org/licens
es/by-sa/2.0/
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?
05/29/15
05/29/15
05/29/15
Modern Times
% Energy
100
50
% 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
05/29/15
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??
05/29/15
Personalized diets?
05/29/15
Nutrigenomics
Target Genes
Mechanisms
Pathways
Foods
Nutrition
Molecular Nutrition
& Genomics
Signatures
Profiles
Biomarkers
Nutritional
Systems Biology
10
Energy
homeostasis
Cell
proliferation
Nutrient
absorption
05/29/15
11
100000
transcripts
20-25000
05/29/15 genes
12
Transcription-factor pathways
mediating nutrient-gene interaction
05/29/15
13
05/29/15
14
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
05/29/15
15
Gene regulation
by nutrients
Gene expression
Prevention of
Signatures
Metabolic Syndrome
Dietary
Programming
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
Molecular Biology
Tools
05/29/15
Transcriptome
Proteome
Metabolomics
Systems Biology
Early Molecular
Biomarkers
16
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
Periconceptual
nutrition
Systems biology
Nutrigenetics
Genetic epidemiology
Toxicogenomics
EARNEST
early life nutrition
(EU, 14M)
05/29/15
Lipid metabolism
Early biomarkers
Nuclear
transcription
factors
LIPGEN
Lipids & genes
(EU, 14M)
Diabetes II
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.
05/29/15
18
Zebrafish
(Danio rerino)
Mouse
05/29/15
05/29/15
20
05/29/15
21
05/29/15
05/29/15
05/29/15
24
25
Future
05/29/15
personalized diets
26
To Do
05/29/15
27
Functions of PPARs
PPAR
-Nutrient metabolism
(lipid, glucose, AAs)
PPAR
- Lipid and glucose
metabolism
PPAR
- Lipid metabolism
- Proliferation
- Keratinocyte
differentiation
- Inflammation
- Inflammation
- Inflammation
05/29/15
28
fatty acids
PPAR
RXR
PPAR
Protein
synthesis
Gene
Response element
AGGTCAaAGGTCA
05/29/15
DNA transcription
29
PPAR
SREBP1
SP1/NF-Y
PPRE
Lipogenic genes
FA synthesis
Triglyceride synthesis
VLDL-TG
05/29/15
30
Pharmacological
activation
WY14643
PPAR+/+
PPAR-/-
05/29/15
Physiological
activation
Fasting
PPAR+/+
PPAR-/-
Nutritional
activation
PPAR-/-
31
Physiological
activation
WY14643
Nutritional
activation
Fasting
fa
hi
gh
Kersten et al.
lo
w
fa
s
te
fe
d
Y
W
+
-W
05/29/15
PPAR-/4 PPAR+/+
PPAR-/4 PPAR+/+
PPAR-/4 PPAR+/+
fa
t
Pharmacological
activation
32
Elucidation by employing:
1) k.o.-mice
2) specific ligands
3) transcriptome analysis
4) In vitro studies (Promoter
studies, ChIP, etc)
Liver
05/29/15
CMLS,
CMLS, Cell.
Cell. Mol.
Mol. Life
Life Sci. 61 (2004) 393416
33
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
05/29/15
Increased
gluconeogenesis
in liver
Decreased
insulin
secretion
Diabetes
34
Ppar
PC
FFA
TG
+
+ Fxr/Lxr
+
Portal blood
Mdr2
-Acute phase
Gluconeogenesis
05/29/15
ABCG5/G8
response
Hepatocyte
Bile
35
Blood
DHAP
FFA
Glycerol
TG
G3P
FFA
WAT
Liver
05/29/15
36
37
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
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
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
glucose-6-phosphatase
sorbitol dehydrogenase
amino levulinate synthase (ALAS-H)
aldehyde dehydrogenase II
05/29/15
D4
D5
D5
D2
D2
D3
D1
D5
D4
D2
D4
D4
X80899
U14390
Z37107
U33557
D49744
U12922
J03733
D16333
J02652
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
05/29/15
39
Hypertension
Diabetes 1 2
3
Inflammation
Hyperlipidemia
MSX
05/29/15
40
tress
s
c
i
l
o
Metab
on
Nutriti
Homeostasis
Health
05/29/15
e
m
o
dr
n
sy
c
i
ol
b
ma
a
r
t
a
Me
Ph
TIME (months/years)
41
Absorbed
nutrients
Diet
Digestion
and
absorption
Unabsorbed
nutrients
05/29/15
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
05/29/15
43
Knockout mice
is useful
05/29/15
45
Nature reviews/genetics (2003) , 4:315-322
05/29/15
46