NBA12 nutrient sensing
12 important questions on NBA12 nutrient sensing
What are the intracellular nutrient sensors?
fats
CHO
- Nuclear receptors are ligand-activated transcription factors
- The human genome encodes for 48 nuclear receptors
- Some nutrients / metabolic intermediates are very potent activators of nuclear receptors
Nuclear receptors regulate gene expression
Which receptors are present in the
- serum
- liver
- muscle
- arterial macrophage
- intestine
- fat
- serum
- PPARy - decreased lipid concentration
- LXR - increased reverse cholesterol transport
- liver
- LXR - increased cholesterol catabolism, storage, and excretion - increased fat synthesis
- FXR - decreased synthesis of bile acids and fatty acids
- PPARa - increased fat oxidation - increased fasting response
- muscle
- PPARy - increased insulin action
- PPARa - increased fat oxidation
- PPARd - increased energy expenditure - increased fat oxidation
- arterial macrophage
- LXR
- PPARa
- PPARd
- intestine
- LXR - decreased cholesterol absorption
- FXR - increased bile salt recirculation
- PPAR - improved lipid handling
- fat
- PPARy
- PPARd
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What does the bile acids activate?
IMAGE
NRs: absorbing the good, neutralising the bad
in entreocytes - portal circulation
VDR; FXR; PXR; CAR
vitD; bile acids; xenobiotics; xenobiotics
Phase 1 - oxidation/reduction
Phase 2 - conjugation
Phase 3 - transport
binding of the bile acids or ...
sensing mechanism for enterocytes
What does the fatty acids activate? Which NR
fatty acids --> PPARa --> PPARa + RXR --> gene transcription
RXR - vitamin A is needed
Fatty acids activate the NR PPARa, explain
- ligand
- PUFAs WY 14,643
- Retinoic acid
- PPARa + RXRa
- gene transcription
- mRNA
- protein synthesis
What happens with activation of
- pharmacological
- physiological
- nutritional
Typical experiment: investigating the role of PPARa in the small intestine using a genomics approach
study the effects of the synthesis PPARs ligend WY-14,643 on gene expression in the small intestine of wild cypress and PPARa -/- mice
- Mice have free access to chow and water
- after five days, animal are anesthetized and killed
- where after the organs are removed
- RNA is isolated
- its quality checked (ratio 2:1)
- the arrays are scanned
- and now the hard work starts ...
Conclusion
- by activating PPARa, fatty acids reprogram enterocytes, shifting them towards increased lipid handling capacity and reduced immune surveillance
What is the hard work of the mice study?
- Quality of the arrays
- validation
- data analyses
- biological interpretation!
What to do with your gene lists?
- Ontology / gene sets
- ErmineJ
- gene set enrichment analysis
- pathway analysis
- GenMAPP
- ingenuity patyway analysis
- metacore
- clustering / time course
- spotfire
Functional implications: metabolic pathways
Functional implications: regulatory precesses
- intracellular free fatty acid pool
- glucose metabolism
- membrane lipid transporters
- fatty acid binding
- fatty acid catabolism
- biogenesis
- omega oxidation
Functional implications: regulatory precesses
- intracellular free fatty acid pool
- immune response & cell adhesion
- apoptosis & cell cycle
- G-coupled receptor & signal transduction
- transcription factors
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