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Transcript
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 2 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 3 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 4 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 8 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) 9 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 10 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 12 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. 13 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 …. 14 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 15 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: 16 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 19 CBS, Department of Systems Biology The human plasma lipidome Quehenberger O et al. J. Lipid Res. 2010;51:3299-3305 20 CBS, Department of Systems Biology Examples on lipids, genes and pathway data http://www.lipidmaps.org