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05/29/15

Nutrigenomics
Prof:Rui Alves
ralves@cmb.udl.es
973702406
Dept Ciencies Mediques Basiques,
1st Floor, Room 1.08
Website of the Course:http://web.udl.es/usuaris/pg193845/Courses/Bioinformatics_2007/
Course: http://10.100.14.36/Student_Server/

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, lifestage and life-style without preconceived ideas.

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Problem 1: Nutrition tasty + complex

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Genes Lifestyle Calories

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The same genes The changed


diet
Paleolithic era

Modern Times

1.200.000 Generations between


feast en famine

% Energy

100

50

2-3 Generations in energy abundance

% Energy
Low-fat meat
Chicken
Eggs
Fish

Fruit
Vegetables (carrots)
Nuts
Honey

100

50

Grain
Milk/-products
Isolated Carbohydrates
Isolated Fat/Oil
Alcohol
Meat
Chicken
Fish
Fruit
Vegetables
Beans

Molecular nutrition

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Problem 2:
Our gene passports andOptimal
nutrition
Nutrition
Individual genotype
Functional phenotype
AA
AB
BB

Lifestyle

Improvement
of Health
Maintenance
Eat right for your genotype??
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Personalized diets?

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Nutrigenomics
Target Genes
Mechanisms
Pathways

Foods
Nutrition

Molecular Nutrition
& Genomics

Signatures
Profiles
Biomarkers
Nutritional
Systems 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 consortia
Big money

Small research groups


Small budgets
Complexity
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Nutrients acts as dietary


signals
Nutritional factors
Transcription factors
Gene transcription

Energy
homeostasis

Cell
proliferation

Nutrient
absorption
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Molecular Nutrition &


Genomics
The strategy of Nutrigenomics
50000 (?)
metabolites
80-100000
proteins

100000
transcripts
20-25000
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Transcription-factor pathways
mediating nutrient-gene interaction

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A key instrument in Nutrigenomics


research:
The GeneChip System

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Nutritional Systems Biology


Gene

Sample Types:

protein index

metabolite index

Protein

10 ApoE3 mice
10 wildtype mice
liver tissue
plasma
urine

Biostatistics
Biostatistics
Bioinfomatics
Bioinfomatics

Metabolite
9

0 ppm

Targets
Targets
and
and
Biomarkers
Biomarkers

Figure 1. A typical Systems Biology strategy for study of atherosclerosis [1] using
a transgenic ApoE3 Leiden mouse model.

Onset of
disease

Predisposition
Genotype

Surrogate
Biomarkers
Late biomarkers
of disease
Early biomarkers
of disease
Diagnostic
markers
Prognostic
markers

Changes in pathway dynamics


to maintain homeostasis

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Gene regulation
by nutrients

Gene expression
Prevention of
Signatures
Metabolic Syndrome

Dietary
Programming

Nutrient-related cellular sensing + Metabolic stress


Nutrients

Signaling

Target
genes
of nutrients

Transporters
Transcription
factors
Lipids
Fatty acids
Sugars
Calcium

Enterocytes
Hepatocytes
Adipocytes
Lymphocytes

Signaling

Cells

Functions

Proteins

Genes

Cells

Metabolic
Implications
Metabolites

Proteins
Posttranslational
Regulation
Genes

Organs

Proteins

Animal

Healthy Food

Mouse
Models

Intestine
Liver, Muscle
Blood
Adipose tissue
Functions

Humans

Organs

Animal

Intervention
Studies

Humans

Diet-related organ sensing, Sensitivity genes + Molecular Phenotype

Molecular Biology
Tools
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Transcriptome
Proteome

Metabolomics
Systems Biology

Early Molecular
Biomarkers
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Linking to other EU programs


NuGO

DIOGENES
obesity
(EU, 12M)

Proliferation
Differentiation
Apoptosis

Absorption

Host-microbe
interaction

Carotenoids

Metabolic stress

Gut Health
Metabolic health
Life stage nutrition

Adipocyte
fat oxidation

Inflammation
Muscle insulin
resistance

Risk Benefit analysis

Periconceptual
nutrition
Systems biology

Nutrigenetics

Genetic epidemiology
Toxicogenomics

EARNEST
early life nutrition
(EU, 14M)
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Lipid metabolism

Early biomarkers

Nuclear
transcription
factors

LIPGEN
Lipids & genes
(EU, 14M)

Diabetes II

Innovative Cluster Nutrigenomics


Chronic metabolic stress
(Dutch, 21M)
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Two Strategies
(1) 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.
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Use model organisms in nutrition


research
Caenorhaboditis
elegans
(completed genome
segence)

Zebrafish
(Danio rerino)

Mouse
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Role of nutrients in Alzhelmer and


Parkinson diseases.

