Oxidation of Fatty Acids

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Oxidation of
Fatty Acids

• Fatty acids are an important source of energy
• Oxidation is the process where energy is produced
  by degradation of fatty acids
• There are several types of fatty acids oxidation.
• ß- oxidation of fatty acid
• a- oxidation of fatty acids
• ?- oxidation of fatty acids

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ß- oxidation of fatty acid

• Beta-oxidation is the process by which fatty
  acids, in the form of Acyl-CoA molecules, are
  broken down in mitochondria and/or in peroxisomes
  to generate Acetyl-CoA, the entry molecule for
  the Citric Acid cycle.
• It occurs in many tissues including liver kidney
  and heart.
• Fatty acids oxidation doesn't occur in the brain,
  as fatty acid can't be taken up by that organ.

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• The beta oxidation of fatty acids involve three
  stages
• Activation of fatty acids in the cytosol
• Transport of activated fatty acids into
  mitochondria (carnitine shuttle)
• Beta oxidation proper in the mitochondrial matrix

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• 1) Activation of FA
• This proceeds by FA thiokinase (acyl COA
  synthetase) present in cytosol
• Thiokinase requires ATP, COA SH, Mg. The
  product of this reaction is FA acyl COA and
  water.

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2- Transport of fatty acyl CoA from cytosol into
mitochondria ( rate-limiting step)

• Long chain acyl CoA traverses the inner
  mitochondria membrane with a special transport
  mechanism called Carnitine shuttle.

The cytosol
The matrix
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2-Transport of acyl CoA into the mitochondria
(rate-limiting step)

• Acyl groups from acyl COA is transferred to
  carnitine to form acyl carnitine catalyzed by
  carnitine acyltransferase I, in the outer
  mitochondrial membrane.
• Acylcarnitine is then shuttled across the inner
  mitochondrial membrane by a translocase enzyme.
• The acyl group is transferred back to CoA in
  matrix by carnitine acyl transferase II.
• Finally, carnitine is returned to the cytosolic
  side by translocase, in exchange for an incoming
  acyl carnitine.

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3. Proper of ß oxidation in the mitochondrial
matrix

• There are 4 steps in ß C oxidation
• Step I Oxidation by FAD linked dehydrogenase
• Step II Hydration by Hydratase
• Step III Oxidation by NAD linked dehydrogenase
• Step IV Thiolytic clevage Thiolase

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• The first reaction is the oxidation of acyl CoA
  by an acyl CoA dehyrogenase to give a-ß
  unsaturarted acyl CoA (enoyl CoA).
• FAD is the hydrogen acceptor.

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• The second reaction is the hydration of the
  double bond to ß-hydroxyacyl CoA (p-hydroxyacyl
  CoA).

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• The third reaction is the oxidation of
  ß-hydroxyacyl CoA to produce ß-Ketoacyl CoA a
  NAD-dependent reaction.

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• The fourth reaction is cleavage of the two carbon
  fragment by splitting the bond between a and ß
  carbons
• By thiolase enzyme.

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• The release of acetyl CoA leaves an acyl CoA
  molecule shortened by 2 carbons.
• This acyl CoA molecule is the substrate for the
  next round of oxidation starting with acyl CoA
  dehydrogenase.
• Repetition continues until all the carbons of the
  original fatty acyl CoA are converted to acetyl
  CoA.
• In the last round a four carbon acyl CoA (butyryl
  CoA) is cleaved to 2 acetyl CoA.

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• Energetics of FA oxidation
• e.g. Palmitic (16C)
• ß-oxidation of palmitic acid will be repeated 7
  cycles producing 8 molecules of acetyl COA.
• In each cycle FADH2 and NADHH is produced and
  will be transported to the respiratory chain.
• FADH2 2 ATP
• NADH H 3 ATP
• So 7 cycles 5x7 35 ATP

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• Each acetyl COA which is oxidized in citric cycle
  gives 12 ATP (8 x 12 96 ATP)
• 2 ATP are utilized in the activation of fatty
  acid (It occurs once).
• Energy gain Energy produced - Energy utilized
• 35 ATP 96 ATP - 2 ATP 129 ATP

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Lipid transport
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Plasma Lipoproteins (Structure)
All the lipids contained in plasma, including
fat, phosphalipids, cholesterol, cholesterol
ester and fatty acid, exist and transport in the
form of lipoprotein

• Non-covalent assemblies of lipids and proteins
• LP core
• Triglycerides
• Cholesterol esters
• LP surface
• Phospholipids
• Proteins
• cholesterol

