9/11/20151 es/by-sa/2.0
TRANSCRIPT
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http://creativecommons.org/licenses/by-sa/2.0/
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Nutrigenomics
Prof:Rui [email protected] Ciencies Mediques Basiques,1st Floor, Room 1.08Website of the Course:http://web.udl.es/usuaris/pg193845/Courses/Bioinformatics_2007/ Course: http://10.100.14.36/Student_Server/
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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.
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Problem 1: Nutrition – tasty + complex
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Genes – Lifestyle – Calories
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100
50
0
% Energy
Low-fat meatChickenEggsFish
FruitVegetables (carrots)NutsHoney
100
50
0
% Energy
FruitVegetablesBeans
MeatChickenFish
GrainMilk/-productsIsolated CarbohydratesIsolated Fat/OilAlcohol
1.200.000 Generations between feast en famine
Paleolithic era
2-3 Generations in energy abundance
Modern Times
The same genes – The changed diet
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Molecular nutrition
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Optimal Nutrition
Lifestyle
Individual genotype Functional phenotype
Problem 2:Our “gene passports” and nutrition
AA AB BB
ImprovementMaintenance
of Health
“Eat right for your genotype??”
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Personalized diets?
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Nutrigenomics
Target GenesMechanisms
Pathways
Target GenesMechanisms
Pathways
SignaturesProfiles
Biomarkers
SignaturesProfiles
Biomarkers
FoodsNutrition
Molecular Nutrition& Genomics
Molecular Nutrition& Genomics
NutritionalSystems Biology
NutritionalSystems Biology
•Identification of dietary signals•Identification of dietary sensors•Identification of target genes•Reconstruction of signaling pathways
•Identification of dietary signals•Identification of dietary sensors•Identification of target genes•Reconstruction of signaling pathways
•Measurement of stress signatures•Identification of early biomarkers•Measurement of stress signatures•Identification of early biomarkers
Small research groupsSmall budgets
Large research consortiaBig money
Complexity
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Energy homeostasis
Energy homeostasis
Nutrient absorptionNutrient
absorption
Cell proliferation
Cell proliferation
Nutritional factors
Transcription factors
Gene transcription
Nutrients acts as dietary signals
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“Molecular Nutrition & Genomics” The strategy of Nutrigenomics
80-100000proteins
20-25000 genes
100000 transcripts
50000 (?)metabolites
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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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ppm0123456789
Gene
Protein
MetaboliteTargets
andBiomarkers
Targets and
Biomarkers
BiostatisticsBioinfomatics
BiostatisticsBioinfomatics
gene
inde
x
prot
ein
inde
x
metabolite index
Sample Types:
• 10 ApoE3 mice• 10 wildtype mice
• liver tissue• plasma• urine
Figure 1. A typical Systems Biology strategy for study of atherosclerosis [1] usinga transgenic ApoE3 Leiden mouse model.
