Hypoxic Regulation of Lipid Metabolism

M.C.PrabhathUniversity of Sri Jayawardenepura Sri Lanka 4th Year 2nd Semester03.03.2016Hypoxic Regulation of Lipid Metabolism1

ContentIntroductionLipidsMetabolismHypoxia and Hypoxic conditionsRegulation of Lipid metabolism by HIFs Hypoxic regulation of Glutamine metabolism suports lipid synthesis.Hypoxia related lipid peroxidation.Changes in Lipid Metabolism with Hypoxia as an environmental stress.Hypoxia,Lipid Metabolism and cancerDiscussion References.

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IntroductionLipids play a main role in cellular activities.Fatty acids as a precursor.Synthesis and degradationHypoxic conditions Hypoxic regulation of lipid metabolism

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Lipids4Heterogeneous group of compoundsOrganic substances containing C,H and OSolubility - Relatively insoluble in water - soluble in nonpolar solvents

Classification of Lipids 5Simple lipids Complex lipids Derived lipids

Metabolism 6Metabolism is the term used to describe the interconversion of chemical compounds in the body , the pathways taken by individual molecules, their interrelationships, and the mechanisms that regulate the flow of metabolites through the pathways - Harpers illustrated Biochemistry 29th Edition

7Anabolic pathways Catabolic pathways

8Lipid metabolism is concerned mainly with fatty acids . Fatty acids Acetyl-CoACO2 + H2OCholesterol and other steroids Ketone bodies

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Figure- Overview of the fatty acid metabolism Source- Hrpers illustrated Biochemistry

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Hypoxia and Hypoxic conditions 11Oxygen is essential for the growth and development of multicellular organisms.Mammals have evolved a physiological network to maintain homeostasis.That involves Capture Binding Transport Delivery of molecular oxygen. - Giaccia et al .,2004

12Hypoxia is the condition in which dissolved oxygen is below the level necessary to sustain most animal life generally defined by dissolved oxygen levels below 2mg/l. - Rankin et al.,2009

13For cells to adapt to hypoxic conditions they must be able to sense changes in Oxygen and respond accordingly.The initiation of these responses can be rapid and involve transcriptional and post transcriptional mechanisms .

14Hypoxic cells activate a number of pathways that affect cell signaling and gene regulation.One of the best described mechanisms by which hypoxic cells adapt to their hostile environment is through the activation of Hypoxia Inducible transcription Factors. - Parathath et al.,2011

15HIF-1

HIF-1 -Oxygen liable protein Stabilized in Hypoxic conditionsMany genes are regulated by hypoxia and HIFs Hypoxia Inducible Factors A common mechanism of Lipid Accumulation?

HIF-1HIF-1

HIF-1 and HIF-2 inhibits de novo fatty acids synthesis and b-oxidation, respectively, in the liver. In addition, HIF-2 also stimulates lipid droplet formation to promote triacylglycerol storage. Although HIF-mediated regulation of lipid metabolism is complicated, HIF activation appears to lead to reduction in consumption of both ATP and oxygen.

16Figure- HIFS mediated lipid metabolism in liverSource-Goda and Kanai , 2012

Hypoxic Regulation of Glutamine Metabolism Supports Lipid Synthesis! 17

18Glutamine is the most abundant amino acid in blood.It is second only to Glucose as a carbon source for energy production and anabolic processes.

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20Hypoxia HIF- 1Pyruvate Dehydrogenase KinasePyruvate Acetyl Co A

C?

21Cells under hypoxia take up glutamine at higher levels than under normoxia and use it for lipid synthesis.

Using this approach it was found that rather than generating citrate going through the forward oxidative direction of the TCA cycle,glutamine utilzes the reductive carboxylation of glutamine derived alpha keto glutarate.Experiment !!!!

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23Hypoxia VHL deletion

HIF-1 Stable or Mitochondrial respiration is limitedGlutamine Cytoplasmic IDH 1Mitochondrial IDH 2 Acetyl Co-A LIPIDS

Reductive Glutamine Metabolism

Lipid degradation under hypoxic regulation 24

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Lipid Peroxidation26Can be defined as the oxidative deterioration of lipids containing any number of carbon carbon double bonds.An excessive load of reactive oxygen species generated under hypoxia conditions may result in cell injury and dysfunction.ROS affect lipids specially unsaturated fatty acids.

