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Sevilla may 2012 nutrition & inflammation

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Presentation at a conference on "Biomarkers of Inflammation" in Sevilla / Spain.

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Sevilla may 2012 nutrition & inflammation

  1. 1. Nutrition & Inflammation Michael Müller Netherlands Nutrigenomics Centre & Nutrition, Metabolism and Genomics Group Division of Human Nutrition, Wageningen University
  2. 2. I will not talk about theAnti-inflammatory foods
  3. 3. Content “Nutrition & Inflammation” 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 Examples from Human Nutrigenomics Conclusions
  4. 4. The two hitsNon-resolving metabolic & proinflammatory stress 2003
  5. 5. “2 hits” in Metabolic SyndromeToo much metabolic & inflammatory stress 2012
  6. 6. PPARaTHE LIVER & THE 2 HITS
  7. 7. More steatosis in mouse livers from PPARa -/- mice on a high fat diet Endocrinology. 2007 Jun;148(6):2753-63
  8. 8. PPARa controls acute phase response induced by HF dietsEndocrinology. 2007 Jun;148(6):2753-63
  9. 9. 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 Endocrinology. 2007 Jun;148(6):2753-63
  10. 10. OBESITY & NASHINTERACTION OF WAT & LIVER
  11. 11. 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
  12. 12. 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
  13. 13. A subpopulation of mice fed HFD develops NASH
  14. 14. Immunohistochemical staining confirms enhanced liver inflammation and early fibrosis in HFH mice Macrophage CD68 Collagen Stellate cell GFAP
  15. 15. Upregulation of inflammatory and fibrotic gene expression in HFH responder mice
  16. 16. Adipose dysfunction in HFH mice
  17. 17. Change in adipose gene expressionindicate adipose tissue dysfunction
  18. 18. Plasma proteins as early predictivebiomarker for NASH in C57Bl/6 mice
  19. 19. Plasma proteins as early predictivebiomarker for NASH in C57Bl/6 mice Multivariate analysis of association of protein plasma concentrations with final liver triglyceride content
  20. 20. Conclusions• The data support the existence of a tight relationship between adipose tissue dysfunction and NASH pathogenesis. Duval et al. Diabetes 2010
  21. 21. How inflammation is initiated and developed in obesity Annu. Rev. Nutr. 2012. 32:6.1–6.26
  22. 22. TOO MUCH SATURATED FAT& MACROPHAGES
  23. 23. Chylomicron CE /TG Angptl4 LPL CE/TG FFA Chylomicron remnant
  24. 24. Examination of the role of Angptl4 under conditions of lipid overload Low fatAngptl4 +/+ High fat Low fatAngptl4 -/- High fat
  25. 25. Angptl4-- mice on HFD become very ill
  26. 26. Systemic inflammation in Angptl4-/- mice fed HFD Angptl4+/+ Angptl4-/-
  27. 27. Inflammatory response independent of microbiota
  28. 28. No effect of medium chain or PUFA TGs
  29. 29. Massive enlargement of mesenteric lymph nodes in Angptl4-/- mice fed HFD
  30. 30. Angptl4 protects against lipolysis and subsequent foam cell formation
  31. 31. Angptl4 protects against lipolysis and subsequent foam cell formation
  32. 32. 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
  33. 33. PLoS ONE 5(12): e14422HUMAN NUTRIGENOMICS
  34. 34. Fish-oil supplementation induces anti-inflammatory gene expression profiles in human blood mononuclear cells Less inflammation & decreased pro-arteriosclerosis markers Bouwens et al. Am J Clin Nutr. 2009
  35. 35. “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
  36. 36. 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 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).
  37. 37. Sander KerstenRinke StienstraLydia AfmanGuido HooiveldMark BoekschotenLaetitia LichtensteinCaroline Duval& NMG groupChristian TrautweinFolkert KuipersBen van Ommen& many more

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