Nutrigenomics of FAT
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Transcript of Nutrigenomics of FAT
Nutrigenomics of FAT: What is “good” or “bad” for human health?
Michael MüllerNetherlands Nutrigenomics Centre
& Nutrition, Metabolism and Genomics GroupDivision of Human Nutrition, Wageningen University
2 Meals a day, work as long as possible & embrace challenge
Walter Breuning (1896 - 2011)
We have a tsunami of health problems
100
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% Energy
Low-fat meatChickenEggsFish
FruitVegetables (carrots)NutsHoney
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% Energy
FruitVegetablesBeans
MeatChickenFish
GrainMilk/-productsIsolated CarbohydratesIsolated Fat/OilAlcohol
1.200.000 Generations between feast en famine
Paleolithic era
2-3 Generations in energy abundance
Modern Times
Our “paleolithic” genes + modern diets
Nutrigenomics Quantification of the nutritional genotype-
phenotype
Phenotype
Metabolome
Proteome
Transcriptome
Epigenome
Genotype
Lifestyle
Nutrition
Environment
1 Genotype => 5 nutritional phenotypes
155 kg 76 kg
VLDL LPL
Remnant
FFA
Lipids
Chylomicrons
Organ and systemic responses to dietary lipids
Understanding NutritionHow nutrients regulate our genes: via sensing molecular
switches
Improved organ
capacity by PUFAs
J Clin Invest. 2004;114:94-103J Biol Chem. 2006;28:934-44 Endocrinology. 2006;147:1508-16Physiol Genomics. 2007;30:192-204Endocrinology. 2007;148:2753-63 BMC Genomics 2007; 8:267 Arterioscler Thromb Vasc Biol. 2007;27:2420-7
Am J Clin Nutr. 2007;86(5):1515-23PLOS 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.Plos One 2009;4(8):e6796HEPATOLOGY 2010;51:511-522
Am J Clin Nutr. 2009; 90:415-24Am J Clin Nutr. 2009;90:1656-64Mol Cell Biology 2009;29:6257-67Am J Clin Nutr. 2010;91:208-17BMC Genomics 2009Physiol. Genomics 2009Circulation 2010Diabetes 2010Cell Metabolism 2010Nature 2011
LPL
CE/TG
Chylomicron
CE/TG
Chylomicron remnant
FFA
Angptl4
Kersten, S. et al. Arterioscler Thromb Vasc Biol 2009;29:969-974
Expression profile of ANGPTL4 mRNA in human tissues
Angptl4-\- mice on HFD become very ill
Lichtenstein et al. Cell Metabolism 2010
Inflammatory response independent of microbiota
Lichtenstein et al. Cell Metabolism 2010
Massive enlargement of mesenteric lymph nodes in Angptl4-/- mice fed HFD
Lichtenstein et al. Cell Metabolism 2010
No effect of medium chain or PUFA TGs
Lichtenstein et al. Cell Metabolism 2010
Angptl4 protects against lipolysis and subsequent foam cell formation
Angptl4 protects against lipolysis and subsequent foam cell formation
Adipocytes at the crossroads of energy homeostasis
Normal
Type 2 Diabetes
Visceral Fat Distribution:Normal vs Type 2 Diabetes
Metabolic defects leading to the development of hepatic steatosis
Metabolism & Inflammation
Liver, FAT & NASH/NAFLD
Nonalcoholic Fatty Liver Diseases (NAFLD): Liver component of Metabolic Syndrome
Different stages in NAFLD progression:
Molecular events involved in NASH pathogenesis: Role of PPARa (Endocrinology 2008 & Hepatology 2010) Role Kupffer cells (Hepatology 2010)
Role of macrophages in lipid metabolism (JBC 2008; Cell Metabolism 2010)
hepatic steatosis steatohepatitis (NASH) & fibrosis cirrhosis
Interaction between WAT and liver tissue essential for NASH/NAFLD in C57Bl/6 mice
• Objective: – Nonalcoholic fatty liver disease (NAFLD) is
strongly linked to obesity and diabetes, suggesting an important role of adipose tissue in the pathogenesis of NAFLD.
