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


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


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


Major Types of Lipids

Fatty acids Glycerophospholipids

Sphingolipids

Ceramide

Sphingosine

Sphingomyelin

Glycosphingolipids

Sterols

cholesterol

cholesterolesters


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)


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


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


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)

Picture from Cuzzòcrea , 2006

Binding of polyunsaturated fatty acids, or structures derived from polyunsaturated fatty acids are required for their activation.


Lipid signalling – Lipids are important intra- and extracellular signalling molecules


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 ….


Lipid signalling


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


Lipid signalling through direct lipid protein interactions


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


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


The human plasma lipidome

Quehenberger O et al. J. Lipid Res. 2010;51:3299-3305

Examples on lipids, genes and pathway data

http://www.lipidmaps.org

http://www.lipidmaps.org/

lipidomics in cell regulation

Documents

examples fatty acids

lipid differerent lipid

lipid patterns

fatty acid chains variation

lipids triacylglycerols

lipid metabolismfa metabolites

lipid receptorslipid

metabolism of sphingolipids