining drug combinations that expand
therapeutic windows, overcome resistance mechanisms and
enable personalized cancer treatments.
REFERENCES
F eature
stor y — R E F E R E N C E S
References
1. Wallace, D.C., Mitochondria and cancer. Nat Rev Cancer,
2012. 12(10): p. 685-698.
2. Cairns, R.A., I.S. Harris, and T.W. Mak, Regulation of
cancer cell metabolism. Nat Rev Cancer, 2011. 11(2): p.
85-95.
3. Ward, P.S. and C.B. Thompson, Metabolic reprogramming:
a cancer hallmark even warburg did not anticipate. Cancer
Cell, 2012. 21(3): p. 297-308.
4. Levine, A.J. and A.M. Puzio-Kuter, The control of the
metabolic switch in cancers by oncogenes and tumor
suppressor genes. Science, 2010. 330(6009): p. 1340-4.
5. Vander Heiden, M.G., Targeting cancer metabolism: a
therapeutic window opens. Nat Rev Drug Discov, 2011.
10(9): p. 671-84.
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6. Hitosugi, T., et al., Phosphoglycerate mutase 1 coordinates
glycolysis and biosynthesis to promote tumor growth.
Cancer Cell, 2012. 22(5): p. 585-600.
7. Budhu, A., et al., Integrated metabolite and gene
expression profiles identify lipid biomarkers associated with
progression of hepatocellular carcinoma and patient
outcomes. Gastroenterology, 2013. 144(5): p. 10661075 e1.
8. Komurov, K., et al., The glucose-deprivation network
counteracts lapatinib-induced toxicity in resistant ErbB2positive breast cancer cells. Mol Syst Biol, 2012. 8: p.
596.
P R E S S
R E L E A S E
Press Release: IMDEA Food and Metabolon, Inc.
Announce Strategic Collaboration to Advance
Nutrition-based Personalized Medicine
Raleigh, NC – July 09, 2013 -- IMDEA Food, a Translational
Research Institute from the Community of Madrid, dedicated to
investigating the relationships among nutrition, food and health,
and the US-based company Metabolon Inc., the pioneering leader
in the field of metabolomics and molecular diagnostics serving the
pharmaceutical and food industries, today announced an ambitious
collaboration program. The agreement, signed today in Madrid by
Dr. John Ryals, President and CEO of Metabolon, and Dr. Guillermo
Reglero, Director of IMDEA Food, establishes the framework for
future strategic projects aimed to develop functional foods and
diagnostic tools.
Of particular interest is the prevention of prevalent chronic diseases
with high societal impact, such as cardiovascular disease, cancer,
obesity and neurological diseases, which are highly dependent on
understanding food science and nutritional impact. To achieve this
goal, individual in-depth studies to characterize the molecular
mechanisms underlying the health benefits of foods and food
components are needed.
Scientists from IMDEA Food and Metabolon have met in IMDEA
Food’s new headquarters located in Madrid to define the lines of
common interest and greatest priority and to launch the first of a
series of studies aimed at defining the molecular basis of action of
key food ingredients.
Dr. Steve Watkins, Chief Technology Officer, Metabolon
commented, “Collaborative studies with IMDEA will employ the
combined resources and expertise of our organizations to identify
appropriate biomarkers of disease risk and prevention and to
monitor biological impact of nutritional components in foods. This
strategic collaboration is pivotal to advancing our understanding of
nutrition’s influence on health and disease.”
About Metabolon:
Metabolon, Inc. is the world leader in the field of metabolomics
by pioneering and patenting the industry’s leading biochemical
biomarker discovery and profiling platform. It has developed the
technology to quickly identify and measure all of the biochemicals
in a biological sample through its proprietary global processing
method. Quantose™ is the first diagnostic test discovered by
Metabolon using its technology. Metabolon has a broad pipeline
of diagnostic products in the fields of obesity-related conditions
and cancer. Metabolon’s technology expertise is being embraced
by a wide range of pharmaceutical, biotechnology, food and
agricultural companies. Metabolytics, its biomarker discovery and
analysis business, has completed over 2,500 client studies with
more than 500 customers. For more information about Metabolon,
please contact Matt Zaske at [email protected], 919-5952200 or visit www.metabolon.com.
“These studies promise to lead toward an efficient decrease of
morbimortality due to chronic degenerative diseases and a better
quality of life. IMDEA Food and Metabolon will combine their
knowledge to advance towards this objective. A combined
functional genomics and metabolomics approach involving
complementary technologies and multidisciplinary expertise is
paramount to achieve the scientific rigor and level of evidence
required to bring nutrition-based personalized medicine to the
public with the final objective of living longer and healthier”,
commented Prof. Jose Ordovas of Tufts University, a worldrenowned pioneer in nutirgenomics. Prof. Ordovas serves as the
Media Contact:
Senior Scientist and Director for the Nutrition and Genomics
Mackenzie Mills, Account Director, SpecOps Communications
Laboratory and as the Chair of the Functional Genomics Core of
212.518.7721 Ph. | 913.558.2492 Cell
the Jean Mayer USDA Human Nutrition Research Center on Aging
www.SpecOpsComm.com | @SpecOpsComm
at Tufts University. Since its inception in 2007 Prof. Ordovas has
been Chairman of the Board and Scientific Director of IMDEA Food.
The IMDEA Food Institute carries out human nutrigenomic studies,
which are reviewed by a Research Ethical Committee, on its
platform comprised of common services for genomics, biostatistics,
bioinformatics and nutritional counseling. Metabolon is the world
leader in metabolomic analysis of complex biological samples and
has made major contributions to the discovery of biomarkers and
biochemical pathways associated with nutrients and drugs, and
which have led to the development of unique diagnostic tools.