PredispositionGenotype
Prognosticmarkers
Diagnosticmarkers
Changes in pathway dynamicsto maintain homeostasis
SurrogateBiomarkers
Late biomarkersof disease
Early biomarkersof diseaseOnset of
disease
Nutritional Systems Biology
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IntestineLiver, Muscle
BloodAdipose tissue
IntestineLiver, Muscle
BloodAdipose tissue
Nutrients Signaling Cells Animal HumansOrgansFunctionsProteinsGenes Healthy Food
LipidsFatty acids
SugarsCalcium
LipidsFatty acids
SugarsCalcium
TransportersTranscription
factors
TransportersTranscription
factors
EnterocytesHepatocytesAdipocytes
Lymphocytes
EnterocytesHepatocytesAdipocytes
Lymphocytes
Target genes
of nutrients
Target genes
of nutrients
MouseModelsMouseModels
InterventionStudies
InterventionStudies
ProteinsPost-
translationalRegulation
ProteinsPost-
translationalRegulation
MetabolicImplicationsMetabolites
MetabolicImplicationsMetabolites
Signaling Cells Animal HumansOrgansFunctionsProteinsGenes
Nutrient-related cellular sensing + Metabolic stress
Diet-related organ sensing, Sensitivity genes + Molecular Phenotype
Gene expressionSignatures
Gene expressionSignatures
Gene regulation by nutrients
Gene regulation by nutrients
Prevention ofMetabolic Syndrome
Prevention ofMetabolic Syndrome
Dietary Programming
Dietary Programming
MetabolomicsSystems Biology
MetabolomicsSystems Biology
Molecular BiologyTools
Molecular BiologyTools
Early MolecularBiomarkers
Early MolecularBiomarkers
TranscriptomeProteome
TranscriptomeProteome
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LIPGENLipids & genes
(EU, 14M€)
DIOGENESobesity
(EU, 12M€)
Innovative Cluster NutrigenomicsChronic metabolic stress
(Dutch, 21M€)
EARNESTearly life nutrition
(EU, 14M€)
Linking to other EU programs
Lipid metabolism
Life stage nutrition
Risk Benefit analysis
Metabolic health
ProliferationDifferentiation
Apoptosis
Inflammation
Muscle insulin resistance
Nutrigenetics
Early biomarkers
Periconceptualnutrition
Nuclear transcription
factors
Systems biology
Host-microbeinteraction
Gut Health
Absorption
Genetic epidemiology
Toxicogenomics
Metabolic stress
Adipocytefat oxidation
Diabetes II
Carotenoids
Lipid metabolism
Life stage nutrition
Risk Benefit analysis
Metabolic health
ProliferationDifferentiation
Apoptosis
Inflammation
Muscle insulin resistance
Nutrigenetics
Early biomarkers
Periconceptualnutrition
Nuclear transcription
factors
Systems biology
Host-microbeinteraction
Gut Health
Absorption
Genetic epidemiology
Toxicogenomics
Metabolic stress
Adipocytefat oxidation
Diabetes II
Carotenoids
NuGO
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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 warning’molecular
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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Caenorhaboditis elegans
(completed genome segence)
Zebrafish(Danio rerino)
Mouse
Role of nutrients in Alzhelmer and Parkinson diseases.
Use model organisms in nutrition research
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
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
Science (1999) 285:1390-1393
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04/21/23 23Science (1999) 285:1390-1393
Caloric restriction–induced alterations in gene expression
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Conclusion of gene expression profile of aging and its retardation by caloric restriction
Science (1999) 285:1390-1393
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(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).
Conclusion and future perspective
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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 personalized diets
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To Do
Find examples in the literature of nutrigenomic studies.
Review their finding Prepare a presentation about it.
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-Nutrient metabolism (lipid, glucose, AAs)
- Proliferation
- Inflammation
- Lipid and glucose metabolism
- Cell cycle control
- Inflammation
- Lipid metabolism
- Keratinocyte differentiation
- Inflammation
PPAR PPAR PPAR
Functions of PPARs
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PPARs are ligand activated transcription factors
PPAR
9 cis retinoic acidfatty acids
DNA transcription
PP
AR
RX
R
AGGTCAaAGGTCA
+
Gene
Response element
-
Proteinsynthesis
Function
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Why are PUFAs healthy?
-OxidationFA synthesis
Triglyceride synthesis
PPAR
PPRE
Fatty acid oxidation genes
+SREBP1
SP1/NF-Y
Lipogenic genes
-
VLDL-TG
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Pharmacologicalactivation
Physiologicalactivation
Nutritionalactivation
WY14643 Fasting High fat diet
PPAR+/+
PPAR-/-
PPAR+/+
PPAR-/-
PPAR+/+
PPAR-/-
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Pharmacologicalactivation
Physiologicalactivation
Nutritionalactivation
WY14643 Fasting High fat diet- W
Y+
WY
low fa
t
fast
edfed
high fa
t
PPAR-/-
PPAR+/+
PPAR-/-
PPAR+/+
PPAR-/-
PPAR+/+
Kersten et al.
