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Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress
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Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress

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My 1. talk Oct3 2012 at #INCON12 Costa Rica …

My 1. talk Oct3 2012 at #INCON12 Costa Rica
Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress

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  • A subpopulation of mice fed HFD develops NASH. Haematoxylin and eosin staining (D) and oil red O staining (E) of representative liver sections of the 4 subgroups
  • (Immuno)histochemical staining confirms enhanced inflammation and early fibrosis in HFH miceImmunohistochemical staining of macrophage activation in representative liver section of HFL and HFH mice using antibody against the specific macrophagemarker Cd68Collagen staining using fast green FCF/sirius red F3B. Staining of stellate cell activation using antibody against GFAP.
  • - Number of genes up- or down-regulated in the various subgroups in comparison to the LFL mice, as determined by Affymetrix GeneChip analysis. Genes with a p-value below 0.05 were considered significantly regulated. - Heat map showing changes in expression of selected genes involved in lipid metabolism, inflammation and fibrosis in liver. Changes in gene expression of selected genes as determined by real-time quantitative PCR. Mean expression in LFL mice was set at 100%. Error bars reflect standard deviation. Bars with different letters are statistically different (P<0.05 according to Student’s t-test). Number of mice per group: n=4 (LFL, HFL, HFH), n=6 (LFH).
  • Haematoxylin and eosin staining of representative adipose tissue sections. Immunohistochemical staining of macrophages using antibody against Cd68. Collagen staining using fast green FCF/sirius red F3B.
  • Adipose tissue mRNA expression of a selected group of genes was determined by quantitative real-time PCR after 21 weeks of dietary intervention. Mean expression in LFL mice was set at 100%. Error bars reflect standard deviation. * = significantly different from HFL mice according to Student’s t-test (P<0.05). Number of mice per group: n=4 (LFL, HFL, HFH), n=6 (LFH).
  • . A) Plasma concentration of haptoglobin, TIMP-1, IL-1β, leptin and insulin were determined by multiplex assay at specific time points during the 21 weeks of dietary intervention after a 6h fast. White squares: LFL, Light grey squares: LFH, dark grey squares: HFL, black squares: HFH. Error bars reflect standard deviation. * = significantly different from HFL mice according to Student’s t-test (P<0.05). Number of mice per group: n=4 (LFL, HFL, HFH), n=6 (LFH).
  • Graphs illustrating the result of multivariate analysis showing the association of protein plasma concentrations at various time points with final liver triglyceride content. Significant proteins display an inverse RSD value higher than 2 (bold line indicates the inverse RSD threshold value of 2).RSD = Relative standard deviation.
  • Transcript