BACK TO NEWSLETTER
A Bloodspot-based Diagnostic Test for
Fibromyalgia Syndrome and Related Disorders
Hackshaw, K. | Analyst, 2013
Abstract
The aim of this study was to investigate the ability of a rapid
biomarker-based method for diagnosis of fibromyalgia
syndrome (FM) using mid-infrared microspectroscopy
(IRMS) to differentiate patients with FM from those with
osteoarthritis (OA) and rheumatoid arthritis (RA), and to
identify molecular species associated with the spectral
patterns. Under IRB approval, blood samples were collected
from patients diagnosed with FM (n=14), RA (n=15),
or OA (n=12). Samples were prepared, placed onto a highly reflective
slide, and spectra were collected using IRMS. Spectra were analyzed using
multivariate statistical modeling to differentiate groups. Aliquots of samples also
were subjected to metabolomic analysis. IRMS separated subjects into classes
based on spectral information with no misclassifications among FM and RA or
OA patients. Interclass distances of 15.4 (FM vs. RA), 14.7 (FM vs. OA) and
2.5 (RA vs. OA) among subjects, demonstrating the ability of IRMS to achieve
reliable resolution of unique spectral patterns specific to FM. Metabolomic
analysis revealed that RA and OA groups were metabolically similar, whereas
biochemical differences were identified in the FM that were quite distinctive
from those found in the other two groups. Both IRMS and metabolomic analysis
identified changes in tryptophan catabolism pathway that differentiated patients
with FM from those with RA or OA.
For more information, visit here.
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Metabolics in Pneumonia and Sepsis: an Analysis
of the GenIMS Cohort Study
Seymour, C. et al. | Intensive Care Medicine, 2013
Abstract
Purpose: To determine the global metabolomic profile as measured in circulating
plasma from surviving and non-surviving patients with community-acquired
pneumonia (CAP) and sepsis.
Methods: Random, outcome-stratified case–control sample from a prospective
study of 1,895 patients hospitalized with CAP and sepsis. Cases (n=15) were
adults who died before 90 days, and controls (n=15) were adults who
survived, matched on demographics, infection type, and procalcitonin. We
determined the global metabolomic profile in the first emergency department
blood sample using non-targeted mass-spectrometry. We derived metabolitebased prognostic models for 90-day mortality. We determined if metabolites
stimulated cytokine production by differentiated Thp1 monocytes in vitro, and
validated metabolite profiles in mouse liver and kidney homogenates at 8 h in
cecal ligation and puncture (CLP) sepsis.
Results: We identified 423 small molecules, of which the relative levels of 70
(17 %) were different between survivors and non-survivors (p B 0.05). Broad
differences were present in pathways of oxidative stress, bile acid metabolism,
and stress response. Metabolite-based prognostic models for 90-day survival
performed modestly (AUC=0.67, 95 % CI 0.48, 0.81). Five nucleic acid
metabolites were greater in non-Intensive Care Med DOI 10.1007/s00134013-2935-7 ORIGINAL survivors (p B 0.05). Of these, pseudouridine increased
monocyte expression of TNFa and IL1b versus control (p\0.05). Pseudouridine
was also increased in liver and kidney homogenates from CLP mice versus sham
(p\0.05 for both).
Conclusions: Although replication is required, we show the global metabolomic
profile in plasma broadly differs between survivors and nonsurvivors of CAP and
sepsis. Metabolite-based prognostic models had modest performance, though
metabolites of oxidative stress may act as putative damage-associated molecular
patterns.
BACK TO NEWSLETTER
For more information, visit here.
Integrated Metabolite and Gene Expression
Profiles Identify Lipid Biomarkers Associated with
Progression of Hepatocellular Carcinoma and
Patient Outcomes
Budhu al. | Gastroenterology, 2013
Metabolon results led to:
• Biomarkers of outcome and aggressiveness for hepatocellular carcinoma (HCC)
• Potential new target for HCC (stearoyl-CoA-desaturase (SCD))
• Confirmation that the addition of metabolomics to gene expression data
provides clarity
Key metabolomic observations:
• A SCD-related lipid signature with aggressive HCC
Synopsis
Hepatocellular carcinoma (HCC) is a common and aggressive malignancy
with a poor prognosis. Thus, investigators sought to understand the molecular
networks of aggressive HCC to more readily identify aggressive HCC and find
new targets and biomarkers in HCC patient tumor biopsy. Integration of gene
expression and metabolomic data identified a lipogenic network that involves
stearoyl-CoA-desaturase (SCD) and its substrate and product (palmitate and
palmitoleate). SCD was independently associated with survival times and tumor
recurrence in the test and validation sets. Further, palmitoleate was increased in
aggressive HCCs and increased migration and invasion of cultured HCC cells.
Suppressing SCD with siRNA decreased cell migration and colony formation in
culture and reduced tumorigenicity in mice. Thus, the imbalance of lipogenic
components and pathways, centering on SCD, may function as key biomarkers
for aggressive cancer and enable the strategic development of clinically relevant
therapies.
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Phosphoglycerate Mutase | Coordinates
Glycolysis and Biosynthesis to Promote
Tumor Growth
Hitosugi et. al | Cancer Cell, 2012
Metabolon results led to:
• Discovery of a glycolysis enzyme critical for coordinating glucose utilization for
energy production vs. anabolic biosynthesis in tumor cells
• Discovery that small molecule inhibition of that enzyme effectively reduced
tumor size in pre-clinical models, and that effect translated to primary cell
lines from human cancer patients
Key metabolomic observations:
• PGAM1 knockdown (gene or small molecule) altered levels of the substrate
and product of the enzyme. Those metabolites regulate other pathways
through competitive inhibition.
• PGAM1 coordinates regulation of glycolysis and the PPP, which generates
substrates for proliferation.
