Download Lipidomics in Cell Regulation

Lipidomics in Cell Regulation
Lars I Hellgren
Associate Professor
February 24th, 2012
Learning objectives
After this lecture you should be able to:
-Describe the major types of lipids
- Describe the main functions of lipids in the cell
- Describe at least two mechanisms of action by
which lipids regulate cell-metabolism or celldevelopment
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CBS, Department of Systems Biology
Outline
•Why must we bother - Relation between lipid
– patterns and human disease
• What is a lipid – Differerent lipid types.
•How does lipids affect cellular regulation ?
–Effects in membranes
–Direct effects on enzymes
–Effects through lipid receptors
•Lipid pathways  What determines the
lipidome?
•Interpretting the lipidome
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CBS, Department of Systems Biology
Lipids and Human Health
• Cardiovascular diseases – Strongly linked to levels of
different fatty acids and lipid metabolism in the arteries,
in the blood and in the heart
• Insulin resistance/ Type-2 diabetes – Strongly linked
to concentration of certain lipids and lipid metabolism in
skeletal muscles, adipose tissue, the liver and insulin
producing b-cells in the pancreas
• Several rheumatic diseases – Strongly linked to the
concentration of certain fatty acids
• Many cancer forms – Strongly linked to the metabolism
of sphingolipids, such as ceramide and sphingosine-1-P
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CBS, Department of Systems Biology
Lipids – some examples
Fatty acids
Triacylglycerol
R = fatty acids
Phosphoglyceride
Ganglioside GM2
So, what´s a lipid ?
Some examples from the literature
– ”Naturally occurring compounds, which have in common a
ready solubility in organic solvents and low solubiltiy in
water”
– ”Hydrophobic or amphipathic small molecules that may
originate entirely or in part by carbanion-based condensations
of thioesters (fatty acids, polyketides, etc.) and/or by
carbocation-based condensations of isoprene units (prenols,
sterols, etc.)” Fahy et al. (J. Lipid Res., 46, 839-862 (2005))
– ”Lipids are fatty acids and their derivatives, and substances
related biosynthetically or functionally to these compounds. ”
Bill Cristie on www.lipidlibrary.co.uk
–
Lipids – some examples
Fatty acids
Triacylglycerol
R = fatty acids
Glycerophospholipids
Ganglioside GM2
Major Types of Lipids
Fatty acids
Sphingolipids
Glycerophospholipids
Sterols
Sphingosine
Ceramide
cholesterol
Sphingomyelin
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CBS,
Department of Systems Biology
Glycosphingolipids
cholesterolesters
Lipid structures – Fatty acids
 Most abundant: C14 – C24
 0 – 6 double bonds

C16:0
saturated, monounsaturated,
polyunsaturated
 Only minute amounts are free.
C18:1
Arachidonic acid
(C20:4; n-6)
Docosahexaenoic acid (DHA)
(C20:4; n-6)
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CBS, Department of Systems Biology
 Normally constitutents of other
lipids; triacylglycerols,
phosphoglycerides, sphingolipids
etc
 Certain FA are important
regulators of gene-transcription in
glucose and lipid metabolism
 FA – metabolites are important
signalling molecules involved in:
 Induction and resultion of
inflammation (f. ex.
prostaglandins and resolvins)
 Appetite regulation
(endocannabinoids)
Lipid structures – Glycerophospholipids
 Major lipid component of
membranes
 Varying polar headgroups and fatty
acid chains
 Variation in headgroup and fatty acid
chains alter their properties 
altered membrane properties
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CBS, Department of Systems Biology
 Some phosphoglyceride are directly
modulating enzyme activity, f ex
phosphpatidylserine and
Proteinkinase C of the classical type
Glycerophospholipids-variation in structure
30 – 35 different fatty acids are
commonly identified in
glycerophospholipids
Lipid functions in cell biology
The biological membrane
 Defines the cell and the cell organelles
Semipermeable – efflux and influx of polar molecules are controlled
 Is the basis for energy metabolism –
proton-gradients
 Ensure a stable cellular environment
 Provides a 2-D space for efficient chemical reaction
 The lipids creates an optimal environment for protein function in the
membrane
 More than 300 lipid species are found in the plasma membrane
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CBS, Department of Systems Biology
Lipid functions in cell biology
Regulation of gene-transcription
 Transcriptional regulation of genes in glucose and fat metabolism are partly
controlled by lipid levels through lipid-activated transcription factors
Example of lipid regulated transcription factors:
The family of Peroxisome Proliferator Activated- Receptors
(PPAR)
Binding of polyunsaturated fatty
acids, or structures derived from
polyunsaturated fatty acids are
required for their activation.
