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Key Words: coronary heart disease diabetes integrative metabolism metabolomics nutrient-gene interaction polymorphism systems biology
Since the times of the renowned Greek physician
Hippocrates, nutrition has clearly had a predominant
and recognizable role in health management. However, with time our understanding of diet and its effects
on health has evolved from crude associations to conclusive facts. The advent of modern science led to the
realization that not only are certain nutrients essential,
but also that specific quantities of each were necessary
for optimal health, thereby leading to such notions as
dietary recommendations, nutritional epidemiology,
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predominant genomic derivative has been coined functional genomics, which aims to uncover both the functional roles of different genes and how these genes
interact with, and/or influence, each other in the
functional network underlying health and disease.
However, other extensions such as structural genomics
and comparative genomics are rapidly becoming popular methods to further annotate the genome. Transcriptomics, using either cDNA or oligonucleotide microarray technology, describes the approach in which
gene expression (mRNA) is analyzed in a biological
sample at a given time under specific conditions. This
field is certainly the most widely used of the omic
technologies, in part due to the intense activity of such
initiatives as the minimum information about microarray experiments (MIAME)2 (8, 9) and the gene
expression omnibus (GEO)3 (10, 11) to standardize
experimental procedures and the storage of data, respectively.
Studying the other facets of biological complexity,
such as proteins and metabolites, is especially important with the realization that the principle of one gene
leads to one protein leads to one metabolite is a
simplistic and often incorrect notion, as experimentally
demonstrated (12). Therefore, proteomics aims to
characterize all proteins in a biological sample, including their relative abundance, distribution, post-translational modifications, functions, and interactions with
other biological molecules (7). Metabolomics, or metabonomics, can be simply defined as the quantitative
analysis of all metabolites in an isolated cell system,
tissue, or biological fluid. Although these two terms
tend to be used interchangeably, metabonomics is
generally associated with drug discovery and refers to a
systems approach to metabolite profiling, whereas the
more widely used term metabolomics refers more specifically to cell-based metabolite profiling. For the purpose of this review, metabolite profiling will be referred
to as metabolomics from here on. In contrast with
transcriptomics, proteomics and metabolomics are not
yet routine and standardized procedures, and continue
to face challenges such as sample preparation, technological sensitivity, lack of standardized statistical methods and public databases (1318). Nevertheless, their
potential benefits for health management are undisputed and have fuelled current efforts to assess, utilize,
interpret, and ultimately integrate these global technologies in order to define a phenotype characterizing
health status.
These analytical platforms are now widely used by
both the pharmaceutical and nutritional communities
alike; however, whereas pharmaceuticals have a targeted approach aimed at restoring health, diet is a
multi-parametric approach to preserve and/or optimize health. Indeed, the diet is comprised of a multitude of nutritional and chemical molecules each capable of regulating disparate biological processes, and
thus cannot use an approach similar to the pharmaceutical industry, i.e., the one drug one target paradigm
(19). Hence, nutrition is a true integrative science that
NUTRITION IN THE POSTGENOMIC ERA
Vol. 19
October 2005
NUTRIGENOMICS
As previously mentioned, nutrigenomics offers a powerful and exciting approach to unravel the effects of
diet on health. The potential of such an approach for
nutrition and its role in health management is enormous; however, for this to be successfully accomplished, it requires a radical addition to the current
conception of nutrition. Nutrition can no longer be
viewed as simply epidemiological studies whose aims
are to identify relationships between nutrition and
chronic disease in genetically uncharacterized populations; rather, complex cell and molecular biology coupled with biochemistry and genetics are required if the
ambitious goals of nutrigenomics are to be realized.
Prior to the complete sequencing of genomes, the
research community was unable to take an integrative
metabolism approach to explore the role of diet on
disease onset. Thus, the majority of experimental designs, including epidemiological studies, were obliged
to use common and well-characterized biomarkers to
advance our understanding of various disease states.
For example, studies aimed at elucidating the molecular mechanisms promoting cardiovascular disease
(CVD) and other CVD-related diseases have often used
classical biomarkers, such as plasma cholesterol, triglycerides, or C-reactive protein (37). Inasmuch as these
studies are constantly improving the validity and accuracy of our knowledge of these disease states, they all
suffer from a similar inherent quandary; namely, that
these studies have been designed using current dogma.
Thus, the ability to identify novel mechanisms of action
and/or biomarkers that may more accurately depict
health status is greatly diminished, as only accepted and
characterized endpoints are examined. As demonstrated in the following sections, nutrigenomic technologies resolve this tunnel vision by providing a means to
identify previously unrecognized and unanticipated
molecular endpoints (7).