Synopsis
Cancer cells have long been known increase glucose uptake to generate
building blocks for cell proliferation. Understanding how cancer cells divert
glucose to anabolic pathways may reveal new drug targets. This study with
several cancer cell types identified the glycolysis enzyme PGAM1 as a critical
branch point for diverting glucose into the pentose phosphate pathway (PPP),
which generates anabolic precursors including NADPH and nucleotides. This
discovery of metabolic remodeling effects of PGAM1 led to several additional
discoveries: (1) PGAM1 knockdown reduced tumor mass in a mouse xenograft
model system. (2) The PGAM1 substrate 3-phosphoglycerate is a competitive
inhibitor of the PPP enzyme 6-phosphogluconate dehydrogenase, and this
connection underlies the coordinated regulation of glycolysis and anabolic
biosynthesis. (3) Results were translated to human studies where a new PGAM1
inhibitor decreased proliferation of primary leukemia cells from 7 of 8 leukemia
patients, suggesting PGAM1 is a promising target for combating human cancers.
BACK TO NEWSLETTER
The Downregulation of miR-125b in Chronic
Lymphocytic Leukemias Leads to Metabolic
Adaptation of Cells to a Transformed State
Tili, E., J.J. Michaille, et al. | Blood, 2012
Metabolon results led to:
• Identification of a master metabolic regulator that is defective in the
transformed state
• Biomarkers for segregating indolent versus aggressive forms of chronic
lymphocytic leukemia (CLL)
• Potential therapeutic targets
Key metabolomic observations:
• A clear signature of Warburg metabolism
• An increase in growth and survival promoting polyamines
• Increased lipogenesis
Synopsis
miR-125b is one of the most conserved miRNAs and maps to a chromosomal
epicenter for deletions in chronic lymphocytic leukemia (CLL). Thus, posing the
question of whether miR-125b has a potential role in CLL? Investigators used
gene expression profiling and metabolomicsto reveal that miR-125b is underexpressed in isolated lymphocytes from CLL subjects resulting in a profound
change in the metabolic state featuring “Warburg” metabolism, elevation in
growth promoting polyamines, and a lipogenic signature. Metabolites distinct
from these could differentiate indolent from aggressive forms of CLL, suggesting
the possibility of using these markers to identify at risk subjects. Finally, the
identification of miR-125b as a master regulator and a driver for a cancer
metabolic phenotype offers the possibility of targeting key metabolic pathways
that are activated by the under-expression of this metabolic regulator.
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Metabolomic Profiles Delineate Potential Role for
Sarcosine in Prostate Cancer Progression
Sreekumar, A., L. M. Poisson, et al. | Nature, 2009
Metabolon results led to:
• Identification of a biomarker of cancer progression
• Discovery of a “oncometabolite” that participates in neoplastic progression
• Candidate drug targets for prostate cancer
Key metabolomic observations:
• Sarcosine was identified as a metabolite that tracked with prostate
cancer progression
• Increasing sarcosine levels in a benign prostate cell line increased cell
invasiveness
• Decreasing sarcosine levels in an aggressive prostate cancer cell line
decreased cell invasiveness
Synopsis
Current screening methods for diagnosing prostate cancer provide little insight
into cancer aggressivity. Among more than 600 metabolites measured in human
prostate tissues with metabolomics, sarcosine (N-methyl glycine) was identified
as the metabolite that tracked most robustly with cancer progression. This
biomarker was further validated with an independent sample cohort and
targeted assay. Increasing levels of sarcosine through direct addition, or
manipulation of regulatory enzymes, conferred invasive properties to a benign
prostate cell line. Together these results suggest that sarcosine participates in
neoplastic transformation and that sarcosine’s proximal regulatory enzymes could
be targeted to combat cancer progression. Additionally, these results indicate
metabolite panels can be developed to distinguish slow-growing from aggressive
cancers and inform clinicians and patients in selecting a treatment strategy.
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The Small Molecule GMX1778 is a Potent
Inhibitor of NAD+ Biosynthesis: Strategy for
Enhanced Therapy in Nicotinic Acid
Phosphoribosyltransferase 1-Deficient Tumors
Watson et al. | Molecular and Cellular Biology, 2009
Metabolon results led to:
• Determination of the mechanism of action of an anti-cancer drug
• Identification of a new therapeutic strategy to specifically target cancer cells
and spare healthy cells
Key metabolomic observations:
• The cofactor NAD+ was greatly depleted in drug-treated cells
• An enzyme involved in NAD+ salvage as the molecular target of the drug
• Tumor cells dependent on this NAD+ salvage pathway are more sensitive to
the drug than healthy cells that can synthesize NAD+ de novo
Synopsis
The long-standing hypothesis that anti-cancer effects of GMX1778 resulted from
NF-kB inhibition were challenged by metabolomics results showing that
GMX1778 actually perturbed an entirely different pathway, depleting the
cofactor NAD+ from cells early after drug addition. This observation allowed for
straight-forward validation experiments that unambiguously identified an enzyme
required for NAD+ salvage (nicotinamide phosphoribosyltransferase, NAMPRT)
as the direct target of the drug, and showed that effects of the drug on NF-kB
activity and cancer cell viability were downstream of NAD+ salvage inhibition.
Identification of NAMPRT as the true drug target led to a new therapeutic
strategy in glioblastomas and neuroblastomas. These tumors depend on NAD+
salvage because they lack enzymes necessary for de novo NAD+ synthesis,
suggesting that addition of niacin to be utilized by healthy cells could increase
the therapeutic window of this anti-cancer drug.
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Inhibition of Nonsense-Mediated RNA Decay
Activates Autophagy
Wengrod, J. et al. | Molecular Cell Biology, 2013
Abstract
Nonsense mediated RNA decay (NMD) is a mRNA surveillance mechanism
which rapidly degrades select cytoplasmic mRNAs. We and others have
shown that NMD is a dynamically regulated process inhibited by amino acid
deprivation, hypoxia, and other cellular stresses commonly generated by the
tumor microenvironment. This inhibition of NMD can result in the accumulation
of misfolded, mutated, and aggregated proteins, but how cells adapt to these
aberrant proteins is unknown. Here we demonstrate that the inhibition of NMD
activates autophagy, an established protein surveillance mechanism, both in
vitro and in vivo. Conversely, the hyperactivation of NMD blunts the induction
of autophagy in response to a variety of cellular stresses. The regulation of
autophagy by NMD is due, in part, to stabilization of the documented NMD
target ATF-4. NMD inhibition increases intracellular amino acids, a hallmark
of autophagy, and the concomitant inhibition of autophagy and NMD, either
molecularly or pharmacologically, leads to synergistic cell death. Together these
studies indicate that autophagy is an adaptive response to NMD inhibition, and
uncover a novel relationship between a mRNA surveillance system and a protein
surveillance system with important implications for the treatment of cancer.