0
1
2
3
4
0
1
2
3
4
0
1
2
3
4
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Role of PPAR in the hepatic response to fasting
Liver
FFAFFAElucidation by employing:1) k.o.-mice2) specific ligands3) transcriptome analysis4) In vitro studies (Promoter
studies, ChIP, etc)
Elucidation by employing:1) k.o.-mice2) specific ligands3) transcriptome analysis4) In vitro studies (Promoter
studies, ChIP, etc)
CMLS, Cell. Mol. Life Sci. 61 (2004) 393–416CMLS, Cell. Mol. Life Sci. 61 (2004) 393–416
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Decreasedglucose
tolerance
Decreasedglucose
tolerance
Muscle insulinresistence
Muscle insulinresistence
Cellcompensation
Cellcompensation
Increasedgluconeogenesis
in liver
Increasedgluconeogenesis
in liver
Increased lipolysis in visceral fat
Increased lipolysis in visceral fat
Celldecompensation
Celldecompensation
GenesGenes AgeingAgeing
ObesityObesity hyperinsulemia
Increased fatty acids levels
Increasedglucose output
Decreasedinsulin
secretion
DiabetesDiabetes
Metabolic Syndrome and Diabetes
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FFAMdr2
Portal bloodPortal blood HepatocyteHepatocyte BileBile
WATWAT
TGTG
PC
+
+
+
Acute phase response
Fatty acid oxidationFatty acid hydroxylation Hydrolysis of Acyl-CoAFatty acid transport Hepatobiliary lipid transport
Gluconeogenesis
-
+Fxr/Lxr
Gene regulation by fatty acids
ABCG5/G8
Ppar
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What happens during fasting?
TG
glucose
FFA
WAT
G3P
DHAP
Blood
FFAGlycerol
LiverLiver
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Mouse liver gene expression signatures during fasting
Metabolic reprogramming during fasting
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clu
ster
Avg
Dif
f
Fo
ld-
Ch
ang
e
Acc
. N
o. down
clu
ster
Avg
Dif
f
Fo
ld-
Ch
ang
e
Acc
. N
o. up
transcription factors transcription factorsSREBP-1 3 104.3 D1 X61800 C/EBP 3.3 73 U1SREBP-1 10.4 580.3 D1 X62600 C/EBP 2.3 261.3 U1SREBP-1 8.5 172.4 D1 AA106163 CAR 2.9 134.8 U1retinoid O receptor RORgamma 4.5 267.3 D1 U09416 FXR 2.3 531.7 U1retinoid O receptor RORalpha1 1.8 266.6 D2 U09419 LXR 2 110.3 U2
AA061461AA068578AA067092U39071Y08640U44752 hepatic nuclear factor HNF3alpha 3.5 72 D2 X57638 PPAR 2.6 217.8 U5
M34476 RAR 3.8 100.2 U3
receptors and binding proteins receptors and binding proteinsX70533 corticosteroid binding globulin 4.3 2351.5 D1 X81579 insulin-like growth factor binding protein 1 5.9 300.7 U4M33324 high molecular weight growth hormone receptor 3.8 168.5 D2 L05439 insulin-like growth factor binding protein 2 3.4 1993.4 U1AA038239 plasma retinol binding protein RBP 3.1 3248.1 D3 L38613 glucagon receptor 2.3 462.8 U2X14961 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 U3J03398 Abcb4 (Mdr2) 4.4 504.1 U1M65034 intestinal fatty acid binding protein I-FABP 2.4 486.5 U3
amino acid metabolismZ14986 adenosylmethionine decarboxylase 3.3 335.2 D1M17030 *ornithine transcarbamylase 2.3 3615.5 D2X51942 phenylalanine hydroxylase 2.2 4171.4 D2J02623 aspartate aminotransferase 1.6 783.6 D4U38940 asparagine synthetase 2.2 177.9 D4U24493 tryptophan 2,3-dioxygenase 1.7 4116.4 D5X16314 glutamine synthetase 2 925 D5