Plant sterols and sitosterolemia
The power of omic protocols to compare gene expression profiles to understand spontaneous differences in
phenotype due to disease was creatively extended by
inducing differences in phenotype through molecular
intervention. This was eloquently executed in a study
that simultaneously identified a mechanism for the
regulation of sterol uptake in the intestine and the
molecular basis for a genetic disease: sitosterolemia
(38). Until this study, no mechanism could explain why
plant sterols, which are structurally similar to choles-
MUTCH ET AL.
oxisome proliferator activated receptors, hepatic nuclear factor-4, sterol regulatory expressed binding proteins, liver-X-receptor , and nuclear factor , which
are able to disseminate the biological activity of LCPUFA throughout the various tissues of the body (48,
49). Additionally, fatty acids have been found to modulate protein activity (50) and localization (51). Furthermore, LC-PUFA are associated with alterations in
lipid metabolism and the remodeling of several lipid
species, such as phospholipids (PLs), triglycerides
(TGs), and cholesterol esters (CEs) (5255). Indeed,
the extensive influence of dietary LC-PUFA on metabolism, in addition to the many epidemiological studies
demonstrating their beneficial health effects, renders
this class of nutrients ideal for study by a nutrigenomics
approach.
Carcinogenesis is a process composed of multiple
stages in which gene expression, and protein and
metabolite function begin to operate aberrantly (56).
In the post-genomic era, the cellular events mediating
the onset of carcinogenesis, in addition to their modulation by dietary factors, has yielded important information in our understanding of this disease. The most
commonly studied dietary lipids, with respect to their
effects on cancer, are LC-PUFA (57). Previous findings
have found that fish oil, rich in omega-3 fatty acids,
inhibit the growth of colonic tumors in both in vitro
and in vivo systems (58 60). Modern nutrigenomic
technologies, coupled with bioinformatics, have begun
to reveal the complexity of LC-PUFA signaling (Fig. 2);
however, current lipid metabolic pathways have proven
to be relatively underdeveloped (57). Thus, the deluge
of information derived from microarray technology
provides a potential method to further annotate the
biological functions of these common dietary compounds and complete the poorly defined pathways.
Preliminary microarray work has found that LC-PUFA
mediate the functions of several transcription factors,
cell-cycle regulatory genes, RNA transcription processes, prostaglandin synthesis, and inducible nitric
oxide synthase and related proinflammatory genes (61
63); however, it remains unclear to what extent LCPUFA are directly and indirectly involved in modulating these biological processes. Further work, in which
specific inhibitors, small inhibiting RNA technology
and alternate analytical (proteins, metabolites) platforms are incorporated, can clarify the biological functions mediated by dietary lipids. Although clearly at the
beginning, nutrigenomics offers an attractive means to
decipher the molecular networks regulated by LCPUFA, and promises an exciting future for nutritionists
and biochemists alike.
Rosiglitazone and type 2 diabetes mellitus
More recently, metabolomic technologies have established their ability to identify novel and potential
biomarkers characterizing unseen tissue toxicity. Currently, no concrete examples exist in the field of
nutrition; thus the following demonstrates the power of
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NUTRIGENETICS
Vol. 19
October 2005
Nutrigenetics, as previously defined, aims to understand how the genetic makeup of an individual coordinates the response to diet. Indeed, if the human
population were genetically identical and lived in a
constant environment, then our response to diet and
drugs would be equivalent; however, this is clearly not
the case. Since the complete sequencing of the human
genome, the Single Nucleotide Polymorphisms (SNP)
Consortium is mapping important polymorphic sites
within the genome that dictate individual phenotypic
differences among the population (http://ncbi.nih
.gov/SNP). The largest public repository for SNP data
is the dbSNP, containing 7.7 million SNPs for which
4.8 million can be linked to discrete locations on the
whole human genome map (65). The importance of
genetic variation in the need for, and physiological
response to, particular nutrients is already well described in principle, and examples continue to emerge.
Furthermore, it is already apparent that there are many
polymorphisms that influence risk in cardiovascular
disease and diabetes. SNP analysis provides a powerful
molecular tool for investigating the role of nutrition in
human health and disease, and their consideration in
clinical, metabolic and epidemiological studies can
contribute enormously to the definition of optimal
diets (66).
Clearly, the potential influence of nutrients on the
genome cannot be underestimated; however, there will
be certain genes (often referred to as candidate or
susceptibility genes) that will have a heightened sensitivity to diet (67 69). The identification of these
candidate genes often meets one or more of the
following conditions:
1. Genes that are chronically activated during a
disease state and have been previously demonstrated to
be sensitive to dietary intervention.