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Metabolic Alterations in Mammary Cancer
Prevention by Withaferin A in a Clinically Relevant
Mouse Model
Hahm, E. et al. | Journal of the National Cancer Institute, 2013
Abstract
Background: Efficacy of withaferin A (WA), an Ayurvedic medicine constituent,
for prevention of mammary cancer and its associated mechanisms were investigated
using mouse mammary tumor virus–neu (MMTV-neu) transgenic model.
Methods: Incidence and burden of mammary cancer and pulmonary metastasis
were scored in female MMTV-neu mice after 28 weeks of intraperitoneal
administration with 100 μg WA (three times/week) (n=32) or vehicle (n=29).
Mechanisms underlying mammary cancer prevention by WA were investigated
by determination of tumor cell proliferation, apoptosis, metabolomics, and
proteomics using plasma and/or tumor tissues. Spectrophotometric assays were
performed to determine activities of complex III and complex IV. All statistical
tests were two-sided.
Results: WA administration resulted in a statistically significant decrease in
macroscopic mammary tumor size, microscopic mammary tumor area, and the
incidence of pulmonary metastasis. For example, the mean area of invasive
cancer was lower by 95.14% in the WA treatment group compared with the
control group (mean=3.10 vs 63.77 mm2, respectively; difference=–60.67
mm2; 95% confidence interval=–122.50 to 1.13 mm2; P=.0536). Mammary
cancer prevention by WA treatment was associated with increased apoptosis,
inhibition of complex III activity, and reduced levels of glycolysis intermediates.
Proteomics confirmed downregulation of many glycolysis-related proteins in the
tumor of WA-treated mice compared with control, including M2-type pyruvate
kinase, phosphoglycerate kinase, and fructose-bisphosphate aldolase A isoform 2.
Conclusions: This study reveals suppression of glycolysis in WA-mediated
mammary cancer prevention in a clinically relevant mouse model.
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t h e
pat h
for w ard — continued
Is it Time to Go “All-in” on Leveraging Metabolic
Reprogramming of Cancer?
A Technical Commentary by Michael Milburn, CSO
Lack of efficacy or acquired resistance to therapies can result
from upregulation of pathway components or activation of
parallel signaling pathways. Hence, these therapies often require
combinations to drive efficacy and to reduce the potential for
resistance. Ideally, the combination agent should be highly
specific to a characteristic of the particular cancer or all cancers
in general.
As our feature article outlines, one of the most promising
exploitable characteristics, common to almost all cancers, is
metabolic reprogramming. As Dr. Stirdivant details therein,
nearly all oncogenic roads are revealing themselves to enable
the anabolic mission of the tumor. These include classic driver
substrate combinations such as Myc/glutamine, Akt/glucose as
well mTOR/amino acid and nucleotide metabolism. In addition,
a host of new metabolic targets are emerging that all have the
common feature of supporting the anabolic mission of the cell
(e.g. PGAM1, IDH1, SCD1). Hence, a clear opportunity has
emerged for determining the metabolic features of a given tumor
(metabotyping) in combination with the genotype (see the June
newsletter for additional detail on metabotyping). The idea is to
devise targeted efficacious combinations based on an individual
genotype and metabotype, where the signaling component is
analogous to a water spigot and the metabolic target the hose
outlet. Not only would a tumor be precisely targeted from two
vantage points, but this dual-targeted therapy would decrease
the chances of drug resistance arising. Despite the above
findings, the movement into taking advantage of this information
has been modest.
Ushering in many of these discoveries linking oncogenes to
metabolic reprogramming and uncovering the full extent of
metabolic reprogramming (hence targets and biomarkers)
is traditional scientific discipline and rigor and the field of
metabolomics.
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We have seen firsthand how discoveries in metabolomics and
combination therapies may be realized in work involving the
NAD biosynthesis pathway (a key metabolite in metabolic
reprogramming). Several years ago, we collaborated with
GeminX pharmaceuticals to reveal that a development
compound of unknown mechanism was targeting NAMPT (the
rate limiting enzyme in NAD biosynthesis). Since then, several
companies have initiated programs to pursue this target and
many publications have been produced, but one recent work by
Cagnetta and colleagues in Blood (2013 Jul 3, Epub ahead of
print) provides a striking example of how metabolic targets may
be successfully combined with a targeted therapy to enhance
activity and overcome resistance.
Metabotyping of cells from bortezomib resistant patients revealed
higher expression of NAMPT. Remarkably, when low doses
of a NAMPT inhibitor were combined with the bortezomib, a
synergistic effect and reduced resistance resulted. We imagine
that should researchers and clinicians move more aggressively
into this space, many more success stories like this will result.
Hence, although there is more work to be done to establish
clinical utility of these new metabolic targets (of course, many
of today’s chemotherapeutic agents target metabolism), there is
increasing confidence that metabolite biomarker-driven tumor
metabolic classification combined with therapeutics attacking key
metabolic nodes, may yield the tumor selectivity and durability
of response that has been so elusive with targeted therapies.
Metabolytics combined in a complementary fashion with
oncogenotyping will be a key component in selecting the proper
customized treatment options that will optimize success rates in the
new era of personalized cancer therapy. As details in the feature
article demonstrate, the science is making a compelling case
for optimism.
