**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/

**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.

**Problem 1: Nutrition tasty + complex

**Genes Lifestyle Calories

100500% EnergyLow-fat meat ChickenEggsFishFruitVegetables (carrots)NutsHoney100500% EnergyFruitVegetablesBeansMeatChickenFishGrainMilk/-productsIsolated CarbohydratesIsolated Fat/Oil Alcohol1.200.000 Generations between feast en faminePaleolithic era2-3 Generations in energy abundanceModern TimesThe same genes The changed diet

**Molecular nutrition

**Optimal NutritionLifestyleIndividual genotype Functional phenotypeProblem 2:Our gene passports and nutritionAA AB BBEat right for your genotype??

**Personalized diets?

**NutrigenomicsTarget Genes Mechanisms PathwaysSignatures Profiles BiomarkersFoods NutritionMolecular Nutrition & GenomicsNutritional Systems BiologyIdentification of dietary signalsIdentification of dietary sensorsIdentification of target genesReconstruction of signaling pathways Measurement of stress signaturesIdentification of early biomarkersSmall research groups Small budgetsLarge research consortia Big moneyComplexity

**Nutritional factorsTranscription factorsGene transcriptionNutrients acts as dietary signals

**Molecular Nutrition & Genomics The strategy of Nutrigenomics80-100000 proteins20-25000 genes100000 transcripts50000 (?) metabolites

**Transcription-factor pathways mediating nutrient-gene interaction

**A key instrument in Nutrigenomics research: The GeneChip System

**Predisposition GenotypePrognostic markersDiagnostic markersNutritional Systems Biology

**Intestine Liver, Muscle Blood Adipose tissueLipids Fatty acids SugarsCalciumTransportersTranscriptionfactorsEnterocytesHepatocytesAdipocytes LymphocytesTarget genes of nutrientsMouse ModelsIntervention StudiesProteinsPost- translational RegulationMetabolic ImplicationsMetabolitesSignalingCellsAnimalHumansOrgansFunctionsProteinsGenesNutrient-related cellular sensing + Metabolic stressDiet-related organ sensing, Sensitivity genes + Molecular PhenotypeGene expression SignaturesGene regulation by nutrientsPrevention of Metabolic SyndromeDietary ProgrammingMetabolomics Systems BiologyMolecular Biology ToolsEarly Molecular BiomarkersTranscriptome Proteome

**LIPGENLipids & genes(EU, 14M)DIOGENESobesity(EU, 12M)Innovative Cluster NutrigenomicsChronic metabolic stress(Dutch, 21M)EARNESTearly life nutrition(EU, 14M)Linking to other EU programsNuGO

**Two StrategiesThe 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.

**Caenorhaboditis elegans (completed genome segence) Zebrafish(Danio rerino)MouseRole of nutrients in Alzhelmer and Parkinson diseases.Use model organisms in nutrition researchRole of nutrients in development and organ functions.Role of nutrition in development and organ functions.

**Nutrigenomics and nutritional systems biology apply the same set of technologiesNutrition (2004) , 20: 4-8

**Integration of enabling technologies in nutrigenomicsMicroarray & SAGE

**Aging-related changes in gene expression in gastrocnemius muscleScience (1999) 285:1390-1393

**Science (1999) 285:1390-1393Caloric restrictioninduced alterations in gene expression

**Conclusion of gene expression profile of aging and its retardation by caloric restrictionScience (1999) 285:1390-1393

**(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

**(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.

Futurepersonalized diets

**To DoFind examples in the literature of nutrigenomic studies. Review their findingPrepare a presentation about it.

**Nutrient metabolism (lipid, glucose, AAs)

- Proliferation

- Inflammation- Lipid and glucose metabolism

- Cell cycle control

- Inflammation- Lipid metabolism

- Keratinocyte differentiation

- Inflammation

PPARaPPARgPPARbFunctions of PPARs

**PPARs are ligand activated transcription factorsPPAR9 cis retinoic acidfatty acidsDNA transcription PPARRXRAGGTCAaAGGTCA+GeneResponse element-Protein synthesisFunction

**Why are PUFAs healthy?b-OxidationFA synthesis Triglyceride synthesisPPARFatty acid oxidation genes+SREBP1 SP1/NF-YLipogenic genes-VLDL-TG

**PharmacologicalactivationPhysiologicalactivationNutritionalactivationWY14643 Fasting High fat diet

**PharmacologicalactivationPhysiologicalactivationNutritionalactivation WY14643 Fasting High fat diet- WY+ WYlow fatfastedfedhigh fat PPARa-/- PPARa+/+ PPARa-/- PPARa+/+Kersten et al.012340123401234

**Role of PPARa in the hepatic response to fastingElucidation by employing:k.o.-micespecific ligandstranscriptome analysisIn vitro studies (Promoter studies, ChIP, etc)CMLS, Cell. Mol. Life Sci. 61 (2004) 393416

