http://creativecommons.org/licenses/by-sa/2.0/

1
http//creativecommons.org/licenses/by-sa/2.0/
2
Nutrigenomics
ProfRui Alves ralves_at_cmb.udl.es 973702406 Dept
Ciencies Mediques Basiques, 1st Floor, Room
1.08 Website of the Coursehttp//web.udl.es/usuar
is/pg193845/Courses/Bioinformatics_2007/ Course
http//10.100.14.36/Student_Server/
3
What is Nutrigenomics?

• Nutrigenomics is the science that examines the
  response of individuals to food compounds using
  post-genomic and related technologies.
• The long-term aim of nutrigenomics is to
  understand how the whole body responds to real
  foods using an integrated approach.
• Studies using this approach can examine people
  (i.e. populations, sub-populations - based on
  genes or disease - and individuals), food,
  life-stage and life-style without preconceived
  ideas.

4
Problem 1 Nutrition tasty complex
5
Genes Lifestyle Calories
6
The same genes The changed diet
Paleolithic era
Modern Times
1.200.000 Generations between feast en famine
2-3 Generations in energy abundance
Energy
Energy
100
100
Grain Milk/-products Isolated Carbohydrates Isolat
ed Fat/OilAlcohol
Low-fat meatChicken Eggs Fish
50
50
Meat Chicken Fish
Fruit Vegetables (carrots) Nuts Honey
Fruit Vegetables Beans
0
0
7
Molecular nutrition
8
Problem 2Our gene passports and nutrition
Optimal Nutrition
Individual genotype Functional phenotype
AA AB BB
Lifestyle
Eat right for your genotype??
9
Personalized diets?
10
Nutrigenomics
FoodsNutrition
Target GenesMechanismsPathways
SignaturesProfilesBiomarkers
Molecular Nutrition Genomics
NutritionalSystems Biology

• Identification of dietary signals
• Identification of dietary sensors
• Identification of target genes
• Reconstruction of signaling pathways

• Measurement of stress signatures
• Identification of early biomarkers

Large research consortiaBig money
Small research groupsSmall budgets
Complexity
11
Nutrients acts as dietary signals
Nutritional factors
Transcription factors
Gene transcription
12
Molecular Nutrition Genomics The strategy of
Nutrigenomics
50000 (?)metabolites
80-100000proteins
100000 transcripts
20-25000 genes
13
Transcription-factor pathways mediating
nutrient-gene interaction
14
A key instrument in Nutrigenomics research The
GeneChip System
15
Functions of PPARs
PPARa
PPARg
PPARb

• Nutrient metabolism
• (lipid, glucose, AAs)
• - Proliferation
• - Inflammation

- Lipid and glucose metabolism - Cell cycle
control - Inflammation
- Lipid metabolism - Keratinocyte
differentiation - Inflammation
16
PPARs are ligand activated transcription factors
Function
9 cis retinoic acid
fatty acids
PPAR
Proteinsynthesis
-

PPAR
RXR
DNA transcription
Gene
AGGTCAaAGGTCA
Response element
17
Why are PUFAs healthy?
SREBP1SP1/NF-Y
PPAR

-
Fatty acid oxidation genes
Lipogenic genes
FA synthesisTriglyceride synthesis
b-Oxidation
VLDL-TG
18
Pharmacological activation
Physiological activation
Nutritional activation
WY14643 Fasting
High fat diet
19
Pharmacological activation
Physiological activation
Nutritional activation
WY14643 Fasting
High fat diet

• PPARa-/-

• PPARa-/-

4

• PPARa/

• PPARa/

4
4
3
3
3
2
2
2
1
1
1
0
0
0
fed
- WY
WY
fasted
low fat
high fat
Kersten et al.
20
Role of PPARa in the hepatic response to fasting

• Elucidation by employing
• k.o.-mice
• specific ligands
• transcriptome analysis
• In vitro studies (Promoter studies, ChIP, etc)

CMLS, Cell. Mol. Life Sci. 61 (2004) 393416
21
Metabolic Syndrome and Diabetes
22
Gene regulation by fatty acids
WAT