Heterogeneity of Tumor-Induced Gene Expression
Changes in the Human Metabolic Network
Hu, J. et al. | Nature Biotechnology, 2013
Abstract
Reprogramming of cellular metabolism is an emerging hallmark of neoplastic
transformation. However, it is not known how the expression of metabolic genes
in tumors differs from that in normal tissues, or whether different tumor types
exhibit similar metabolic changes. Here we compare expression patterns of
metabolic genes across 22 diverse types of human tumors. Overall, the metabolic
gene expression program in tumors is similar to that in the corresponding
normal tissues. Although expression changes of some metabolic pathways
(e.g., upregulation of nucleotide biosynthesis and glycolysis) are frequently
observed across tumors, expression changes of other pathways (e.g., oxidative
phosphorylation) are very heterogeneous. Our analysis also suggests that the
expression changes of some metabolic genes (e.g., isocitrate dehydrogenase
and fumarate hydratase) may enhance or mimic the effects of recurrent mutations
in tumors. On the level of individual biochemical reactions, many hundreds of
metabolic isoenzymes show significant and tumor-specific expression changes.
These isoenzymes are potential targets for anticancer therapy.
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Metabolic Alterations in Lung Cancer-Associated
Fibroblasts Correlated with Increased Glycolytic
Metabolism of the Tumor
Chaudhri, V.K., et al. | Molecular Cancer Research, 2013
Metabolon results led to:
• That autophagy is a distinguishing feature of cancer associated fibroblasts
(CAFs)
• Greater understanding of the tumor microenvironment
• A template for how to investigate tumor metabolism in its isolated parts
(i.e. stroma vs. epithelium)
Key metabolomic observations:
• Marker of protein breakdown (dipeptides) were increased in CAFs
Synopsis
There is significant appreciation that cancer cells undergo metabolic
reprogramming but there is far less understanding of the metabolic phenotypes
of the other cell types comprising the ”ecosystem” of the microenvironment. As a
first step, investigators sought to derive the metabolic profile of primary human lung
tumor cancer-associated fibroblast lines (CAFs) compared to “normal” fibroblast
lines (NFs) generated from adjacent non-neoplastic lung tissue. Dipeptides were
the clearest signature segregating the CAFs from the most glycolytic tumors and led
to the hypothesis that CAFs may engage autophagy more than NFs. Follow-up
experiments confirmed this hypothesis. These distinctions in metabolic features in
the cells comprising the microenvironment may also assist in devising next generation
combination therapies that target aspects of both the cancer cell and the stroma.
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Survival Response to Increased Ceramide
Involves Metabolic Adaptation through Novel
Regulators of Glycolysis and Lipolysis
Nirala, N. et al. | PLoS Genetics, 2013
Abstract
The sphingolipid ceramide elicits several stress responses, however, organisms
survive despite increased ceramide but how they do so is poorly understood.
We demonstrate here that the AKT/FOXO pathway regulates survival in
increased ceramide environment by metabolic adaptation involving changes
in glycolysis and lipolysis through novel downstream targets. We show that
ceramide kinase mutants accumulate ceramide and this leads to reduction in
energy levels due to compromised oxidative phosphorylation. Mutants show
increased activation of Akt and a consequent decrease in FOXO levels.
These changes lead to enhanced glycolysis by upregulating the activity of
phosphoglyceromutase, enolase, pyruvate kinase, and lactate dehydrogenase
to provide energy. A second major consequence of AKT/FOXO reprogramming
in the mutants is the increased mobilization of lipid from the gut through novel
lipase targets, CG8093 and CG6277 for energy contribution. Ubiquitous
reduction of these targets by knockdown experiments results in semi or total
lethality of the mutants, demonstrating the importance of activating them.
The efficiency of these adaptive mechanisms decreases with age and leads
to reduction in adult life span of the mutants. In particular, mutants develop
cardiac dysfunction with age, likely reflecting the high energy requirement of
a well-functioning heart. The lipases also regulate physiological triacylglycerol
homeostasis and are important for energy metabolism since midgut specific
reduction of them in wild type flies results in increased sensitivity to starvation
and accumulation of triglycerides leading to cardiac defects. The central
findings of increased AKT activation, decreased FOXO level and activation
of phosphoglyceromutase and pyruvate kinase are also observed in mice
heterozygous for ceramide transfer protein suggesting a conserved role of this
pathway in mammals. These data reveal novel glycolytic and non-autonomous
lipolytic pathways in response to increased ceramide for sustenance of high
energy demanding organ functions like the heart.
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Metabolomic Signatures in Lipid-Loaded HepaRGs
Reveal Pathways Involved in Steatotic Progression
Strain-Specific Red Blood Cell Storage, Metabolism,
and Eicosanoid Generation in a Mouse Model
Brown, M. et al. | Obesity, 2013
Abstract
Objectives: A spectrum of disorders including simple steatosis, nonalcoholic
steatohepatitis, fibrosis, and cirrhosis is described by nonalcoholic fatty liver
disease (NAFLD). With the increased prevalence of obesity, and consequently
NAFLD, there is a need for novel therapeutics in this area. To facilitate this effort,
a cellular model of hepatic steatosis was developed using HepaRG cells and the
resulting biochemical alterations were determined.
Design & Methods: Using global metabolomic profiling, by means of a novel
metabolite extraction procedure, the metabolic profiles in response to the
saturated fatty acid palmitate, and a mixture of saturated and unsaturated fatty
acids, palmitate and oleate (1:2) were examined.
Results: We observed elevated levels of the branched chain amino acids,
tricarboxylic acid cycle intermediates, sphingosine and acylcarnitines, and
reduced levels of carnitine in the steatotic HepaRG model with both palmitate
and palmitate:oleate treatments. In addition, elevated levels of diacylglycerols
and monoacylglycerols as well as altered bile acid metabolism were selectively
displayed by palmitateinduced steatotic cells.
Conclusions: Biochemical changes in pathways important in the transition to
hepatic steatosis including insulin resistance, altered mitochondrial metabolism,
and oxidative stress are revealed by this global metabolomic approach.