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Changes in Lipid metabolism with Hypoxia as an environmental stress28Mammalian plasma free fatty acids have been measured at high altitude,they are always elevated and this has pften been attributed to an increased reliance on lipid metabolism at altitudes to conserve valuble carbohydrate stores.Anoxia and hypoxia cause opposite effects on plasma free fatty acid in tolerant and intolerant species.

Hypoxia, Lipid Metabolism and Cancer29Rapid Proliferation Daughter CellsConstant supply of Building Blocks LIPIDSSignaling functions Structural functions

30Cancer cells prefer to generate lipids de novo rather than use them directly from the environment. - Anastasiou and Cantley, 2012

Tumor hypoxia Situation where tumor cells have been deprived of Oxygen .

31In order to support continuous growth and proliferation in challenging hypoxic environments cancer cells are found to alter their metabolism.Warburg effect Lipid metabolism is sucessfully carried out by tumor hypoxic microenvironment via glutamine metabolism.Therapeutic targeting SIBIMRT (Simiultaneously integrated boost intensity modulated radiation therapy.Hypoxia activated pro drugs.

Summary !32

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References 34Anastasiou,D. Cantley,C.L.(2012) Breathless cancer cells get fat on glutamine.Cell Research,22:443-446.Behn,C.Araneda,O.F. Llanos,A.J.Celedon,G.Gonzalez,G.(2007) Hypoxia related lipid peroxidation:Evidences,Implications and Approaches.Respiratory Physiology and Neurobiology,158:143-150.Bruder,E.D. Lee,P.C. Raff,H.(2004) Metabolic analysis of adrenal lipids during Hypoxia in the neonatal rat:Implications in Steroidogenesis.AJP Endocrinal Metab, 286:E697-E703.Giaccia,A.J. Simon,M.C. Johnson,R.(2004) The Biology of Hypoxia:The role of oxygen sensing in development,normal function and disease.Genes and Development,18:2183-2194.Goda,N and Kanai,M.(2012) Hypoxic inducible factors and their roles in energy metabolism.International Journal of Haematology,95:457-463.Mackie,R.I. White,A.A. Bryant,M.P. (1991) Lipid metabolism in Anaerobic Environment.Critical reviews in Microbiology,17(6):449-479.Mcclelland,G.B.(2004) Fat to the Fire: the regulation of lipid oxidation with exercise and environmental stress.Comparative Biochemistry and Physiology,B139:443-460.

35Metallo,C.M. Gameiro,P.A. Bell,E.L. Mattaini,K.R. Yanga,J. Hiller,K.Jewell,C.M. Johnson,Z.R. Irvine,J.D. Guarente,l. Kellecher,J.K. Vander,M.G. Iliopoulos,O. Stephanopoulous,G.(2012) Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia.Nature,481:380-386.Nath,P. and Szabo,G.(2012) Hypoxia and Hypoxia Inducible factors and Diverse Roles in liver diseases.Hepatology,55(2):622-633.Prathath,S. Mick,S.L. Feig,J.E. Joaquin,V. Grauer,l. Habiel,D.M. Gassman,m.Gardner,L.B. Fisher,E.A.(2011) Hypoxia is present in murine artherosclerotic plaques and Has multiple adverse effects on Macrophage Lipid Metabolism.Circulation Research,26:1141-1152.Rankin,E.B. Rha,J.Selak,M.A. Unger,T.L. Keith,B. Liu,Q.Haase,V.H.(2009) Hypoxia Inducible factor 2 regulates hepatic lipid metabolism.Molecular and Cellular Biology:29(16):4527-4538.Sun,R.C.and Denko,N.C.(2013) Hypoxic regulation of Glutamine Metabolism through HIF2 and SIAH2 SUPPORTS lipid synthesis that is necessary for tumour growth.Cell metabolism.19:285-292.

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