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

Nutrigenomics

Prof:Rui Alvesralves@cmb.udl.es973702406Dept 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

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

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

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