Moreover, the utility of this in vitro model for investigating the mechanisms
of steatotic progression, insulin resistance, and lipotoxicity in NAFLD
was demonstrated.
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Metabolomics and Incident Hypertension
Among Blacks: the Atherosclerosis Risk in
Communities Study
Zheng, Y. et al. | Hypertension, 2013
Abstract
Development of hypertension is influenced by genes, environmental effects, and
their interactions, and the human metabolome is a measurable manifestation of
gene–environment interaction. We explored the metabolomic antecedents of
developing incident hypertension in a sample of blacks, a population with a
high prevalence of hypertension and its comorbidities. We examined 896 black
normotensives (565 women; aged, 45–64 years) from the Atherosclerosis Risk
in Communities study, whose metabolome was measured in serum collected
at the baseline examination and analyzed by high-throughput methods. The
analyses presented here focus on 204 stably measured metabolites during
a period of 4 to 6 weeks. Weibull parametric models considering interval
censored data were used to assess the hazard ratio for incident hypertension.
We used a modified Bonferroni correction accounting for the correlations among
metabolites to define a threshold for statistical significance (P<3.9×10–4).
During 10 years of follow-up, 38% of baseline normotensives developed
hypertension (n=344). With adjustment for traditional risk factors and estimated
glomerular filtration rate, each +1SD difference in baseline 4-hydroxyhippurate,
a product of gut microbial fermentation, was associated with 17% higher risk of
hypertension (P=2.5×10–4), which remained significant after adjusting for both
baseline systolic and diastolic blood pressure (P=3.8×10–4). After principal
component analyses, a sex steroids pattern was significantly associated with
risk of incident hypertension (highest versus lowest quintile hazard ratio, 1.72;
95% confidence interval, 1.05–2.82; P for trend, 0.03), and stratified analyses
suggested that this association was consistent in both sexes. Metabolomic
analyses identify novel pathways in the pathogenesis of hypertension.
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Associations between Metabolomic Compounds
and Incident Heart Failure among African
Americans: The Atherosclerosis Risk in
Communities (ARIC) Study
Zheng, Y. et al. | American Journal of Epidemiology, 2013
Abstract
Heart failure (HF) is more prevalent among African-Americans. Metabolomic
studies among African-Americans may efficiently identify novel biomarkers of
HF. We used untargeted methods to measure 204 stable serum metabolites
and evaluate their association with incident HF hospitalization (N=276) after
a median follow-up of 20 years (from 1987 to 2008) using Cox regression in
1,744 African-Americans from the Jackson, MS field center of the Atherosclerosis
Risk in Communities Study, aged 45–64 years and without HF at baseline.
After adjusting for established risk factors, 16 metabolites (6 named with known
and 10 unnamed with unknown structural identity; the latter denoted X-12345)
were associated with incident HF (statistical significance based on a modified
Bonferroni procedure<0.0004). Of the six named metabolites, four are involved
in amino acid metabolism; one (pro-hydroxy-pro) is a dipeptide; and one
(erythritol) is a sugar alcohol. After additional adjustment for kidney function,
two metabolites remained associated with incident HF (X-11308, hazard
ratio (HR)=0.75, 95% confidence interval (95% CI): 0.65, 0.86; X-11787,
HR=1.23, 95% CI: 1.10, 1.37). Further structural analysis revealed X-11308
to be a dihydroxy docosatrienoic acid, and X-11787 an isoform of either
hydroxy-leucine or hydroxy-isoleucine. Our metabolomic analysis revealed novel
biomarkers associated with incident HF independently of traditional risk factors.
expression changes. These isoenzymes are potential targets for anticancer therapy.
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Application of Combined ‘Omics Platforms to
Accelerate Biomedical Discovery in Diabesity
Kurland, I. et al. | Annals of the NY Academy of Sciences, 2013
Abstract
Diabesity has become a popular term to describe the specific form of diabetes
that develops late in life and is associated with obesity. While there is a
correlation between diabetes and obesity, the association is not universally
predictive. Defining the metabolic characteristics of obesity that lead to diabetes,
and how obese individuals who develop diabetes different from those who
do not, are important goals. The use of large-scale omics analyses (e.g.,
metabolomic, proteomic, transcriptomic, and lipidomic) of diabetes and obesity
may help to identify new targets to treat these conditions. This report discusses
how various types of omics data can be integrated to shed light on the changes
in metabolism that occur in obesity and diabetes.
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Pharmacological Inhibition to Examine the Role of
DGAT1 in Dietary Lipid Absorption in Rodents
and Humans
Maciejewskiet al. | Gastrointestinal and Liver Physiology: American Journal of
Physiology,, 2013
Metabolon results led to:
• Improved understanding of the full-spectrum of changes induced by
DGAT inhibition
• Translatable pathways, markers and changes from rodent to human
Key metabolomic observations:
• An elevation in polyunsaturated fatty acids (PUFA) within triglycerides (TG)
Synopsis
Elevated plasma triglycerides (TG) and free fatty acids (FFA) are implicated in
the pathogenesis of metabolic diseases such as type 2 diabetes (T2DM) and
cardiovascular disease. Acyl-CoA:diacylglycerolacyltransferase1 (DGAT1) is
being pursued as a therapeutic target for diseases of elevated lipids. To more
completely elucidate the full spectrum of metabolic changes, adosing study using
a selective inhibitor of DGAT1 was performed on rats and humans. Striking
translatability was observed in the overall effects of inhibition of TG absorption
and lipidomicanalysis revealed an unexpected enrichment of polyunsaturated
fatty acids (PUFA) within the TG class. The increase in PUFA may have benefits
for decreasing the risk of coronary artery disease, insulin resistance, dyslipidemia
and hypertension. Collectively, the results suggest that inhibition of DGAT1 could
have the potential to be a pharmacological alternative to gastric bypass surgery
or for T2DM and provides new insights for the impact of inhibition of DGAT1.