    • 1. Nutrigenomics of the two hits: non-resolving metabolic and pro-inflammatory stress Michael Müller Netherlands Nutrigenomics Centre & Nutrition, Metabolism and Genomics Group Division of Human Nutrition, Wageningen University @nutrigenomics
    • 2. I will not talk aboutAnti-inflammatory foods
    • 3. Content The two hits: Non-resolving metabolic & pro-inflammatory stress The liver & the two hits Obesity & NASH - Interaction of the white adipose tissue & the liver Too much saturated fat & macrophages Human Nutrigenomics examples Conclusions
    • 4. A consideration of biomarkers to be used for evaluation of inflammation in human nutritional studies ILSI working group BJN 2012 submitted
    • 5. The two hitsNon-resolving metabolic & proinflammatory stress 2003
    • 6. “2 hits” in Metabolic SyndromeToo much metabolic & inflammatory stress 2012
    • 7. PPARaTHE LIVER & THE 2 HITS
    • 8. More steatosis in mouse livers from PPARa -/- mice on a high fat diet Stienstra R, Mandard S, Patsouris D, Maass C, Kersten S, Müller M PPAR{alpha} protects against obesity-induced hepatic inflammation Endocrinology. 2007 Jun;148(6):2753-63
    • 9. PPARa controls acute phase response induced by HF diets Stienstra R, Mandard S, Patsouris D, Maass C, Kersten S, Müller M PPAR{alpha} protects against obesity-induced hepatic inflammation Endocrinology. 2007 Jun;148(6):2753-63
    • 10. Increased plasma levels of chemokines in HF-diet fed PPARa -/- mice Wildtype PPARα-/-Chemokine Low fat diet High fat diet Low fat diet High fat dietMCP-1 (CCL2) 18 29 37 75Mip1α (CCL3) 260 260 200 160Mip-1β (CCL4) 28 12 43 69MCP-3 (CCL7) 52 54 52 70Eotaxin (CCL11) 793 780 753 879MCP-5(CCL12) 23 22 25 36Mip-1γ (CCL15) 8.6 9.8 14 14Mip-3β (CCL19) 140 110 110 160MDC (CCL22) plasma (n=5) was used for determining the concentration of multiple chemokines Pooled mouse 82 84 92 99 (Rules Based Medicine). pg/ml plasma, except for Mip-1γ (ng/ml plasma).Mip-2 (CXCL2) 12 15 14 18IP-10 (CXCL10) 28 31 46 109
    • 11. de Wit NJ, Afman LA, Mensink M, Müller M. Phenotyping the effect of diet on non- alcoholic fatty liver disease J Hepatol 2012
    • 12. OBESITY & NASHINTERACTION OF WAT & LIVER
    • 13. Interaction between WAT and liver tissue essential for NASH/NAFLD in C57Bl/6 mice run-in diet 20 weeks diet intervention tissue collection • stratification • plasma collection • liver on body weight frozen sections: histological feat. multiple protein assays lipid content RNA extraction: Affx microarrays 10 LFD-3 20 LFD 0 2 4 8 12 16 20 weeks quality control & 10 HFD Mouse data analysis 10% low genome pipeline fat diet 45% high 430 2.0 (palm oil) fat diet (palm oil) • ep. white adipose tissue paraffin sections: histological feat. RNA extraction: real-time PCR
    • 14. High fat diet-induced obesity 25 LFL HFL LFH HFH 20 BW gain (g) * * 15 ** * 10 * * * 5 * 0 0 2 4 8 12 16 20 weeks under diet intervention Liver TG content Hepatomegaly ALT plasma activity 200 10 100 Ratio LW/BW (%) *** ALT activity (UI)mg TG/g liver 160 8 ** *** 80 120 ** 6 60 * 80 4 40 * * 40 2 20 0 0 0 LFL LFH HFL HFH
    • 15. A subpopulation of mice fed HFD develops NASH
    • 16. Immunohistochemical staining confirms enhanced liver inflammation and early fibrosis in HFH mice HFL HFH Macrophage CD68 Collagen Stellate cell GFAP
    • 17. Upregulation of inflammatory and fibrotic gene expression in HFH responder mice
    • 18. Adipose dysfunction in HFH mice
    • 19. Change in adipose gene expressionindicate adipose tissue dysfunction
    • 20. Plasma proteins as early predictivebiomarker for NASH in C57Bl/6 mice
    • 21. Plasma proteins as early predictivebiomarker for NASH in C57Bl/6 mice Multivariate analysis of association of protein plasma concentrations with final liver triglyceride content
    • 22. Conclusions• The data support the existence of a tight relationship between adipose tissue dysfunction and NASH pathogenesis. Duval et al. Diabetes 2010
    • 23. How inflammation is initiated and developed in obesity Annu Rev Nutr. 2012 Mar 9.
    • 24. TOO MUCH SATURATED FAT& MACROPHAGES
    • 25. Chylomicron CE /TG Angptl4 LPL CE/TG FFA Chylomicron remnant
    • 26. Examination of the role of Angptl4 under conditions of lipid overload Low fatAngptl4 +/+ High fat Low fatAngptl4 -/- High fat
    • 27. Angptl4-- mice on HFD become very ill
    • 28. Systemic inflammation in Angptl4-/- mice fed HFD Angptl4+/+ Angptl4-/-
    • 29. Inflammatory response independent of microbiota
    • 30. No effect of medium chain or PUFA TGs
    • 31. Massive enlargement of mesenteric lymph nodes in Angptl4-/- mice fed HFD
    • 32. Angptl4 protects against lipolysis and subsequent foam cell formation
    • 33. Angptl4 protects against lipolysis and subsequent foam cell formation
    • 34. Conclusion• A high saturated fat diet causes massive inflammation in Angptl4-/- mice originating in mesenteric lymph nodes.• In the absence of this protective mechanism, feeding a diet rich in saturated fat rapidly leads to enhanced lipid uptake into MLN-resident macrophages, triggering foam cell formation and a massive inflammatory response. Lichtenstein et al. Cell Metab. 2010
    • 35. Nutritional regulation of immune capacity Veldhoen M, Brucklacher-Waldert V. Dietary influences on intestinal immunity. Nat Rev Immunol. 2012; 12 (10):696-708
    • 36. Human study: Plasma Protein Profiling Reveals Protein Clusters Related to BMI and Insulin Levels in Middle-Aged Overweight Subjects AIM• Associate plasma protein profiles with BMI• Identify potential marker profile of early disease state . PLoS One. 2010 Dec 23;5(12):e14422
    • 37. We are different“Personal” systemic inflammatory states .PLoS One. 2010 Dec 23;5(12):e14422
    • 38. Human nutrigenomics studyDietary fat and inflammation in adipose tissue ? Change in diet composition Van Dijk et al. AJCN 2009 de Luca, C and Olefsky JM, Nature Medicine 12, 41 - 42 (2006)
    • 39. Design of the SFA vs MUFA-rich intervention studyT=0 wks T=2 wks T=10 wks Run-in SFA-rich diet (n=10) SFA-rich diet (n=20) MUFA-rich diet (n=10) Baseline After intervention - Clamp - Clamp - Adipose tissue biopsy - Adipose tissue biopsy - Blood sampling - Blood sampling Van Dijk et al. AJCN 2009
    • 40. “Obese-linked” pro-inflammatorygene expression profile by saturated fatSFA diet MUFA diet • The SFA-rich diet: • Induces a pro- inflammatory obese-linked gene expression profile • Decreases expression and plasma level of the anti- inflammatory cytokine adiponectin • “Personal Transcriptomes” Van Dijk et al. AJCN 2009
    • 41. Fish-oil supplementation induces anti-inflammatory gene expression profiles in human blood mononuclear cells Less inflammation & decreased pro-arteriosclerosis markers = Anti-immuno-senescence Bouwens et al. Am J Clin Nutr. 2009
    • 42. General conclusions• (Over)nutrition and inflammation are intimately linked => non-resolving metabolic and pro-inflammatory stress (the two hits).• It will be essential to get a better understanding of the very early events that lead to non-resolving organ inflammation and the precise role of nutrition (causal or preventive) in this pathophysiological development.• We need biomarkers specifically for organ function (“2 hit state”) to be able to specifically target and modulate.• The challenge will be the translation of the findings from mice studies to the human situation (“individual” health).
    • 43. Sander KerstenRinke StienstraLydia AfmanGuido HooiveldMark BoekschotenLaetitia LichtensteinCaroline Duval& NMG groupChristian TrautweinFolkert KuipersBen van Ommen& many more

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