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From Nutrigenomics to nutritional systems biology of fatty acid sensing,[object Object],Michael MüllerNetherlands Nutrigenomics Centre,[object Object],& Nutrition, Metabolism and Genomics GroupDivision of Human Nutrition, Wageningen University,[object Object]
The Nutrigenomics challenge: What's healthy?,[object Object]
What do we know about the health network?,[object Object]
We eat different foods,[object Object]
We are different,[object Object]
How many human genes do we have?Not so many but….,[object Object]
Duality of biological information:Epigenetic & Genetic,[object Object]
Nutrigenomics Quantification of the nutritional genotype-phenotype ,[object Object],Lifestyle,[object Object],Nutrition,[object Object],Environment,[object Object]
Phenotype plasticity,[object Object],	Phenotypic plasticity is the ability of an organism to change its phenotype in response to changes in the environment (e.g. nutrition).,[object Object]
Objectives of our mechanistic nutrigenomics research,[object Object],Comprehensively understand the cellular specific responses to dietary lipids.,[object Object],Characterize the role of fatty acid sensing transcription factors such as PPARs.,[object Object],Identify target genes of dietary fatty acids& reconstruct related pathways.,[object Object],Demonstrate organ-specific difference of fatty acid-specific transcriptomes.,[object Object],Characterize the molecular basis for interaction between lipid and inflammatory signaling (related to “two hits” in initiation of organ dysfunction).,[object Object]
Metabolic organs & energy homeostasis,[object Object]
Lipids,[object Object],FFA,[object Object],Remnant,[object Object],LPL,[object Object],VLDL,[object Object],Chylomicrons,[object Object],Organ and systemic responses to dietary lipids,[object Object]
We build databases forevidence-basednutrition,[object Object],Evidence-basedNutrition,[object Object],Genes regulated by fatty acidsGenes regulated by high fat,[object Object],Genes also regulated by inflammation,[object Object],Query,[object Object],DIET,[object Object],GenomeEpigenomeTranscriptomeProteomeMetabolome,[object Object],“DIETome”database,[object Object],Query,[object Object],Nutrigenomics,[object Object],Potential BiomarkersOrgan-specific secreted proteins,[object Object]
How nutrients regulate our genes: via sensing molecular switches,[object Object],Improved organcapacity by PUFAs,[object Object],Am J ClinNutr. 2009; 90:415-24Am J ClinNutr. 2009;90:1656-64Mol CellBiology2009;29:6257-67,[object Object],Am J ClinNutr. 2010;91:208-17BMC Genomics2009,[object Object],Physiol. Genomics2009Circulation 2010Diabetes 2010,[object Object],Cell Metabolism 2010Nature 2011,[object Object],Am J Clin Nutr. 2007;86(5):1515-23,[object Object],PLOS ONE 2008;3(2):e1681 BMC Genomics 2008; 9:231BMC Genomics 2008; 9:262J Biol Chem. 2008;283:22620-7Arterioscler Thromb Vasc Biol. 2009;29:969-74.,[object Object],Plos One 2009;4(8):e6796HEPATOLOGY 2010;51:511-522,[object Object],J Clin Invest. 2004;114:94-103,[object Object],J Biol Chem. 2006;28:934-44 ,[object Object],Endocrinology. 2006;147:1508-16,[object Object],Physiol Genomics. 2007;30:192-204Endocrinology. 2007;148:2753-63 ,[object Object],BMC Genomics 2007; 8:267 Arterioscler Thromb Vasc Biol. 2007;27:2420-7 ,[object Object]
We have to improve existing “biased” pathways,[object Object]
Function of hepatic mouse & human PPARa,[object Object],Studies in mice have shown that PPARa is an important regulator of hepatic lipid metabolism and the acute phase response. ,[object Object],However, little information is available on the role of PPARain human liver. ,[object Object],Here we set out to compare the function of PPARain mouse and human hepatocytes via analysis of target gene regulation. ,[object Object],Primary hepatocytes from 6 human and 6 mouse donors were treated with PPARa agonist Wy14643 and gene expression profiling was performed using Affymetrix GeneChips followed by a systems biology analysis. ,[object Object],Rakhshandehroo M, Hooiveld G, Müller M, Kersten S (2009) Comparative Analysis of Gene Regulation by the Transcription Factor PPARa between Mouse and Human. PLoS ONE 4(8): e6796,[object Object]
