Download Metabolism of lipids

BIOQUÍMICA E BIOLOGIA CELULAR
António Ascensão, José Magalhães
Metabolism of lipids
Faculdade de Desporto, Universidade do Porto, 1º Ciclo, 1º Ano
2011_20012
Metabolic conversions of nutrients
Metabolic pathways overview
Molecular structure of triglycerides
Adapted from “Understanden human anatomy and physiology”, 5fh Edition, McGraw-Hill, 2004
Steps of lipid catabolism
• 
Mobilization - hydrolysis of TG stored on adipocytes
• 
Circulation – Plasmatic transport of free fatty acids with albumin to
muscle
• 
Absortion - entrance of fatty acids in muscle (FABP)
• 
Activation – formation of fatty acyl-CoA in cytosol (ATP dependent)
• 
Translocation – Transport of fatty acyl-CoA to mitochondria through
carnitine shuttle
• 
Beta-oxidation – production of NADH, FADH2 and acetyl-CoA from
fatty acyl-CoA
• 
Mitochondrial oxidation – Krebs cycle and electron transport chain
The example of G Protein on lipolysis …
↑ Catecolamines
↑ Glucagon
Triacylglycerols
Lipase
Fatty acids transport from adipocytes to myocytes
↑ Catecolamines
↑ Glucagon
Lipid metabolism animation
http://www.wiley.com/legacy/college/boyer/0470003790/
animations/fatty_acid_metabolism/
fatty_acid_metabolism.htm
Entry of fatty acids into mitochondria – the Carnitine Shuttle
(fatty acid binding proteins)
1
2
Carnitine Shuttle
(3 steps process)
3
β - oxidation
Carnitine Shuttle (rate limiting step for fatty acids oxidation)
2
Acyl-CoA
synthetase
Carnitine
acyltransferase
I
1
3
Carnitine
acyltransferase
II
Beta (β)-oxidation cycle (4 steps)
(continues for new cycle)
(end of the process)
(beginning of the process)
1º Step
4º Step
FADH2
H+ + NADH
2º Step
(HADH)
3º Step
Beta (β)-oxidation cycle
( Fatty-Acyl CoA )
Electron Transport Chain
Electron Transport Chain
Re-enters β - oxidation
with 2 less carbons
2 carbon compound to
Krebs cycle
Steps of Beta (β) oxidation cycle (summary)
• 
Reaction 1 (1st Step)
• 
–  Oxidation of fatty Acyl-CoA
Reaction 3 (3rd Step)
–  Oxidation
–  Catalyzed by Acyl-CoA Dehydrogenase –  Catalyzed by Hydroxyacyl-CoA
Dehydrogenase
–  Generates 1 FADH2 (ETC)
–  Generates 1 NADH (ETC)
• 
Reaction 2 (2nd Step)
–  Hydration
• 
Reaction 4 (4th Step)
–  Catalyzed by Enoyl-CoA Hydratase
–  Bond Cleavage between β and α carbon
–  Forms β-Hydroxyacyl-CoA
–  Catalyzed by Thiolase
–  Requires CoA
–  Forms Acetyl-CoA (enters Krebs
cycle)
–  Forms Fatty Acyl-CoA (2 carbons
shorter (re-enters β - oxidation)
Beta (β)-oxidation
•  Breakdown of fats into
–  Acetyl coenzyme A (CoA) --> Kreb Cycle
–  FADH2 --> Oxidative Phosphorylation
–  NADH --> Oxidative Phosphorylation
•  Breaks off two carbons at a time to acetyl CoA
–  Remaining Acyl-CoA goes another round
Beta (β)-oxidation cycle … goes on …
Beta (β)-oxidation … an example
γ
β
α
O
CH3 – CH2 – CH2 – CH2 – CH2 – CH2 – CH2 – CH2 – CH2 – CH2 – CH2 – CH2 – CH2 – C
SCoA
14 carbon fatty acid
6 rounds on Beta-oxidation
7 acetyl-CoA formed
Beta (β)-oxidation cycle interconnections
Lets remind Krebs cycle !
Lets remind Krebs cycle !
Glycolysis
β - oxidation
Mitochondrial electron transport chain
Summary of the flow of electrons and protons through the four complexes of the respiratory chain.
Electrons reach CoQ via Complexes I and II. CoQH2 serves as a mobile carrier of electrons and
protons. It transfers electrons to Complex III, which transfers them to another mobile connecting
link, cytochrome c. Complex IV transfers electrons from reduced cytochrome c to O2. Electron flow
through Complexes I, III and IV is accompanied by proton flow from the matrix to the
intermembrane space. Electrons from fatty acid b-oxidation can also enter the respiratory chain
though UQ.
Mitochondrial electron transport pathway
Beta (β)-oxidation cycle … an example !
Fatty acids oxidation … the energetic yelding !
Beta (β)-oxidation of odd-numbered fatty acids
Integration of β-oxidation with Krebs cycle !
Glycolysis
Even-numbered
fatty acids
β - oxidation
Odd-numbered
fatty acids
Propionyl-CoA
Ketogenesis (formation of ketone bodies)
Physiological condition
Biochemical impact
Ketogenesis
Ketone bodies
Ketosis
Fasted-state (starvation)
Prolonged exercise
Diabetes …
Glycogen deplection (↓ oxaloacetate - gluconeogenesis)
Excess of β-oxidation (↑ acetyl-CoA)
Liver
Acetoacetate
Acetone
β-hydroxybutyrate
Metabolic acidosis
↑ plasma ketonic bodies
Ketogenesis (formation of ketone bodies) in liver
X
Ketogenesis (formation of ketone bodies)
Extreme ketogenesis … the case of diabetes
Mitochondrial metabolism_overview