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Paraoxonase-1 Deficiency is Associated with
Severe Liver Steatosis in Mice Fed a High-fat
High-cholesterol Diet: A Metabolomic Approach
Garcia-Heredia, A. et al. | Journal of Proteome Research, 2013
Abstract
Oxidative stress is a determinant of liver steatosis and the progression to
more severe forms of disease. The present study investigated the effect of
paraoxonase-1 (PON1) deficiency on histological alterations and hepatic
metabolism in mice fed a high-fat high-cholesterol diet. We performed
nontargeted metabolomics on liver tissues from 8 male PON1-deficient mice
and 8 wild-type animals fed a high-fat, high-cholesterol diet for 22 weeks. We
also measured 8-oxo-20-deoxyguanosine, reduced and oxidized glutathione,
malondialdehyde, 8-isoprostanes and protein carbonyl concentrations. Results
indicated lipid droplets in 14.5% of the hepatocytes of wild-type mice and in
83.3% of the PON1-deficient animals (P < 0.001). The metabolomic assay
included 322 biochemical compounds, 169 of which were significantly
decreased and 16 increased in PON1-deficient mice. There were significant
increases in lipid peroxide concentrations and oxidative stress markers. We
also found decreased glycolysis and the Krebs cycle. The urea cycle was
decreased, and the pyrimidine cycle had a significant increase in orotate. The
pathways of triglyceride and phospholipid synthesis were significantly increased.
We conclude that PON1 deficiency is associated with oxidative stress and
metabolic alterations leading to steatosis in the livers of mice receiving a high-fat
high-cholesterol diet.
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The Role of Adipocyte XBP1 in Metabolic
Regulation during Lactation
Gregor, M. et al. | Cell Reports, 2013
Abstract
The adipocyte is central to organismal metabolism and exhibits significant
functional and morphological plasticity during its formation and lifespan.
Remarkable transformations of this cell occur during obesity and lactation, and
thus it is essential to gain a better understanding of adipocyte function in these
two metabolic processes. Considering the critical importance of the cellular
organelle endoplasmic reticulum (ER) in adapting to fluctuations in synthetic
processes, we explored the role of XBP1, a central regulator of ER adaptive
responses, in adipocyte formation and function. Unexpectedly, deletion
of adipocyte-XBP1 in vivo in mice (XBP1DAd) had no effect on adipocyte
formation or on systemic homeostatic metabolism in mice fed a a regular or
high-fat diet. However, during lactation, XBP1DAd dams displayed increased
adiposity, decreased milk production, and decreased litter growth as compared
with control dams. Moreover, we demonstrate that XBP1 is regulated during
lactation and responds to prolactin to alter lipogenic gene expression. These
results demonstrate a role for adipocyte-XBP1 in the regulation of lactational
metabolism.
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Metabolic Analysis of Sun Exposed Skin
Randhawa, M. et al. | Molecular BioSystems, 2013
Metabolon results led to:
• Novel mechanistic insights for photoaging
• Biomarkers of photoaging
• Treatment strategies for skin care
Key metabolomic observations:
• A total of 341 metabolites were detected from skin biopsies and 147 were
significantly altered
• Among the significantly changed metabolites were glycolytic, beta-oxidation
and oxidative stress markers
Synopsis
The ability to slow, reverse, or protect sun-exposed skin from the effects of
photoaging is limited by the understanding of the underlying mechanisms that
disrupt skin architecture and the skin permeability barrier. Thus investigators at
Johnson and Johnson sought to derive a deeper understanding and biomarkers
that could be used to monitor efficacy by performing metabolomics on skin
biopsy samples. Diverse metabolites (341) were detected in the samples and
147 were significantly different between normal and sun-exposed samples. In
addition to validation of expected oxidative stress markers, many novel
biomarkers and targets were identified. Among these were metabolites that
produced a metabolic model for the cascade of derangements induced by
sun-exposure. The results demonstrate that skin metabolomics is a promising
approach for skin researchers, product developers, and for discovering efficacy
biomarkers that, given the conservation of metabolites, are likely to translate into
in vitro models. Notably, this approach could be markedly extended through the
addition of a lipidomics analysis.
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Lacritin Rescues Stressed Epithelia Via
Rapid FOX03 Associated Autophagy That
Restores Metabolism
Wang, N. et al. | The Journal of Biological Chemistry, 2013
Abstract
Homeostasis is essential for cell survival. Yet, homeostatic regulation of surface
epithelia is poorly understood. The eye surface, lacking the cornified barrier
of skin, provides an excellent model. Tears cover the surface of the eye, and
are deficient in dry eye, the most common eye disease affecting at least 5%
of the worlds population. Only a tiny fraction of the tear proteome appears
to be affected, including lacritin, an epithelial-selective mitogen that promotes
basal tearing when topically applied to rabbit eyes. Here we discover that
homeostasis of cultured corneal epithelia is entirely lacritin dependent, and
elucidate the mechanism as a rapid autophagic flux to promptly restore cellular
metabolism and mitochondrial fusion—in keeping with lacritin’s short residence
time on the eye. Accelerated flux appears to derive from lacritin stimulated
acetylation of FOXO3 as a novel ligand for ATG101 and coupling of stress
acetylated FOXO1 with ATG7 (that remains uncoupled without lacritin), and
is sufficient to selectively divert huntingtin mutant Htt103Q aggregates largely
without affecting non-aggregated Htt25Q. This is in keeping with stress as a
prerequisite for lacritin stimulated autophagy. Lacritin targets the cell surface
proteoglycan syndecan-1 via its C-terminal amino acids leu108-leu109phe112, and is also available in saliva, plasma and lung lavage. Thus lacritin
may promote epithelial homeostasis widely.
