From Nutrigenomics to nutritional systems biology of fatty acid sensing

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My recent lecture at COSBI June 2011

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From Nutrigenomics to nutritional systems biology of fatty acid sensing

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

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