Transcript ppt - iadsa

Нутригеномные исследования:
потенциальная возможность
интерпретации эффективности и риска
использования БАД
А.В. Васильев
НИИ питания РАМН, Россия
Международный симпозиум
«Оптимальное питание: роль биологически активных
компонентов пищи»
18 июня 2009г
Москва
Molecular nutrition
We should eat and drink as
much as to restore our forces,
but not suppress them.
Cicero Marcus Tullius
106-43 BC
There is no need to prove that nutrition is
one of the central problems whose solving is
a constant concern for the humanity.
Apparently, one of the greatest delusions is
the belief that the problem of correct human
nutrition may be solved through creating a
sufficient quantity of required foodstuffs.
Objective analysis shows that a free, or,
more precisely, spontaneous choice of such
products in the today's human society in
most cases leads to nutrition disorders
that, depending on many genetic and
phenotypic characteristics of a human being,
provoke development of hard diseases.
A.M. Ugolev
"Evolution of digestion and some principles of evolution of
functions", 1977
Nutrigenomics vs.
Nutrigenetics
Nutrigenomics
Nutrigenetics
“Nutrigenomics refers to
the application of
genomics in nutrition
research, enabling
associations to be made
between specific nutrients
and genetic factors, e.g.
the way in which food or
food ingredients influence
gene
expression…Nutrigenomics
should facilitate greater
understanding of how
nutrition affects
metabolic pathways and how
this process goes awry in
diet-related diseases.”
“Nutrigenetics is the
study of individual
differences at the
genetic level influencing
response to diet. These
individual differences
may be at the level of
single nucleotide
polymorphisms rather than
at the gene level…It is
envisaged that
nutrigenetics may lead to
individualized dietary
advice.”
Chadwick R. (2004) Proceedings of the Nutrition Society 63:161-166.
Nutrigenomics vs.
Nutrigenetics
Nutrigenomics
Nutrigenetics
“Nutrigenomics describes
the use of functional
genomic tools to probe a
biological system
following a nutritional
stimulus that will permit
an increased
understanding of how
nutritional molecules
affect metabolic pathways
and homeostatic control.”
“Nutrigenetics embodies
the science of
identifying and
characterizing gene
variants associated with
differential responses to
nutrients, and relating
this variation to disease
states.”
Mutch D, et al. (2005) FASEB Journal 19:1602-1616.
Nutrigenomics & Nutrigenetics:
Two Sides of a Coin
Mutch D, et al. (2005) FASEB Journal 19:1602-1616.
What is the evidence?
• Single Gene Disorders
•PKU
•Lactose intolerance
•Prader-Willi (Chromosome 15 q11-13)
•FTO gene (fat mass and obesity associated)
Chromosome 16
•Genes encoding the melanocortin -4 receptor
(MC4R)
• Complex conditions
•Genes involved in susceptibility to complex
diseases have been identified
•Nutritional environment modifies the
expression of
genes
•Metabolism of nutrients may vary by genotype,
ultimately affecting health
Micronutrient Deficiency and DNA Damage
Micronutrient
Folic acid
Vitamin B12
Vitamin B6
Vitamin C
Vitamin E
Iron
Zinc
Niacin
%US Population
DNA Damage
Health Effects
Colon Cancer,
Chromosome
Heart Disease
10%
breaks
Brain
dysfunction
(same as Folic
acid)
4% (<half RDA)
Uncharacterized
Neuronal
damage
(same as Folic
10% (<half RDA) Uncharacterized
acid)
Radiation mimic Cataracts (4X)
15% (<half RDA)
(DNA oxidation) Cancer
Colon cancer
(2X), Heart
Radiation mimic
20% (<half RDA)
disease (1.5X),
(DNA oxidation)
Immune
dysfunction
Brain and
7% (<half RDA)
DNA breaks
Immune
(19% women 12Radiation mimic dysfunction,
50 years of age)
Cancer
Brain and
Chromosome
Immune
18% (<half RDA) breaks
dysfunction,
Radiation mimic
Cancer
Disables DNA
Neurological
2% (<half RDA)
repair (polyADP symptoms
ribose)
Memory loss
Nutritional Genomics
DNA
RNA
gene regulation, SNP’s
transcriptional control,
histone interaction
translational control,
processing, stability,
transport of mRNA
FOOD
COMPAUND
HEALTH
EFFECT
protein
receptor interaction gene
control, signal
transduction, enzyme
regulation inhibition,
modification transport
regulation channel or
pump interaction
metabolite multitude of functions
van Ommen B. (2004) Nutrition 20:4-8.