ABCG5/G8
Mdr2
FFA
TG
Portal blood
Hepatocyte
Bile
23
What happens during fasting?
glucose
Blood
DHAP
TG
G3P
FFA
WAT
Liver
24
Mouse liver gene expression signatures during
fasting
Metabolic reprogramming during fasting
25
down
up
Avg Diff
Acc. No.
Acc. No.
Fold- Change
Fold- Change
cluster
cluster
Avg Diff
transcription factors
transcription factors
SREBP-1
3
104.3
D1
X61800
C/EBPd
3.3
73
U1
AA061461
SREBP-1
10.4
580.3
D1
X62600
C/EBPb
2.3
261.3
U1
AA068578
SREBP-1
8.5
172.4
D1
AA106163
CAR
2.9
134.8
U1
AA067092
retinoid O receptor RORgamma
4.5
267.3
D1
U09416
FXR
2.3
531.7
U1
U39071
retinoid O receptor RORalpha1
1.8
266.6
D2
U09419
LXRb
2
110.3
U2
Y08640
PPAR a
U44752
hepatic nuclear factor HNF3alpha
3.5
72
D2
X57638
2.6
217.8
U5
M34476
RARg
3.8
100.2
U3
receptors and binding proteins
receptors and binding proteins
X70533
corticosteroid binding globulin
4.3
2351.5
D1
X81579
insulin-like growth factor binding protein 1
5.9
300.7
U4
M33324
high molecular weight growth hormone receptor
3.8
168.5
D2
L05439
insulin-like growth factor binding protein 2
3.4
1993.4
U1
AA038239
plasma retinol binding protein RBP
3.1
3248.1
D3
L38613
glucagon receptor
2.3
462.8
U2
X14961
heart fatty acid binding protein H-FABP
2.7
143.4
D1
X57796
tumor necrosis factor receptor 55 kD
3.2
166.2
U4
U40189
pancreatic polypeptide/neuropeptide Y receptor
3.2
34.4
U3
J03398
Abcb4 (Mdr2)
4.4
504.1
U1
M65034
intestinal fatty acid binding protein I-FABP
2.4
486.5
U3
amino acid metabolism
Z14986
adenosylmethionine decarboxylase
3.3
335.2
D1
M17030
ornithine transcarbamylase
2.3
3615.5
D2
X51942
phenylalanine hydroxylase
2.2
4171.4
D2
Metabolic reprogramming during fasting
J02623
aspartate aminotransferase
1.6
783.6
D4
U38940
asparagine synthetase
2.2
177.9
D4
U24493
tryptophan 2,3-dioxygenase
1.7
4116.4
D5
X16314
glutamine synthetase
2
925
D5
nucleotide metabolism
X75129
xanthine dehydrogenase
1.8
395.9
D1
M27695.0
urate oxidase
2.2
2848.7
D5
X56548
purine nucleoside phosphorylase
2
1149.7
D2
other enzymes
other enzymes
W54790
ATP synthase A chain
4.4
456.7
D4
X80899
SIG81 (cytochrome c oxidase VIIa homologue)
2
762.5
U2
W91222
cytochrome c oxidase subunit VIIa
2.9
913.2
D5
U14390
aldehyde dehydrogenase (Ahd3)
3.6
660.9
U3
X01756
cytochrome c
1.7
1678.7
D5
Z37107
epoxide hydrolase
1.8
3012.6
U3
U39200
epidermal 12(S)-lipoxygenase
2.3
142
D2
U33557
folylpolyglutamate synthetase
2.1
648.8
U5
W41963
acetyl-CoA synthetase
3.3
106.6
D2
D49744
farnesyltransferase alpha
1.9
475.8
U3
M27796
carbonic anhydrase III
8.7
4283.8
D3
U12922
CD1 geranylgeranyl transferase beta subunit
2.1
260.1
U3
X51971
carbonic anhydrase V
1.7
787.4
D1
J03733
ornithine decarboxylase
1.6
257.8
U3
AA106634
cis-retinol/3-alpha-hydroxysterol short chain
dehydr.
4.5
3997.4
D5
D16333
coproporphyrinogen oxidase
2.5
216.9
U3
U00445
glucose-6-phosphatase
1.8
1587.7
D4
J02652
malate NADP oxidoreductase
1.7
249
U3
U27014
sorbitol dehydrogenase
2.2
3607.4
D2
M63245
amino levulinate synthase (ALAS-H)
2.5
1842.4
D4
M74570
aldehyde dehydrogenase II
2.6
4177.9
D4
26
How to crack the code?

• Rosetta Resolver 5/Base 2
• Bioconductor et al. (WWW)
• Spotfire
• MS Excel
• Pathway assistGeneGoIngenuity
• Thinking!!