Role of nutrients in development and


organ functions.

Role of nutrition in development and


organ functions.
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Nutrigenomics and nutritional systems


biology apply the same set of technologies

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Nutrition (2004) , 20: 4-8

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Integration of enabling technologies in


nutrigenomics
Microarray & SAGE

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Aging-related changes in gene


expression in gastrocnemius muscle

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Science (1999) 285:1390-139322

Caloric restrictioninduced alterations in


gene expression

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Science (1999) 285:1390-1393


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Conclusion of gene expression profile of


aging and its retardation by caloric restriction

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Science (1999) 285:1390-1393

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).
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(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

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personalized diets
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To Do

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Find examples in the literature of nutrigenomic


studies.
Review their finding
Prepare a presentation about it.

27

Functions of PPARs
PPAR
-Nutrient metabolism
(lipid, glucose, AAs)

PPAR
- Lipid and glucose
metabolism

PPAR
- Lipid metabolism

- Proliferation

- Cell cycle control

- Keratinocyte
differentiation

- Inflammation

- Inflammation

- Inflammation

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PPARs are ligand activated transcription


factors
Function

9 cis retinoic acid

fatty acids

PPAR
RXR

PPAR

Protein
synthesis

Gene
Response element

AGGTCAaAGGTCA

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DNA transcription
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Why are PUFAs healthy?

PPAR

SREBP1
SP1/NF-Y

PPRE

Fatty acid oxidation


genes
-Oxidation

Lipogenic genes

FA synthesis
Triglyceride synthesis

VLDL-TG
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Pharmacological
activation

WY14643
PPAR+/+

PPAR-/-

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Physiological
activation

Fasting
PPAR+/+

PPAR-/-

Nutritional
activation

High fat diet


PPAR+/+

PPAR-/-

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Physiological
activation

WY14643

Nutritional
activation

Fasting

High fat diet

fa

hi
gh

Kersten et al.

lo
w

fa
s

te

fe
d

Y
W
+

-W
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PPAR-/4 PPAR+/+

PPAR-/4 PPAR+/+

PPAR-/4 PPAR+/+

fa
t

Pharmacological
activation

32

Role of PPAR in the hepatic


response to fasting
FFA

Elucidation by employing:
1) k.o.-mice
2) specific ligands
3) transcriptome analysis
4) In vitro studies (Promoter
studies, ChIP, etc)

Liver
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CMLS,
CMLS, Cell.
Cell. Mol.
Mol. Life
Life Sci. 61 (2004) 393416

33

Metabolic Syndrome and Diabetes


Genes

Muscle insulin
resistence
Obesity

Increased
lipolysis in
visceral fat

Ageing

Increased
fatty acids levels

hyperinsulemia

Cell
compensation

Increased
glucose output
Decreased
glucose
tolerance

Cell
decompensation
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Increased
gluconeogenesis
in liver

Decreased
insulin
secretion

Diabetes

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Gene regulation by fatty acids


WAT
Fatty acid oxidation
Fatty acid hydroxylation
Hydrolysis of Acyl-CoA
Fatty acid transport
Hepatobiliary lipid transport

Ppar

PC

FFA

TG

+
+ Fxr/Lxr
+

Portal blood

Mdr2

-Acute phase

Gluconeogenesis

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ABCG5/G8

response

Hepatocyte

Bile

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What happens during fasting?


glucose

Blood

DHAP

FFA
Glycerol

TG

G3P

FFA

WAT

Liver
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Mouse liver gene expression


signatures during fasting

Metabolic reprogramming during fasting


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4.3
3.8
3.1
2.7

2351.5
168.5
3248.1
143.4

D1
D2
D3
D1

3.3
2.3
2.2
1.6
2.2
1.7
2

335.2
3615.5
4171.4
783.6
177.9
4116.4
925

D1
D2
D2
D4
D4
D5
D5

1.8
2.2
2

395.9
D1
2848.7 D5
1149.7 D2

4.4
2.9
1.7
2.3
3.3
8.7
1.7
4.5
1.8
2.2
2.5
2.6

456.7
913.2
1678.7
142
106.6
4283.8
787.4
3997.4
1587.7
3607.4
1842.4
4177.9

3.3
2.3
2.9
2.3
2
2.6
3.8

73
261.3
134.8
531.7
110.3
217.8
100.2

U1
U1
U1
U1
U2
U5
U3

5.9
3.4
2.3
3.2
3.2
4.4
2.4

300.7
1993.4
462.8
166.2
34.4
504.1
486.5

U4
U1
U2
U4
U3
U1
U3

transcription factors
X61800 C/EBP
X62600 C/EBP
AA106163 CAR
U09416 FXR
U09419 LXR
X57638 PPAR
M34476 RAR

receptors and binding proteins


X70533
corticosteroid binding globulin
M33324 high molecular weight growth hormone receptor
AA038239 plasma retinol binding protein RBP
X14961
heart fatty acid binding protein H-FABP

cluster

D1
D1
D1
D1
D2
D2

Avg
Diff

cluster

104.3
580.3
172.4
267.3
266.6
72

SREBP-1
SREBP-1
SREBP-1
retinoid O receptor RORgamma
retinoid O receptor RORalpha1
hepatic nuclear factor HNF3alpha