2. Genes with functionally important variations.
3. Genes that have an important hierarchical role in
biological cascades.
MUTCH ET AL.
been accredited to genetic differences in the population, thereby emphasizing the importance of identifying those genes that play a critical role in the onset or
protection from CHD, and unravel their interactions
with common dietary compounds (74). To date, several
candidate genes, and their common SNPs, have been
identified and preliminary evidence supports the notion that genetic variations in such genes as cholesterol
ester transfer protein (CETP), lipoprotein lipase
(LPL), hepatic triglyceride lipase (HL), LDL-receptor,
apolipoprotein E (APOE), apolipoprotein A1
(APOA1), ATP binding cassette transporter A1
(ABCA1), and lecithin-cholesterol acyltransferase
(LCAT) will alter individual sensitivity to developing
CHD (75 82). Additionally, a nutrigenetic approach
has begun to reveal that several of the aforementioned
genes and their polymorphisms, such as APOA1 and
LPL, are susceptible to dietary intervention and may
modulate the onset of CHD.
Apolipoprotein A1 (APOA1)
HDL plays a critically important role in the prevention
of CHD, predominantly through the transport of cholesterol from peripheral tissues to the liver for excretion in bile. APOA1 is a major component of plasma
HDL (83) and is thought to contribute to the transport
of cholesterol from ABCA1 to HDL particles (84).
Recently, it has been found that HDL levels are sensitive to dietary factors, such as PUFA. In the context of
the Framingham Heart Study (85), individuals with a
polymorphism in the APOA1 gene promoter region
(75 G/A) were found to differentially respond to
dietary PUFA (86). In brief, the authors found that
individuals with the A allele showed an increase in HDL
levels following an increased consumption of PUFA. In
contrast, those with the more common G allele showed
an inverse relationship between HDL levels and PUFA
consumption. Furthermore, the authors revealed that
differences in sex also mediate the response. Indeed,
men did not show a relationship between HDL and
PUFA consumption, irrespective of their APOA1 polymorphism. However, women with the A allele and a
high intake of PUFA (8% of energy derived from
PUFA) were found to have high levels of HDL. In
comparison, women with the common G allele were
found to have high HDL levels when fed low quantities
of PUFA (4% of energy derived from PUFA). This
example highlights the complex interactions that arise
between dietary molecules and genotype, and the additional influence that gender may have.
Lipoprotein lipase (LPL)
LPL is responsible for catalyzing the hydrolysis of TGs
present in circulating chylomicrons and VLDL particles, providing nonesterified fatty acids and 2-monoacylglycerol for tissue utilization. Dysfunctional LPL has
been associated with various disease states, such as
atherosclerosis, chylomicronaemia, obesity, Alzhei1607
mers disease, and the dyslipidemia related with diabetes and insulin resistance (87). Furthermore, several
polymorphisms have been described that disrupt normal LPL function and contribute to the premature
development of CHD, primarily through the increased
levels of circulating TGs (88). Indeed, several of the
common LPL polymorphisms described by Merkel et
al. have recently been established to influence circulating lipid levels in pregnant women, whom are often
characterized with high levels of circulating TGs and
increased total cholesterol. Although TG levels were
unaffected, certain LPL SNPs modulated HDL levels
and may alter the susceptibility of pregnant women to
developing CHD (89); however, further studies are
required to definitively define a relationship between
lipid levels, CHD, and pregnant women. Therefore, the
importance of LPL in the whole-body regulation of
lipid metabolism has been avidly demonstrated and
merits further exploration.
One common LPL polymorphism, known as T495G
HindIII, has been extensively examined and demonstrates the complexity of disease prediction associated
with a single SNP. Indeed, preliminary indications
suggest that this polymorphism may play a role in the
onset of several important diseases, such as CHD,
diabetes and obesity. This SNP has been associated with
the higher plasma TG and lower HDL levels characteristic with the early onset of diabetes (90). Preliminary
results have also suggested a positive association between the HindIII polymorphism and a predisposition
to developing obesity (91). Finally, this polymorphism
has been associated with variations in lipid levels and
heart disease, and that these alterations were attenuated by such environmental factors as physical exercise
(92) and low calorie diets (93), reiterating the important interactions arising between lifestyle, nutrition,
and disease. Although these associations are not conclusive, they do suggest that LPL variants play a critically important role in the regulation of whole-body
lipid metabolism that may predispose an individual to
the onset of several metabolic diseases.