Partial conservation of PPARa-regulated genes in hepatocytes,[object Object],between human and mouse,[object Object],between mouse and human,[object Object],PLoS ONE 4(8): e6796. ,[object Object]
Species-specific regulation of two gene sets originating from gene set enrichment analysis (GSEA),[object Object],Glycolysis-gluconeogenesis as a mouse-specific upregulated gene set,[object Object],Xenobiotic metabolism as a human-specific upregulated gene,[object Object],set,[object Object],PLoS ONE 4(8): e6796. ,[object Object]
PPARa controls lipid metabolism & is the hepatic sensor for dietary fatty acids in mice & men,[object Object]
Conclusion I,[object Object],Species-specific differences in PPARa signaling (underlying mechanisms?),[object Object],Common part in PPARa-dependent biology between human & mouse.,[object Object]
Collection of livers,[object Object],Oral gavage,[object Object],PPARα knock-out,[object Object],Removal of food,[object Object],5 am,[object Object],3 pm,[object Object],9 am,[object Object],wild-type,[object Object],78 Affymetrix Mouse Genome 430 2.0 microarrays,[object Object],QPCR,[object Object],Is there a significant role of PPARa in gene regulation by dietary fatty acids in vivo ?,[object Object],Sanderson, PlosONE 2008,[object Object]
Experimental design,[object Object],4 or 5 mice per group, in total 78 arrays,[object Object]
Fatty acids regulate gene expression via PPARa,[object Object],Sanderson, PlosONE 2008,[object Object]
Gene regulation by dietary fat requires PPARa,[object Object],Sanderson, PlosONE 2008,[object Object]
Conclusions II,[object Object],Dietary fatty acids are able to ligand-activate Ppara in mouse liver.,[object Object],The effects of dietary fatty acids on hepatic gene expression are almost entirely mediated by Ppara.,[object Object]
Liver,[object Object],http://pathways.embl.de/,[object Object]
PPARβ/δ but not PPARα serves as plasma free fatty acid sensor in liver,[object Object],Sanderson Mol CellBiology2009 Dec;29(23):6257-67  PPARβ/δ but not PPARα serves as plasma free fatty acid sensor in liver ,[object Object]
The intestine as a gatekeeper,[object Object],Food intake,[object Object],Satiety,[object Object],FGF21ANGPTL4,[object Object],SFAGlucoseFructose,[object Object],LPL,[object Object],Adipokines:,[object Object],Adiponectin,[object Object],Leptin,[object Object],ResistinANGPTL4,[object Object],TNFa,[object Object],etc,[object Object],LPL,[object Object],LPL,[object Object],GI hormones:Insulin,[object Object],GIP,[object Object],GLP1,[object Object],PYY,[object Object],Ghrelin,[object Object],ANGPTL4,[object Object],FGF15/19,[object Object]
The small intestine as primary organ is response to nutrients & food components,[object Object]
A major role for PPARa in intestinal fatty acid sensing ,[object Object],Physiol Genomics. 2007 ;30(2):192-204,[object Object]
Intestinal fatty acid sensing by PPARa,[object Object],Physiol Genomics. 2007 ;30(2):192-204,[object Object]
Intestinal PPAR target genes are largely regulated by dietary PUFAS/MUFAs,[object Object]
Intestine,[object Object]
Comparison intestine / liver,[object Object]
Dose-dependent effects of dietary fat on development of obesity in relation to intestinal differential gene expression in C57BL/6J mice,[object Object],PLOS one 2011,[object Object]
Robust & concentration dependent effects in small intestineDifferentially regulated intestinal genes by high fat diet,[object Object],C1,[object Object],C2,[object Object],C3,[object Object],C4,[object Object],C5,[object Object],C6,[object Object],C7,[object Object],C8,[object Object],C9,[object Object],C10,[object Object],PLOS one 2011,[object Object]