Function as transport vehicles for
triacylglycerols and cholesterol in the blood
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Lipoprotein Nomenclature, Composition and
separation
CM
VLDL
LDL
HDL
Major apoB 48 apoB 100 apoB 100
apoA-I Protein Major TG TG
CE CE Lipid
1.Electrophoresis method CM (chylomicron)
slow ?-Lipoprotein pre ?-Lipoprotein
fast ?- Lipoprotein
2. Ultra centrifugation method CM (chylomicron )
slow very low
density lipoprotein ( VLDL) low density
lipoprotein ( LDL) high density lipoprotein
(HDL) high
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Apolipoproteins (apoproteins) and functions

• They are protein components of lipoproteins
• consisting 60 of some lipoproteins (HDL) and
  1 of some lipoproteins (chylomicrons)
• To combine and transport lipids.
• To recognize the lipoprotein receptors
• Apo-B100 is the ligand for LDL-receptors
• Apo-B48 for chylomicron remmenant
• Apo-A1 is the ligand for HDL receptor.
• Activators for certain enzymes involved in
  lipoprotein metabolism
• Apo C II activates lipoprotein lipase and
• apo-A1 activates LCAT (Lecithin Cholesterol
  Acyltransferase,
• formation of cholesterol esters in
  lipoproteins).

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Lipids are Transported as Lipoproteins

• All lipids in plasma are transported in the form
  of lipoproteins .
• Transport dietary lipids from intestine to liver
  (exogenous) Chylomicrons
• Transport lipids from liver to peripheral tissues
  (endogenous) VLDL (very low
  density lipoproteins)

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Chylomicrons

• Synthesized in small intestine
• Transport dietary lipids (exogenous TG)
• 98 lipid, large sized, lowest density
• Apo B-48
• Receptor binding
• Apo C-II
• Lipoprotein lipase activator
• Apo E
• Remnant receptor binding

• Nascent chylomicron are formed in the intestinal
  and consists of rich in dietary TG minimal
  amount of dietary cholesterol Apo (B-48)
• Mature chylomicron after Nascent chylomicron
  passage to blood, addition of apoC and apoE from
  HDL
• Lipoprotein lipase hydrolyzes TG present in
  chylomicrons
• Chylomicron remnant taken up by the liver through
  endocytosis.
• Apo C removed and returns to HDL

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Very Low Density Lipoprotein (VLDL)

• Synthesized in liver
• Transport endogenous triglycerides
• 90 lipid, 10 protein
• Apo B-100
• Receptor binding
• Apo C-II
• LPL activator
• Apo E
• Remnant receptor binding
• The major fraction of VLDL remnant further loses
  TG, so as to be converted to LDL

• Nascent VLDLare formed in the liver and consists
  of endogenous TG 17 cholesterol Apo (B-100)
• Mature VLDL after Nascent VLDL passage to blood,
  addition of apoC, apoE and cholesterol esters
  from HDL
• Lipoprotein lipase (LPL) hydrolyzes TG present in
  VLDL
• VLDL remnant containing less of TG and more of
  cholesterol and taken up by the liver through
  endocytosis.
• Apo C removed and returns to HDL

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Blood Cholesterol

• Cholesterol is the most important animal sterols
  which is the precursor of all other steroid in
  the body e.g. corticosteroids, sex hormones, bile
  acids and vitamin D.
• Cholesterol biosynthesis
• All tissues containing nucleated cells are
  capable of synthesizing cholesterol.
• Cholesterol is derived about equally from the
  diet (exogenous) or manufactured de novo
  (endogenous) in cells of humans especially in
  liver , intestine, and adrenal cortex .
• Acetyl CoA is the source of all carbon atoms in
  cholesterol.
• The liver is the main source of plasma
  cholesterol but intestine also participates.
• The liver is the principle organ which removes
  cholesterol from blood.

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• The enzymes involved in cholesterol biosynthesis
  are present in cytosol and microcosms of the
  cell.
• Total cholesterol in plasma is normally between
  140-300 mg/dl.
• Cholesterol esters are continually hydrolysed in
  liver and resynthesized in plasma.
• Cholesterol is present in all the lipoproteins
  but in fasting more than 60 is carried in (LDL).

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Low Density Lipoproteins (LDL - Bad)

• Formation site from VLDL in blood, but a small
  part is directly released from liver
• Function transport cholesterol from liver to the
  peripheral tissues.
• Carries aprox. 50 of blood cholesterol.
  containing only apo B-100.
• LDL concentration in blood has positive
  correlation with incidence of cardiovascular
  diseases.
• Expulsion cholesterol from the cell, and
  transported by HDL and finally excreted through
  liver.

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High Density Lipoproteins (HDL Good)

• Formation site liver and intestine
• Function transport cholesterol from peripheral
  tissues to liver (reverse cholesterol transport)
• converted cholesterol to bile acids and excreted
• Reservoir of apoproteins
• Contain ? protein, ? Cholesterol
• Apo A
• Apo C Activates LPL
• Apo E Remnant receptor binding
• Protects against heart disease