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A systems approach to pathways and networks involved in lipid
metabolism in macrophage activation
the LIPID MAPS ConsortiumUniversity Of California San Diego
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Signaling Pathways
Lipid Metabolic Pathways
LipidAssociated
Proteins
LipidMetabolites
Gene expressionProtein expressionEnzyme activation
Cellular Networks
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Induction of inflammatory and Induction of inflammatory and immune response genesimmune response genes
Cytokines (IL-1Cytokines (IL-1, TNF, TNF), ), Tissue factor, B7, etc.Tissue factor, B7, etc.
MAP3KMAP3K
(Proteolysis)(Proteolysis)
Macrophage or endothelialMacrophage or endothelial cell membranecell membrane
Direct ActivationDirect Activation
ACTIVATE RAW CELLS WITH
Kdo2-Lipid A
LIPID MAPS
TM
Measure time series of Gene, Lipid, protein and Cytokine Responses
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MS MS MSMS MS MSMS MS MS
MS MS MSMS MS MSMS MS MS
MS MS MSMS MS MSMS MS MS
BioReplicates
TechReplicates
Mass SpecRuns
Layers of Replications and Measurements
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Lipidomics Data Display : Gene array-search by pathway http://www.lipidmaps.org/data/results/raw2647/microarray/
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Lipid Pathways and Networks:Visualization toolsVANTED: Displaying lipidomic timecourse data
http://vanted.ipk-gatersleben.de/
Hyperlink toprotein DB
Hyperlink to lipid DB
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Fatty Acids: Omega-9 polyunsaturated and straight chain fatty acids
Integrated lipids, genes, and pathways data across timecourseexperiments for RAW 264.7 cells treated with Kdo2-lipid Awww.lipidmaps.org
LIPID MAPS funded by Glue Grant from:
www.nigms.nih.gov
Fatty Acids: Omega-3 and Omega-6 polyunsaturated fatty acids
Fatty Acids: Eicosanoids
Sterols Glycerophospholipids
Sphingolipids
Overview
PLA
Acetyl CoAcarboxylase
Mal
ony-
CoA
deca
rbox
ylas
e
Fatty acidsynthase
Carnitine Palmitoyl Transferase (CPT-1)
KDO2-lipid A
DNAcytosol
ACS
mitochondria
Acyltransferaseslipases
PLC
TLR4
Microarray results
Metabolic pathwaySignaling pathway
Energy metabolism
HMG-CoAsynthase
HMG-CoAreductase
Serine Palmitoyltransferase
Rate limiting step
Physical interaction
Sterol O-Acyltransferases
LCAT
LDL HDL
ABCA1 ABCG1
ReceptorsProteins
Lipid rafts
PPAR
Fatty Acid
FAT/CD36 FATP
Malonyl-CoA
Acetyl-CoA
HMG-CoA
Acyl-CoA
Citrate
Acyl-CoACitrate
Sphingolipids
Fatty Acids
Glycerolipids
Glycerophospholipids
SterolsIsoprenoidsCE
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2003
Ligand Screen – Time Course
cAMP0.5’1’
3’8’
20’
PhosphoProtein
2.5’5’
15’30’
MicroArray
30’1 hr
2 hr4 hr
Ca++ 10’
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2003
Group Ligand Calcium Cyclic AMP P-Protein Blots Genes Other
Gi S1P ++ + E/A/R SomeSDF ++ + E/A/R SomeBLC ++ + E/A/R SomeELC ++ + E/A/R SomeSLC ++ + E/A/R Some
Gs Terbutaline 0 ++++ 0 SomePGE2 0 ++ (sust) 0 Some
2-MA (?) 0 + 0 Some
Gq & Gs LPA ++ (fast) ++ 0 Some
BCR Antigen ++++ 0 E/A/R Lots Proliferation
IL4 IL4 0 0 Stat 6 Lots
CD40 Anti-CD40 0 0 Delayed E/A/R Lots Proliferation
IL10 IL10 0 0 Stat 3 Yes
BAFF BAFF 0 0 0 Yes Viability
TNF TNFalpha 0 0 0 YesIGF IGF1 0 0 0 YesBOMB BOM 0 0 0 YesfMLP fMLP 0 0 0 YesIFN IFG 0 0 0 YesLeukotriene LTB4 0 0 0 YesNeurokinin NKB 0 0 0NGF NGF 0 0 0 Yes
Summary of Ligand Screen Responses