A presentation about hypoxic regulation of Lipid metabolism. This has to be subjected to further modifications.

1. M.C.Prabhath
University of Sri Jayawardenepura
Sri Lanka
4th Year – 2nd Semester
03.03.2016
Hypoxic Regulation of Lipid
Metabolism
1

2. Content
 Introduction
 Lipids
 Metabolism
 Hypoxia and Hypoxic conditions
 Regulation 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 cancer
 Discussion
 References.
2

3. Introduction
 Lipids play a main role in cellular
activities.
 Fatty acids as a precursor.
 Synthesis and degradation
 Hypoxic conditions
 Hypoxic regulation of lipid
metabolism
3

4. Lipids
4
 Heterogeneous group of
compounds
 Organic substances containing C,H
and O
 Solubility
- Relatively insoluble in
water
- soluble in nonpolar
solvents

5. Classification of Lipids
5
 Simple lipids
 Complex lipids
 Derived lipids

6. Metabolism
6
 Metabolism 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
- Harper’s illustrated Biochemistry 29th
Edition

7. 7
 Anabolic pathways
 Catabolic pathways

8. 8
 Lipid metabolism is concerned
mainly with fatty acids .
Fatty acids Acetyl-CoA
CO2 + H2O
Cholesterol and other
steroids
Ketone
bodies

9. 9
Figure- Overview of the fatty acid metabolism
Source- Hrpers illustrated Biochemistry

10. 10

11. Hypoxia and Hypoxic conditions
11
 Oxygen 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

12. 12
 Hypoxia 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

13. 13
 For 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 .

14. 14
 Hypoxic 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

15. 15
 HIF-1
 HIF-1α -Oxygen liable protein
Stabilized in Hypoxic conditions
 Many genes are regulated by hypoxia and HIFs
Hypoxia Inducible Factors – A common
mechanism of Lipid Accumulation?
HIF-1α
HIF-
1β

16.  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.
16
Figure- HIFS mediated lipid metabolism
in liver
Source-Goda and Kanai , 2012

17. Hypoxic Regulation of
Glutamine Metabolism
Supports Lipid
Synthesis!
17

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

19. 19

20. 20
Hypoxia
HIF- 1
Pyruvate Dehydrogenase Kinase
Pyruvate Acetyl Co A
C

21. 21
 Cells 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
!!!!

22. 22

23. 23
Hypoxia
VHL deletion
HIF-1 Stable or Mitochondrial
respiration is limited
Glutamine
Cytoplasmic
IDH 1
Mitochondrial IDH
2
Acetyl Co-A
LIPIDS
Reductiv
e
Glutamin
e
Metabolis
m

24. Lipid degradation under hypoxic
regulation
24

25. 25

26. Lipid Peroxidation
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 Can 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.

27. 27

28. Changes in Lipid metabolism with
Hypoxia as an environmental stress
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 Mammalian 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.

29. Hypoxia, Lipid Metabolism and
Cancer
29
Rapid Proliferation Daughter Cells
Constant supply of Building
Blocks
LIPIDS
Signaling functions
Structural
functions

30. 30
 Cancer 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 .

31. 31
 In 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.

32. Summary !
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33. 33

34. References
34
 Anastasiou,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.

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 Metallo,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-

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