– Here we aimed to investigate the interaction between adipose tissue and liver in NAFLD, and identify potential early plasma markers that predict NASH.
Experimental Design
• stratificatio
n on body weight
• liver• plasma collection
multiple protein assays
RNA extraction: Affx microarrays
tissue collectionrun-in diet 20 weeks diet intervention
frozen sections: histological feat.
• ep. white adipose tissue
10% low fat diet
(palm oil)
10 LFD
10 HFD
45% high fat diet
(palm oil)
20 LFD
RNA extraction: real-time PCR
paraffin sections: histological feat.
lipid content
quality control & data analysis
pipeline
Mouse genome 430 2.0
0 2 4 8 12 16 20 weeks-3
High fat diet-induced obesity
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0 2 4 8 12 16 20
weeks under diet intervention
BW
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)
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LFLLFH
HFLHFH
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Liver TG content
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TG
/g li
ver
ALT
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ivity
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I)
ALT plasma activity
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Hepatomegaly
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LFL LFH HFL HFH
Adipose dysfunction in HFH mice
Leptin
A subpopulation of mice fed HFD develops NASH
Immunohistochemical staining confirms enhanced inflammation and early fibrosis in HFH mice
Macrophage CD68
Collagen
Stellate cell GFAP
Results I
• Mice exhibited pronounced heterogeneity in liver histological scoring, leading to classification into 4 subgroups: – LF-low (LFL) responders displaying normal liver morphology, – LF-high (LFH) responders showing benign hepatic steatosis, – HF-low (HFL) responders displaying pre-NASH with
macrovesicular lipid droplets, – HF-high (HFH) responders exhibiting overt NASH characterized
by ballooning of hepatocytes, presence of Mallory bodies, and activated inflammatory cells.
Upregulation of inflammatory and fibrotic gene expression in HFH
responder mice
Adipose dysfunction in HFH mice
Change in adipose gene expression indicate adipose tissue dysfunction
Plasma proteins as early predictive biomarker for NASH in C57Bl/6 mice
Conclusions
• Our data support the existence of a tight relationship between adipose tissue dysfunction and NASH pathogenesis.
• It points to several novel potential predictive biomarkers for NASH.
Diabetes. 2010;59:3181-91.
Human applications?Individual protein profiles
Population I (MARIS, n=56)
Van Dijk et al. Plos One 2010
Design of the SFA vs MUFA-rich intervention study
Run-in
SFA-rich diet (n=20)
SFA-rich diet (n=10)
MUFA-rich diet (n=10)
Baseline- Clamp- Adipose tissue
biopsy- Blood sampling
After intervention- Clamp- Adipose tissue
biopsy- Blood sampling
T=0 wks T=2 wks T=10 wks
Van Dijk et al. AJCN 2009
‘Obese-linked’ pro-inflammatory gene expression profile by SFAs
• 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”
SFA diet MUFA diet
Van Dijk et al. AJCN 2009
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
Summary
• Less healthy: Dietary fats rich in long chain saturated fatty acids that can be pro-inflammatory if chronically “overconsumed”
• More favourable: Unsaturated fatty acids (in particular PUFAs from fish oil) have anti-inflammatory properties
• A healthy adipose tissue is essential to efficiently store fat and prevent ectopic fat deposition
• Healthy : Subcutanous fat > visceral fat > ectopic fat : Unhealthy
• Future challenge: To prevent the unhealthy effects of a surplus of added sugars (sucrose, fructose) & high GI carbs– Will be converted into saturated fat– Linked to ectopic fat deposition e.g. NASH– Linked to obesity, diabetes, CVD….– Childhood obesity
Thanks
Lydia AfmanMark BouwensSusan van DijkDiederik EsserSergio Lopez
Lisette de GrootMarianne GeleijnseOndine van de RestMarieke BosEdith FeskensRik HeijligenbergDianne HoelenJeanne de VriesGeert Heidema