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CBS, Department of Systems Biology
Picture from Cuzzòcrea , 2006
Lipid functions in cell biology
Lipid signalling – Lipids are important intra- and extracellular
signalling molecules
Prostaglandin and leukotrien
synthesis (Eicosanoids)
Some lipid signalling
molecules
 Eicosanoids
 Resolvins, Neuroprotectins
 Diacylglycerol
 Ceramide
 Sphingosine-1-phosphate
 Ceramide-1-phosphate
 Phosphoinosotides
Inflammation
Vasoconstriction
Gastic mucosal secretion
….
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 etc, etc
Platelet aggregation  blood
clotting
….
CBS, Department of Systems Biology
Lipid functions in cell biology
Lipid signalling
CH3
H2C
CH2
OH
O
+
N
O
O
NH
H3C
OH
CH3
CH2OH
CH
Example 2: The ceramide / Sphingosine-1-P Rheostat
O
O
OH
P
O
O
C
C
HO
O
P
C
NH2
C
C
HO
NH2
C
O
C
C
C
NH
C
O
Sphingomyelin:
Membrane lipid
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Ceramide:
Cell cycle arrest
Terminal differentation
Apoptosis
CBS, Department of Systems Biology
Sphingosine
Sphingosine-1phosphate:
Cell proliferation
Prevent differentiation
Lipid functions in cell biology
Lipid signalling through direct lipid protein interactions
Examples:
or
Protein kinase C – activated by diacylglycerol
ceramide (some types)
Phosphoinositide Dependent Kinase –
Activated trough binding to the membrane lipid
phosphatidylinositol-tris- phosphate
Clinical implications:
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CBS, Department of Systems Biology
Effects of DAG and ceramide on insulin signalling
Insulin receptor
DAG
PKCθ
IRS-1
Serine phosphorylation
inhibits the interaction with
the insulin-receptor
PI-3 K
PDK-1
Ceramid
PKC
PKB
PP2A
Phosphorylation threonin34
inhibits the binding to PIP3 in
the plasma membrane
Dephosphorylation of
serin473 deactivates PKB
Powell et al (2003). Mol. Cell Biology. 23:7794-7808; Stratford et al (2004) J. Biol . Chem.
279:36608-15; Kim et al (2004) J. Clinical Inv. 114:823-827
Fatty acid metabolism
Acetyl-CoA
FFA
FFA
b-oxidationMitochondria
Acyl-CoA
Palmitoyl-CoA
Acyl-Carnithin
Lyso-phosphatidate
Palmital
Sphingosine 1-P
Phosphatidate
DGAT
Diacylglycerol
Triacylglycerol
Phosphoglycerides
Neutral
glycolipids
Ceramide
Sphingomyelin
Sphingosine
FFA
Gangliosides
Lars I. Hellgren
SBE-Symposium 2008
Lipidomics
Lipid composition
Transcriptomes of lipid metabolism
Pathway fluxes
”Downstream” effects of lipid changes
Data integration
Models of how lipidomic alterations are involved in disease pathologies
New therapies
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CBS, Department of Systems Biology
The human plasma lipidome
Quehenberger O et al. J. Lipid Res.
2010;51:3299-3305
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CBS, Department of Systems Biology
Examples on lipids, genes and pathway data
http://www.lipidmaps.org