Download - Lipidomics in Cell Regulation
Lipidomics in Cell Regulation
Lars I HellgrenAssociate Professor
February 24th, 2012
2 CBS, Department of Systems Biology
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 cell-development
3 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
4 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
Lipids – some examples
Fatty acids
R = fatty acidsTriacylglycerol
Phosphoglyceride
Ganglioside GM2
So, what´s a lipid ?
– ”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
–
Some examples from the literature
Lipids – some examples
Fatty acids
R = fatty acidsTriacylglycerol
Glycerophospholipids
Ganglioside GM2
8 CBS, Department of Systems Biology
Major Types of Lipids
Fatty acids Glycerophospholipids
Sphingolipids
Ceramide
Sphingosine
Sphingomyelin
Glycosphingolipids
Sterols
cholesterol
cholesterolesters
9 CBS, Department of Systems Biology
Lipid structures – Fatty acids
C16:0
C18:1
Arachidonic acid(C20:4; n-6)
Docosahexaenoic acid (DHA)(C20:4; n-6)
Most abundant: C14 – C24 0 – 6 double bonds saturated,
monounsaturated, polyunsaturated
Only minute amounts are free. 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)
10 CBS, Department of Systems Biology
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
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
12 CBS, Department of Systems Biology
The biological membrane
Defines the cell and the cell organellesSemipermeable – 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
Lipid functions in cell biology
13 CBS, Department of Systems 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
Lipid functions in cell biology
Example of lipid regulated transcription factors:The family of Peroxisome Proliferator Activated- Receptors (PPAR)
Picture from Cuzzòcrea , 2006
Binding of polyunsaturated fatty acids, or structures derived from polyunsaturated fatty acids are required for their activation.
14 CBS, Department of Systems Biology
Lipid signalling – Lipids are important intra- and extracellular signalling molecules
Lipid functions in cell biology
Eicosanoids Resolvins, Neuroprotectins Diacylglycerol Ceramide Sphingosine-1-phosphate Ceramide-1-phosphate Phosphoinosotides etc, etc
Some lipid signalling molecules
Prostaglandin and leukotrien synthesis (Eicosanoids)
InflammationVasoconstrictionGastic mucosal secretion….
Platelet aggregation blood clotting ….
15 CBS, Department of Systems Biology
Lipid signalling
Lipid functions in cell biology
Example 2: The ceramide / Sphingosine-1-P Rheostat
C
OH
C CO
NH
C O
PO O
OCH2
CH2
N+CH3
CH3CH3
Ceramide:Cell cycle arrestTerminal differentation Apoptosis
Sphingomyelin:Membrane lipid
COH
CC
OH
NH2
Sphingosine
CHC
H2O
H
NH
OH O
COH
CC
O
NH2
P O
O
O
Sphingosine-1-phosphate:
Cell proliferationPrevent differentiation
16 CBS, Department of Systems Biology
Lipid signalling through direct lipid protein interactions
Lipid functions in cell biology
Examples:
Protein kinase C – activated by diacylglycerol or ceramide (some types)
Phosphoinositide Dependent Kinase – Activated trough binding to the membrane lipid phosphatidylinositol-tris- phosphate
Clinical implications:
Insulin receptor
IRS-1
PI-3 K
PDK-1
PKB
DAGPKCθ
Ceramid PKC
PP2A
Effects of DAG and ceramide on insulin signalling
Serine phosphorylation inhibits the interaction with the insulin-receptor
Phosphorylation threonin34 inhibits the binding to PIP3 in the plasma membraneDephosphorylation 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
FFA
Acyl-CoA
Mitochondria
CPT IAcyl-Carnithin
b-oxidation
FFA ACS
Lyso-phosphatidate
Phosphatidate
Diacylglycerol Phosphoglycerides
Triacylglycerol
Palmitoyl-CoASPT
Ceramide
Gangliosides
SphingosineFFA
Sphingosine 1-P
DGAT
Lars I. HellgrenSBE-Symposium 2008
GPAT
Acetyl-CoA
ACC
FAS
Palmital
Neutralglycolipids Sphingomyelin
19 CBS, Department of Systems Biology
Lipidomics
Lipid composition Transcriptomes of lipid metabolismPathway fluxes ”Downstream” effects of lipid changes
Data integration
Models of how lipidomic alterations are involved in disease pathologies
New therapies
20 CBS, Department of Systems Biology
The human plasma lipidome
Quehenberger O et al. J. Lipid Res. 2010;51:3299-3305