Heat map diagrams of fat-dose dependently regulated genes, categorized according to their biological function ,[object Object],PLOS one 2011,[object Object]
Cellular localization and specific lipid metabolism-related function of fat-dose dependently regulated genes ,[object Object],PLOS one 2011,[object Object]
The intestinal tube model for lipid absorption ,[object Object],40 cm,[object Object],4 cm,[object Object],C1,[object Object],C2,[object Object],C3,[object Object],C4,[object Object],C5,[object Object],C6,[object Object],C7,[object Object],C8,[object Object],C9,[object Object],C10,[object Object],Microbiota,[object Object],             10% FAT ,[object Object],                              45% FAT,[object Object]
The PPAR tube model,[object Object],C1,[object Object],C2,[object Object],C3,[object Object],C4,[object Object],C5,[object Object],C6,[object Object],C7,[object Object],C8,[object Object],C9,[object Object],C10,[object Object]
Conclusions III,[object Object],Transcriptomics is powerful to comprehensively screen for PPAR target genes in various organs.,[object Object],Challenge is get organ & cell specific information on role of PPARs, target genes and (dietary) ligands.,[object Object],Future goal is to construct quantitative models for PPAR function related to organ health / metabolic plasticity.,[object Object]
Controllability of complex networks,[object Object],Naturally occurring networks, such as those involving gene regulation, are surprisingly hard to control. To fully control a gene regulatory network, roughly 80% of the nodes should be driver nodes. (in contrast to social networks),[object Object],To a certain extent this is reassuring, because it means that such networks are fairly immune to hostile takeovers: a large fraction of the network's nodes must be directly controlled for the whole of it to change. ,[object Object],By contrast, engineered networks are generally much easier to control, which may or may not be a good thing, depending on who is trying to control the network.,[object Object],This may explain also the big difference between “food & pharma”.,[object Object],Yang-Yu Liu, Jean-Jacques Slotine& Albert-LászlóBarabási,[object Object],Nature 473, 167–173,[object Object]
Difference between Food & Pharma,[object Object],Drugs,[object Object],A,[object Object],B,[object Object],C,[object Object],PPARg,[object Object],PPARb,[object Object],PPARa,[object Object],Receptor,[object Object],C3,[object Object],C2,[object Object],C1,[object Object],Fatty acids,[object Object],F,[object Object],C6,[object Object],C5,[object Object],C4,[object Object],Multiple targets,[object Object]
Chylomicron,[object Object],CE/TG,[object Object],Angptl4,[object Object],LPL,[object Object],CE/TG,[object Object],FFA,[object Object],Chylomicron remnant,[object Object]
Angptl4- mice on HFD become very ill,[object Object],Lichtenstein et al. Cell Metabolism 2010,[object Object]
Massive enlargement of mesenteric lymph nodes in Angptl4-/- mice fed HFD,[object Object],Lichtenstein et al. Cell Metabolism 2010,[object Object]
No effect of medium chain or PUFA TGs,[object Object],Lichtenstein et al. Cell Metabolism 2010,[object Object]
Angptl4 protects against lipolysis and subsequent foam cell formation,[object Object]
Angptl4 protects against lipolysis and subsequent foam cell formation,[object Object]
Sander KerstenLinda SandersonNatasha Georgiadi,[object Object],Mark BouwensLydia Afman,[object Object],Guido Hooiveld,[object Object],Meike Bunger,[object Object],Philip de Groot,[object Object],Mark Boekschoten,[object Object],Nicole de Wit,[object Object],Mohammad Ohid Ullah,[object Object],Christian Trautwein,[object Object],Folkert Kuipers,[object Object],Ben van Ommen + many more,[object Object]

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From Nutrigenomics to nutritional systems biology of fatty acid sensing

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