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Plasma Metabolomics Identifies Lipid
Abnormalities Linked to Markers of Inflammation,
Microbial Translocation, and Hepatic Function in
HIV Patients Receiving Protease Inhibitors
Cassol et al. | BMC Infectious Diseases, 2013
Metabolon results led to:
• Biomarkers of advanced HIV subjects, with suspected liver decline
• Strategies for attenuating dysregulated immune activation and hepatic
dysfunction for HIV patients
• Yet another independent study bolstering the case that bile acids should be
used as a general marker of hepatic dysfunction
Key metabolomic observations:
• Many altered lipids–bile acids, sulfated steroids, polyunsaturated fatty acids,
and eicosanoids
Synopsis
Despite the success of combination antiretroviral therapy (ART) for improving
morbidity and mortality in HIV subjects, long-term ART is often accompanied by
metabolic abnormalities such as insulin resistance, dyslipidemia and
lipodystrophy. In order to control these side-effects, a detailed understanding of
the underlying mechanisms is required. To this end, investigators performed
metabolomics of plasma from two independent cohorts of HIV-infected
individuals with late stage disease on PI-based ART. A subset of 35 metabolites
strongly segregated disease from healthy with the majority being lipids–bile
acids, steroids, and long chain fatty acids (LCFA). Importantly, these metabolites
represented 3 clusters correlating with underlying components of the disease or
comorbidities–inflammation, microbial translocation, and hepatic function. In
fact, bile acids correlated with markers of liver function and fibrosis, providing,
escalating support for the use of bile acids for disrupted liver function.
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Glycogen Synthesis is a Required Component of
the Nitrogen Stress Response in Synechococcus
Elongatus PCC 7942
Hickman, J. et al. | Algal Research, 2013
Abstract
Carbon fixation and production of reductant by cyanobacteria can exceed
new biomass synthesis rates when the supply of essential nutrients is limiting.
Under these circumstances metabolic balance is achieved by diversion of excess
carbon and reductant to synthesis of glycogen, which can accumulate to more
than 50% of cellular dry biomass. We discovered that when glycogen synthesis
was abolished, by deletion of the gene for glucose-1-phosphate adenylyl
transferase (glgC), Synechococcus elongatus PCC 7942 was unable to
degrade its phycobilisomes in response to nitrogen stress. Furthermore, nitrogen
deprived glgC null cells recalibrated the levels of glycolytic and TCA cycle
intermediates. Specifically, succinate, fumarate, and 2-oxoglutarate, a metabolic
indicator of cellular nitrogen status and metabolic effector of the global nitrogen
regulator NtcA, accumulated within and were excreted by glgC null cells
under nitrogen stress. Moreover, intracellular accumulation and excretion of
2-oxoglutarate from nitrogen stressed glgC null cells coincided temporally
with suppression of nblA transcription, while internalization of 2-oxoglutarate
by nitrogen deprived wild type cells delayed both nblA expression and
phycobilisome degradation. Furthermore, glgC null cells exhibited a nonbleaching phenotype in response to sulfur and phosphate stress. These data
indicate that glycogen synthesis is a required component of the global response
to nutrient stress.
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Mobilization of Lipids and Fortification of Cell
Wall and Cuticle are Important in Host Defense
Against Hessian Fly
Khajuria, C. et al. | BMC Genomics, 2013
Abstract
Objectives: Wheat–Hessian fly interaction follows a typical gene-for-gene
model. Hessian fly larvae die in wheat plants carrying an effective resistance
gene, or thrive in susceptible plants that carry no effective resistance gene.
Results: Gene sets affected by Hessian fly attack in resistant plants were found to
be very different from those in susceptible plants. Differential expression of gene
sets was associated with differential accumulation of intermediates in defense
pathways. Our results indicated that resources were rapidly mobilized in
resistant plants for defense, including extensive membrane remodeling and
release of lipids, sugar catabolism, and amino acid transport and degradation.
These resources were likely rapidly converted into defense molecules such as
oxylipins; toxic proteins including cysteine proteases, inhibitors of digestive
enzymes, and lectins; phenolics; and cell wall components. However, toxicity
alone does not cause immediate lethality to Hessian fly larvae. Toxic defenses
might slow down Hessian fly development and therefore give plants more time
for other types of defense to become effective.
Conclusion: Our gene expression and metabolic profiling results suggested that
remodeling and fortification of cell wall and cuticle by increased deposition of
phenolics and enhanced cross-linking were likely to be crucial for insect mortality
by depriving Hessian fly larvae of nutrients from host cells. The identification of a
large number of genes that were differentially expressed at different time points
during compatible and incompatible interactions also provided a foundation for
further research on the molecular pathways that lead to wheat resistance and
susceptibility to Hessian fly infestation.
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Metabolomic Markers Reveal Novel Pathways
of Ageing and Early Development in
Human Populations
Menni, C. et al. | International Journal of Epidemiology, 2013
Metabolon results led to:
• A 22 metabolite panel strongly correlated with age and age-related clinical traits
• A single novel metabolite highly correlated with age and ageing traits (e.g.
lung function, bone mineral density)
Key metabolomic observations:
• Validating the approach, the identification of compounds previously reported
to associate with aging such as steroids and creatinine
• Novel discovery of C-glycosyltryptophan (C-glyTrp)
Synopsis
Ageing is a multifactorial process with genetic, early developmental, lifestyle,
and environmental factors. Discovery of molecular signatures of the aging
process can serve to better understand how to control it with diet, lifestyle or
pharmaceutical interventions. Thus, investigators used metabolomics to profile
6055 subjects (32–81 years). Statistical analysis produced a panel of 22
metabolites which could be used as a surrogate for age (R2=59%). One of
these was the novel metabolite, C-glycosyltryptophan (C-glyTrp). C-glyTrp is
strongly associated with a developmental determinant of healthy ageing, birth
weight. Further suggesting C-glyTrp may be involved in involved in both ageing
and early development were the results of overlaying epigenome-wide
association study (EWAS) data that showed that C-glyTrp associated with CpG
sites associated with a gene (WDR85) involved in translation, the cell cycle and
embryonic development. These results illustrate how metabolomics combined
with epigenetics can reveal key molecular mechanisms influencing human health
and ageing.
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