FoldChange

Avg
Diff

3
10.4
8.5
4.5
1.8
3.5

transcription factors
AA061461
AA068578
AA067092
U39071
Y08640
U44752

up

Acc.
No.

FoldChange

Acc.
No.

down

receptors and binding proteins


X81579
L05439
L38613
X57796
U40189
J03398
M65034

insulin-like growth factor binding protein 1


insulin-like growth factor binding protein 2
glucagon receptor
tumor necrosis factor receptor 55 kD
pancreatic polypeptide/neuropeptide Y receptor
Abcb4 (Mdr2)
intestinal fatty acid binding protein I-FABP

amino acid metabolism


Z14986
M17030
X51942
J02623
U38940
U24493
X16314

adenosylmethionine decarboxylase
*ornithine transcarbamylase
phenylalanine hydroxylase
aspartate aminotransferase
asparagine synthetase
tryptophan 2,3-dioxygenase
glutamine synthetase

Metabolic reprogramming
during fasting

nucleotide metabolism
X75129
xanthine dehydrogenase
M27695.0 urate oxidase
X56548
purine nucleoside phosphorylase

other enzymes

other enzymes
W54790
W91222
X01756
U39200
W41963
M27796
X51971
AA106634
U00445
U27014
M63245
M74570

ATP synthase A chain


cytochrome c oxidase subunit VIIa
cytochrome c
epidermal 12(S)-lipoxygenase
acetyl-CoA synthetase
carbonic anhydrase III
carbonic anhydrase V

cis-retinol/3-alpha-hydroxysterol short chain dehydr.

glucose-6-phosphatase
sorbitol dehydrogenase
amino levulinate synthase (ALAS-H)
aldehyde dehydrogenase II

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D4
D5
D5
D2
D2
D3
D1
D5
D4
D2
D4
D4

X80899
U14390
Z37107
U33557
D49744
U12922
J03733
D16333
J02652

SIG81 (cytochrome c oxidase VIIa homologue)


aldehyde dehydrogenase (Ahd3)
epoxide hydrolase
folylpolyglutamate synthetase
farnesyltransferase alpha
CD1 geranylgeranyl transferase beta subunit
ornithine decarboxylase
coproporphyrinogen oxidase
malate NADP oxidoreductase

2
3.6
1.8
2.1
1.9
2.1
1.6
2.5
1.7

762.5
660.9
3012.6
648.8
475.8
260.1
257.8
216.9
249

U2
U3
U3
U5
U3
U3
U3
U3
U3

38

How to crack the code?

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Rosetta Resolver 5/Base 2


Bioconductor et al. (WWW)
Spotfire
MS Excel
Pathway assist
GeneGo
Ingenuity
Thinking!!

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The common diseases are complex:

Factors influencing the development of metabolic


syndrome
Obesity

Hypertension

Diabetes 1 2
3

Inflammation

Hyperlipidemia

MSX

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DISEASE STATE (arbitrary units)

Prevention versus Therapy Nutrition


versus Pharma
Complex Disease
Different targets

tress
s
c
i
l
o
Metab
on
Nutriti

Homeostasis
Health
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e
m
o
dr
n
sy
c
i
ol
b
ma
a
r
t
a
Me
Ph

TIME (months/years)
41

Interplay between diet, organs and


metabolic stress
Adipose
tissue

Absorbed
nutrients

Diet

Digestion
and
absorption
Unabsorbed
nutrients

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Muscle
Lipids
Homeostasis

by liver

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

EnteroHepatic
Cycle

Gut
contents

Signals gut mucosa:


Signals gut mucosa:
satiety hormones
satiety hormones
cytokines
cytokines
barrier
barrier
42

Signatures of health & stress -The two hits:


Metabolic and pro-inflammatory stress

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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,
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Nature reviews/genetics (2003) , 4:315-322
transforming growth factor.

The smart combination of molecular nutrition


and nutrigenomics.

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Nature reviews/genetics (2003) , 4:315-322

Strategies we need in gene-nutrient


interactions

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