ProKeys for Healthy DNA &
Genes
• B-complex vitamins
• Energy nutrients, such as CoQ10
• Antioxidants, such as vitamin E
• Nutrient-dense foods
• Avoiding “empty” sugars and carbs
• Nothing proprietary or years away
Preventing DNA Damage
• Replication errors
– Occur when DNA is copied for new cell
– Reduce with B vitamins
• Transcription errors
– Occur when DNA/RNA make protein
– Reduce with B vitamins and amino acids
• Free radicals
– Reduce with antioxidants, CoQ10
• Advanced glycation end products
– Reduce by limiting sugars, maintain normal
glucose
Some dietary chemicals can cause DNA mutations, DNA
rearrangements, changes in epigenetics and gene
expression;
Some others dietary chemicals can protect genome
functions.
Those cuisines based on large amounts of plants
(vegetables, grains, fruits, nuts, beans and legumes),
such as found the Mediterranean diet, are believed to be
health promoting.
Plants produce chemicals to protect themselves, but
recent research has demonstrated that they can also
protect humans against diseases.
A
•
•
•
few of the well-known phytochemicals are :
lycopene in tomatoes,
isoflavones in soy,
flavonoids in fruits.
The thousands of different types of
phytochemicals can be categorized into families,
according to their protective functions.
Medical research indicated that there is no
single magical phytochemical, but there are
synergistic to their medicinal values.
Also, there is increasing evidence that
consumption of whole foods is better than
isolated food components, such as dietary
supplements and nutraceuticals.
For example, increased consumption of carotenoidrich fruits and vegetables was more effective
than carotenoid dietary supplements.
Antioxidants
• Prevent DNA damage from free radicals
– Vitamin E,Vitamin C,Selenium (as part of
glutathione peroxidases),Polyphenolic
flavonoids,Carotenoids
• Turn some genes on and off
– Vitamin E turns off inflammatory genes
– Vitamin C turns stem cells into heart
cells
• Estrogen-alpha receptor expression
− Naringenin, quercetin
• Suppression of NF-kB
− Total flavonoids of Bidens pilosa L.
Mitochondrial Nutrients
• Promote cellular energy
production
– CoQ10, alpha-lipoic acid,
carnitine, ribose, creatine, B1,
B2, B3
– Curb free radical production at
its source
• Increase production of
adenosine triphosphate (ATP)
• ATP and adenine ring form part
of DNA
B-Complex Vitamins
• DNA synthesis
– “One-carbon metabolism”
– Folic acid, B3, B6, B12
• SAMe cycle and methylation (CH3)
• DNA Repair
– Folic acid, B3
– Poor DNA repair increases cancer risk
• DNA regulation
– “DNA methylation” turns off cancer cells
• Methyl groups (CH3) attach to DNA
Genetic Variations & Folic Acid
MTHFR
Gene
Enzyme
Activity
NORMAL
Variation 1
Variation 2
677CC (me)
677CT
677TT
100%
71%
34%
Reduced DNA
“Normal” DNA Reduced DNA
Synthesis
DNA Effects
Synthesis
Synthesis
Folic Acid
Required
400 mcg
800 mcg
1,200 mcg
The SAMe Cycle
Nutrigenetics/nutrigenomics
Results of nutrigenetics/nutrigenomics studies
could help to modify diets to avoid or include
certain nutrients and food combinations in a more
personalized way than the common state of
knowledge of the ordinary consumer currently
allows.
The genetic basis of each individual differs.
Genes and their variants (alleles) can put people
at higher or lower risk of developing chronic
disease, e.g. cardio-vascular diseases, obesity,
or cancer.
Inherited genes, if known, may also help to
predict the risks and benefits of certain foods.
Gene expression and its regulation
Early investigations of gene regulation
revealed that nutrients can modulate gene
expression.
Flavonoids are a well-known example.