A relationship was established between a low calorie
diet and the circulating lipid profile in obese individuals with the HindIII polymorphism (93). Homozygotes
(H2H2) were found to have significantly higher levels
of plasma VLDL-TG and APOB than heterozygotes
(H1). Caloric restriction reduced lipid levels in both
H2H2 and H1 individuals to a point where no difference was observed between the groups. Although
H2H2 individuals responded more strongly (larger
decreases in plasma lipids) to the low calorie diet, these
preliminary results identify an important relationship
between LPL polymorphisms, function, and diet.
Insulin resistance and type 2 diabetes mellitus
T2DM is a metabolic disorder, stemming from either
an insufficient secretion or impaired action of insulin,
characterized by hyperglycemia, dyslipidemia, and associated with impaired carbohydrate, protein and lipid
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October 2005
MUTCH ET AL.
Vol. 19
October 2005
OUTLOOK
Our dependence on food for survival is evident. Furthermore, the ability of foods to contribute to health
management has long been recognized. Yet despite this
recognition, the prevalence of food-related diseases
such as obesity, T2DM, and CHD, are on the rise in
Westernized nations. A primary influence on the onset
of these diseases is thought to arise from changes in our
lifestyle, i.e., an abundance of food coupled with low
levels of physical activity. Even with clear correlations
between disease states and nutrition, the precise mechanisms by which these lifestyle changes modulate
health remain enigmatic. Indeed, this enigma is exemplified by the all too common situation of two individuals with an equivalent level of physical activity eating
an identical diet, and only one gains weight. Although
dietary recommendations have been implemented to
improve health and diminish the risk of CVD, cancer,
hypertension, T2DM, and obesity, these recommendations have been established based on populations and
not the individual. The drastically different responses
between individuals to a given diet clearly highlights
the limitations of population-based nutritional recommendations and suggest that our understanding of the
mechanisms responsible for inter-individual differences are far from being understood. Therefore, an
intense interest has developed in understanding the
biological mechanisms triggered by our environmental
surroundings. Although smoking, physical activity and
toxins are clearly capable of modulating health, it is our
continuous exposure to foods throughout our lifetime
that renders diet the most important environmental
factor challenging our biological system (30).
The observed differences in an individuals response
to diet have been attributed to differences in the
underlying genetic makeup, prompting exploration
into the role of nutrient-gene interactions in the determination of a healthy phenotype. This avenue of research has been facilitated by our recent entrance into
the post-genomic era, which has witnessed the development of analytical platforms and complementary data
mining algorithms capable of comprehensively studying and interpreting a biological system. However,
unlike the pharmaceutical industry, which aims to
target a specific dysfunctional gene or gene product to
improve health, the nutritional industry must manage
health through a complex mixture of nutritional molecules (i.e., diet), each with their own influences on the
biological system. Thus, in comparison with a medicinal
compound, consuming a diet drastically increases the
number of molecular endpoints that are capable of
influencing phenotype, and thereby places the field of
nutrition in a prime position to benefit from the
technological innovations brought forth by the postgenomic era. Indeed, the one drug one target para-
MUTCH ET AL.
Vol. 19
October 2005
these conditions. Rather, the use of annotated microarray results to identify common biological functions,
such as that used by Segal and colleagues to classify
different tumor types (36), suggests that these polygenic diseases may have similar metabolite profiles
despite varied gene expression profiles. For the moment, the metabolite profiles of polygenic diseases have
not been comprehensively explored; however, it insinuates that associating a candidate disease gene with a
metabolite profile may not be an appropriate endpoint.
However, relating perturbed functional networks with
metabolite profiles may have more relevance from a
clinical perspective. Finally, it is vital that this information be stored in publicly available databases that have
stringent and universally accepted criteria for accepting
data (144). The vast quantity of metabolite data produced by profiling diseased and healthy individuals will
be difficult to interpret by a human; however, such
databases will empower supervised biomathematical
algorithms to compare a given metabolomic profile
with those referenced in the database. Although there
is currently no existing database empowering the scrutinization of metabolite profiles and permitting nutritional recommendations to be proposed, the initiatives
of groups such as the American Society for Nutritional
Sciences Long Range Planning Committee will manifest
itself into a database with precisely this objective.
In this regard, the future lies not with the technologies, but with the storage, management, and interpretation of the vast quantity of metabolomic data. No
single lab will be able to achieve the concept of a
personalized nutrition alone; rather, a collective effort
by the scientific community to adhere to guidelines put
forth regarding experimental designs, analysis, and
data storage will generate a database that is readily
available to researchers and clinicians alike. Thus,
nutrition in the 21st century is poised to be an exciting
and highly relevant field of research, as each new day is
accompanied by advances in our understanding of how
the interactions between lifestyle and genotype contribute to health and disease, taking us one step closer to
achieving the highly desirable goal of personalized
nutrition.
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