**Metabolic Syndrome and Diabetes

**FFAMdr2Portal bloodHepatocyteBileWAT

TGGene regulation by fatty acidsABCG5/G8

**What happens during fasting?TGglucoseFFAWATG3PDHAPBloodLiver

**Mouse liver gene expression signatures during fastingMetabolic reprogramming during fasting

**clusterAvg DiffFold-ChangeAcc. No.downclusterAvg DiffFold-ChangeAcc. No.uptranscription factorstranscription factorsSREBP-13104.3D1X61800C/EBPd3.373U1SREBP-110.4580.3D1X62600C/EBPb2.3261.3U1SREBP-18.5172.4D1AA106163CAR2.9134.8U1retinoid O receptor RORgamma4.5267.3D1U09416FXR2.3531.7U1retinoid O receptor RORalpha11.8266.6D2U09419LXRb2110.3U2AA061461AA068578AA067092U39071Y08640U44752hepatic nuclear factor HNF3alpha3.572D2X57638PPAR a 2.6217.8U5M34476RARg3.8100.2U3receptors and binding proteinsreceptors and binding proteinsX70533corticosteroid binding globulin4.32351.5D1X81579insulin-like growth factor binding protein 15.9300.7U4M33324high molecular weight growth hormone receptor3.8168.5D2L05439insulin-like growth factor binding protein 23.41993.4U1AA038239plasma retinol binding protein RBP3.13248.1D3L38613glucagon receptor2.3462.8U2X14961heart fatty acid binding protein H-FABP2.7143.4D1X57796tumor necrosis factor receptor 55 kD3.2166.2U4U40189pancreatic polypeptide/neuropeptide Y receptor3.234.4U3J03398Abcb4 (Mdr2)4.4504.1U1M65034intestinal fatty acid binding protein I-FABP2.4486.5U3amino acid metabolismZ14986adenosylmethionine decarboxylase3.3335.2D1M17030*ornithine transcarbamylase2.33615.5D2X51942phenylalanine hydroxylase2.24171.4D2J02623aspartate aminotransferase1.6783.6D4U38940asparagine synthetase2.2177.9D4U24493tryptophan 2,3-dioxygenase1.74116.4D5X16314glutamine synthetase2925D5nucleotide metabolismX75129xanthine dehydrogenase1.8395.9D1M27695.0urate oxidase2.22848.7D5X56548purine nucleoside phosphorylase21149.7D2other enzymesother enzymesW54790ATP synthase A chain4.4456.7D4X80899SIG81 (cytochrome c oxidase VIIa homologue)2762.5U2W91222cytochrome c oxidase subunit VIIa2.9913.2D5U14390aldehyde dehydrogenase (Ahd3)3.6660.9U3X01756cytochrome c1.71678.7D5Z37107epoxide hydrolase1.83012.6U3U39200epidermal 12(S)-lipoxygenase2.3142D2U33557folylpolyglutamate synthetase2.1648.8U5W41963acetyl-CoA synthetase3.3106.6D2D49744farnesyltransferase alpha1.9475.8U3M27796carbonic anhydrase III8.74283.8D3U12922CD1 geranylgeranyl transferase beta subunit2.1260.1U3X51971carbonic anhydrase V1.7787.4D1J03733ornithine decarboxylase1.6257.8U3AA106634cis-retinol/3-alpha-hydroxysterol short chain dehydr.4.53997.4D5D16333coproporphyrinogen oxidase2.5216.9U3U00445glucose-6-phosphatase1.81587.7D4J02652malate NADP oxidoreductase1.7249U3U27014sorbitol dehydrogenase2.23607.4D2M63245amino levulinate synthase (ALAS-H)2.51842.4D4M74570aldehyde dehydrogenase II2.64177.9D4Metabolic reprogramming during fasting

**How to crack the code?Rosetta Resolver 5/Base 2Bioconductor et al. (WWW)SpotfireMS ExcelPathway assist GeneGo IngenuityThinking!!

**The common diseases are complex:Factors influencing the development of metabolic syndrome MSX13DiabetesObesityHypertensionInflammationHyperlipidemia2

**PharmaNutritionPrevention versus Therapy Nutrition versus PharmaTIME (months/years)DISEASE STATE (arbitrary units) Homeostasis HealthComplex DiseaseDifferent targetsMetabolic stressMetabolic syndrome

**Interplay between diet, organs and metabolic stressSignals gut mucosa: satiety hormones cytokines barrierUnabsorbednutrientsSystemic effects: Glucose intolerance Insulin resistance Lipid disordersAbsorbednutrientsDietEntero- Hepatic CycleHomeostasisby liverAdiposetissueMuscleD Gut contentsDigestionandabsorptionLipids

**Signatures of health & stress -The two hits: Metabolic and pro-inflammatory stress

**Nature reviews/genetics (2003) , 4:315-322HNF, 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 researchKnockout mice is useful

**The smart combination of molecular nutrition and nutrigenomics.Nature reviews/genetics (2003) , 4:315-322

**Strategies we need in gene-nutrient interactions

*Now I am going to switch gears and show a case where we have used the information provided by genomes to test an hypothesis regarding the evolution of a class of cellular proteins.********