Transcription of genes involved in chronic
diseases or involved in inflammation may be
affected by enriching our diet with specific
foods, inherently rich in phytochemicals.
Initiation of gene transcription itself
requires the presence of transcription
factors, enhancers/repressors, accessible
promoters, and RNA polymerase.
Transcriptomics
Many techniques exist to study gene expression at
the mRNA level.
These techniques can be sorted into two classes.
Either they are aimed:
• at finding genes which differential transcription
in a biological process is unknown (high-density
arrays),
• or to know whether a given interesting set of
genes are differentially transcribed (low-density
arrays, microfluidic RT-PCR)
High density oligonucleotide microarrays have been
used for pioneer studies on the multiple gene
expression effects:
• Ginkgo biloba leaf extract
• Studies of flavonoids or garlic constituents
• Correlation of high consumption of soy
isoflavones in Asian diets to a lower incidence of
a certain type of prostate cancer
The complexity of the human genome, the
difficulties in setting-up cohort study
experiments, plus the cost of the chips represent
the main obstacles.
It is generally accepted that food consumption has
impacts on dynamic changes in the human genome, gene
expression, metabolome, and finally in human health,
generally.
A diet rich in phytochemicals, linked with the daily
intake of
fruits & vegetables, may have a protective effect upon
the genome.
We need to gather more comprehensive knowledge on the
variability of the genome, with respect to
allelomorphism and possibly epigenetic changes,
protein, and metabolite levels (and as a consequence of
fruit & vegetable consumption);
We might help to prevent diseases and prolong human
life by personalised nutrition. High throughput methods
have to be employed to understand the food’s
constituents’ interactions with individual genotypes
under different life situations
Transcription-factor pathways
mediating nutrient-gene
interaction
Why are PUFAs healthy?
PPAR
-
+
SREBP1
SP1/NF-Y
PPRE
Fatty acid oxidation
genes
b-Oxidation
Lipogenic genes
FA synthesis
Triglyceride synthesis
VLDL-TG
Dietary Sources of
Phytoestrogens
Phytoestrogens in Human
Health
• Cancer prevention
• Post-menopausal supplement
• Prevention of osteoporosis
• Cardiovascular health
• Fertility
• Breast enhancement
What comes out from
nutrigenomics research?
Ipriflavone
Dimethylaminoethanol
Chromium picolinate
“Things sweet to taste
prove in digestion sour”
William Shakespeare
“Richard II”
Critical points in the alimentary
regulation of the gene expression
Regulatory nutrients
Vitamins and mineral
substances
Action targets
Postprandial
modification
Iron and amino acids
Translation of mRNA
Fatty acids, glucose,
selenium, iron
Stability of mRNA
Polyunsaturated fatty
acids, glucose
Fatty acids, glucose,
cholesterol,
retinoids, vitamin D
Reading of mRNA
Gene transcription
Nutrition factors influencing the gene
expression and protein composition of
human cells
Groups of
substances
Nutrients
Examples
Food substances,
microelements
Antinutrients
Phytates
Metabolites of food
substances
Eicosanoids, retinoids
Substances formed during
preparation of food
Food pollutants of
natural and
anthropogenic origin
Heterocyclic amines
Heavy metals,
toxins, free
radicals
Genomics and proteomics tell you what
might happen,
Metabolomics tells you what actually did
happen
Bill Lasley, U. of California, Davis
Nutrigenomics
Target Genes
Mechanisms
Pathways
Foods
Nutrition
Molecular Nutrition
& Genomics
•Identification of dietary signals
•Identification of dietary sensors
•Identification of target genes
•Reconstruction of signaling pathways
Small research groups
Small budgets
Signatures
Profiles
Biomarkers
Nutritional
Systems Biology
•Measurement of stress signatures
•Identification of early biomarkers
Large research consortia
Big money
Complexity
Food is a much more capacious
definition than we usually think.
It is a complex of hundreds of
thousands of substances, each
having certain biological activity.
Food shall be viewed not only as a
source of energy and plastic
substances, but also as a compound
pharmacological complex.
A.A. Pokrovsky
"Metabolic aspects of pharmacology and
toxicology of food", 1976
Acknowledgement
I want to thank my colleagues from the
Laboratory of Metabolism
Ms. Natalia Kodisova and Mr. Jorqe Soto