27
The common diseases are complexFactors
influencing the development of metabolic syndrome
Hypertension
Obesity
1
Diabetes
2
3
Hyperlipidemia
Inflammation
MSX
28
Prevention versus Therapy Nutrition versus
Pharma
Complex Disease
Different targets
Metabolic syndrome
Pharma
DISEASE STATE (arbitrary units)
Metabolic stress
Nutrition
HomeostasisHealth
TIME (months/years)
29
Interplay between diet, organs and metabolic
stress
Muscle
Adipose tissue
Lipids

• Systemic effects
• Glucose intolerance
• Insulin resistance
• Lipid disorders

Absorbed nutrients
Homeostasis by liver
Digestion and absorption
Entero-HepaticCycle
Diet

• Signals gut mucosa
• satiety hormones
• cytokines
• ? barrier

Unabsorbed nutrients
D Gut contents
30
Signatures of health stress -The two hits
Metabolic and pro-inflammatory stress
31
Nutritional Systems Biology
Diagnosticmarkers
PredispositionGenotype
Prognosticmarkers
32
Gene expressionSignatures
Gene regulation by nutrients
Prevention ofMetabolic Syndrome
Dietary Programming
Nutrient-related cellular sensing Metabolic
stress
Target genesof nutrients
Transporters Transcription factors
MetabolicImplications Metabolites
MouseModels
LipidsFatty acidsSugars Calcium
IntestineLiver, MuscleBloodAdipose tissue
Enterocytes Hepatocytes AdipocytesLymphocytes
Proteins Post-translationalRegulation
InterventionStudies
Humans
Animal
Organs
Functions
Proteins
Cells
Genes
Signaling
Diet-related organ sensing, Sensitivity genes
Molecular Phenotype
MetabolomicsSystems Biology
Early MolecularBiomarkers
Molecular BiologyTools
TranscriptomeProteome
33
Linking to other EU programs
NuGO
DIOGENES obesity (EU, 12M)
LIPGEN Lipids genes (EU, 14M)
EARNEST early life nutrition (EU, 14M)
Innovative Cluster Nutrigenomics Chronic
metabolic stress (Dutch, 21M)
34
Two Strategies

• The traditional hypothesis-driven approach
  specific genes and proteins, the expression of
  which is influenced by nutrients, are identified
  using genomics tools such as transcriptomics,
  proteomics and metabolomics which subsequently
  allows the regulatory pathways through which diet
  influences homeostasis to be identified .
  Transgenic mouse models and cellular models are
  essential tools .
• provide us with detailed molecular data
  on the interaction
• between nutrition and the genome .
• (2) The SYSTEMS BIOLOGY approach gene, protein
  and metabolite signatures that are associated
  with specific nutrients, or nutritional regimes,
  are catalogued, and might provide early
  warningmolecular
• biomarkers for nutrient-induced changes to
  homeostasis.
• Be more important for human nutrition,
  given the difficulty of
• collecting tissue samples from healthy
  individuals.

35
Use model organisms in nutrition research
Caenorhaboditis elegans (completed genome
segence)
Role of nutrients in Alzhelmer and Parkinson
diseases.
Zebrafish (Danio rerino)
Role of nutrients in development and organ
functions.
Role of nutrition in development and organ
functions.
Mouse
36
Use model organisms in nutrition research
Knockout mice is useful !
HNF, hepatocyte nuclear factor LXR, liver X
receptor MTF1, metal-responsive transcription
factor PPAR,peroxisome proliferator-activated
receptor TGF, transforming growth factor.
Nature reviews/genetics (2003) , 4315-322
37
Nutrigenomics and nutritional systems biology
apply the same set of technologies
Nutrition (2004) , 20 4-8
38
The smart combination of molecular nutrition
and nutrigenomics.
Nature reviews/genetics (2003) , 4315-322
39
Strategies we need in gene-nutrient interactions
40
Integration of enabling technologies in
nutrigenomics
Microarray SAGE
41
Aging-related changes in gene expression in
gastrocnemius muscle
Science (1999) 2851390-1393
42
Caloric restrictioninduced alterations in gene
expression
Science (1999) 2851390-1393
43
Conclusion of gene expression profile of aging
and its retardation by caloric restriction
Science (1999) 2851390-1393
44
Conclusion and future perspective

• (1) Nutrigenomics researchers must know the
  challenge of understanding polygenic diet related
  diseases.
• (2) Short-term goals
• 1. to identify the dietary signals.
• 2. to elucidate the dietary sensor mechanisms.
• 3. to characterize the target genes of these
  sensors.
• 4. to understand the interaction between these
  signalling pathways and pro-inflammatory
  signalling to search for sensitizing genotypes.
• 5. to find signatures (gene/protein expression
  and metabolite profiles).

45
(3) Long-term goals Nutrigenomics is to help to
understand how we can use nutrition to prevent
many of the same diseases for which
pharmacogenomics is attempting to identify
cures. SNP database will be effect on disease
risk. Future
personalized diets
46
To Do

• Find examples in the literature of nutrigenomic
  studies.
• Review their finding
• Prepare a presentation about it.