EASL PGC 2005 Paris

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Prof. Michael Müller, Ph.D. Chair Nutrition,
Metabolism and Genomics Division of Human
Nutrition Wageningen University Director
Innovative Cluster Nutrigenomics Wageningen
Centre for Food Sciences michael.muller_at_wur.nl
http//nutrigene.4t.com
HOW GENOMICS TOOLS CAN HELP TO UNDERSTAND LIVER
(PATHO)PHYSIOLOGY

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Role of the liver in the regulation of energy
homeostasis
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Transcription-factor pathways mediating
nutrient-gene interaction
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Functions of PPARs
Fat sensors
PPARa
PPARg
PPARb

• Nutrient metabolism
• (lipid, glucose, AAs)
• - Proliferation
• - Inflammation

- Lipid and glucose metabolism - Cell cycle
control - Inflammation
- Lipid metabolism - Keratinocyte
differentiation - Inflammation
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PPARa is particularly important during fasting
triglycerides
FFA
Acyl-CoA
TG
Acetyl-CoA CO2
Ketone bodies
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Role of PPARa in the hepatic response to fasting

• Elucidation by employing
• k.o.-mice
• specific ligands
• transcriptome analysis
• In vitro studies (Promoter studies, ChIP, etc)

CMLS, Cell. Mol. Life Sci. 200461393-416
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Effect of PPARa deletion according to Affymetrix
chip analysis
Down-regulated in PPARa -/-
Up-regulated in PPARa -/-
- fatty acid oxidation/ ketogenesis -
gluconeogenesis - sterol metabolism - heme
synthesis
- amino acid metabolism - acute phase
genes - inflammatory response
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Model for role of PPARs in glycerol metabolism
J Clin Invest. 2004 Jul114(1)94-103
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Plasma Free Fatty Acids are elevated in obesity
FFA
FFA
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High fat and hepatic gene expression
Cell. 2005 Jan 28120(2)261-273. Hyperlipidemic
Effects of Dietary Saturated Fats Mediated
through PGC-1beta Coactivation of SREBP. Lin J,
Yang R, Tarr PT, Wu PH, Handschin C, Li S, Yang
W, Pei L, Uldry M, Tontonoz P, Newgard CB,
Spiegelman BM.