nucleotide metabolismX75129 xanthine dehydrogenase 1.8 395.9 D1M27695.0 urate oxidase 2.2 2848.7 D5X56548 purine nucleoside phosphorylase 2 1149.7 D2
other enzymes other enzymesW54790 ATP synthase A chain 4.4 456.7 D4 X80899 SIG81 (cytochrome c oxidase VIIa homologue) 2 762.5 U2W91222 cytochrome c oxidase subunit VIIa 2.9 913.2 D5 U14390 aldehyde dehydrogenase (Ahd3) 3.6 660.9 U3X01756 cytochrome c 1.7 1678.7 D5 Z37107 epoxide hydrolase 1.8 3012.6 U3U39200 epidermal 12(S)-lipoxygenase 2.3 142 D2 U33557 folylpolyglutamate synthetase 2.1 648.8 U5W41963 acetyl-CoA synthetase 3.3 106.6 D2 D49744 farnesyltransferase alpha 1.9 475.8 U3M27796 carbonic anhydrase III 8.7 4283.8 D3 U12922 CD1 geranylgeranyl transferase beta subunit 2.1 260.1 U3X51971 carbonic anhydrase V 1.7 787.4 D1 J03733 ornithine decarboxylase 1.6 257.8 U3AA106634 cis-retinol/3-alpha-hydroxysterol short chain dehydr. 4.5 3997.4 D5 D16333 coproporphyrinogen oxidase 2.5 216.9 U3U00445 glucose-6-phosphatase 1.8 1587.7 D4 J02652 malate NADP oxidoreductase 1.7 249 U3U27014 sorbitol dehydrogenase 2.2 3607.4 D2M63245 amino levulinate synthase (ALAS-H) 2.5 1842.4 D4M74570 aldehyde dehydrogenase II 2.6 4177.9 D4
Metabolic reprogramming during fasting
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How to crack the code? Rosetta Resolver 5/Base 2 Bioconductor et al. (WWW) Spotfire MS Excel Pathway assist
GeneGoIngenuity
Thinking!!
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The common diseases are complex:Factors influencing the development of metabolic
syndrome
MSX
1
3
Diabetes
Obesity Hypertension
InflammationHyperlipidemia
2
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Pharma
Nutrition
Prevention versus Therapy – Nutrition versus Pharma
0
20
40
60
80
100
120
TIME (months/years)
DIS
EA
SE
ST
AT
E (
arbi
trar
y un
its)
HomeostasisHealth
Complex Disease
Different targets
Metabolic stress
Metabolic sy
ndrome
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Interplay between diet, organs and metabolic stress
Signals gut mucosa:• satiety hormones• cytokines• barrier
Signals gut mucosa:• satiety hormones• cytokines• barrier
Unabsorbednutrients
Unabsorbednutrients
Systemic effects:• Glucose intolerance• Insulin resistance• Lipid disorders
Systemic effects:• Glucose intolerance• Insulin resistance• Lipid disorders
Absorbednutrients
Absorbednutrients
DietDietEntero-HepaticCycle
Homeostasis
by liverHomeostasis
by liver
Adiposetissue
Adiposetissue
MuscleMuscle
Gut contentsGut
contents
Digestionand
absorption
Digestionand
absorption
LipidsLipids
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Signatures of health & stress -The “two hits”: Metabolic and pro-inflammatory stress
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04/21/23 44Nature reviews/genetics (2003) , 4:315-322
HNF, hepatocyte nuclear factor; LXR, liver X receptor; MTF1, metal-responsive transcription factor; PPAR,peroxisome proliferator-activated receptor; TGF, transforming growth factor.
Use model organisms in nutrition research
Knockout mice is useful !
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The ‘smart’ combination of molecular nutrition and nutrigenomics.
Nature reviews/genetics (2003) , 4:315-322
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Strategies we need in gene-nutrient interactions