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FA oxidation and ketone bodies
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Roles of Lipids
principal form of stored energy
major constituents of cell membranes
vitamins
messengers intra and extracellular
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Glycerol-P Glycerol
Triacylglycerol
Fatty acyl CoA Fatty acid
Malonyl CoA
Acetyl CoA
Glucose
Pyruvate
TCA cycle
Starved state
gluconeogenesis
Ketone bodies
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Oxidation of fatty acids
Central energy-yieldingpathway in animals.
Generates acetyl-CoA
Generates electrons
which pass through the
respiratory chain driving
ATP synthesis.
CH3-C-CoA=O
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Sources of fatty acid fuels
1. de novo synthesis
Fatty acids may be synthesized and areconverted to triacylglycerols
Made in liver and exported to muscle or fat cells
In muscle, used as fuel; In fat cells, stored asdroplets
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Sources of fatty acid fuels
2. diet
Diet on average 40% or more of the daily
energy requirement of humans is supplied inthe diet in the form of triacylglycerols
Stored in cells as lipid droplets
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Extremely suitable as a energy storagemolecule:
1. Contain highly reduced hydrocarbonchains with an energy more than twicethat of the same weight of carbohydrate orprotein
2. Extremely insoluble in water: less heavy
than hydrated molecules, such ascarbohydrates.
3. Chemically inert and so can be stored inlarge quantity in cells.
Triacylglycerols
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Absorption of dietary fat
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Dietary fats are absorbed in the small
intestine
Ingested triacylglycerolsare converted from
insoluble fat particles tofinely dispersed micelles
Bile salts are amphipathiccholesterol derivatives
made in the liver andstored and released by thegall bladder perform thisfunction
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Micelle formation allows lipid
molecules to be accessible towater-soluble lipases (secreted by
pancreas)
Ingested
triacylglycerols
Mono- and di-
acylglycerols,free fatty acids,
glycerol
Lipases
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The products of lipase action diffuse into theepithelial cells lining the intestinal surface
Then they are reconverted to triacylglycerols and packaged with dietary cholesterol and specific lipoprotein aggregates calledchylomicrons.
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Molecular structure of a chylomicron
The surface is a layer ofphospholipids, withhead groups facing theaqueous phase.
Triacylglycerols are inthe interior make upmore than 80% of themass.
Apolipoproteins lipidbinding proteins
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Chylomicrons move through thelymphatic system, enter the bloodstream and are carried to muscleand adipose tissue.
In the capillaries of these tissues,
the extracellular enzymelipoprotein lipase hydrolyzetriacylglycerols to fatty acids andglycerol, which are taken up bycells in the target tissues.
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In muscle, the fatty
acids are oxidized
for energy. In adipose tissue,
they are esterified for
storage.
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Fate of dietary fat
Dietary fat may be utilized immediately or
stored in adipocytes
In fed state, fatty acid synthesis occurs and
the products are also stored in adipocytes
In starved state, these stored forms of fat are
mobilized
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The Mobilization of
triacylglycerols
Triacylglycerols stored in the adipose tissues aremobilized and transported to tissues where fatty
acids can be oxidized for energy production.
Triacylglycerols
Fatty acids
+Glycerol
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What signals the mobilization of
stored triacylglycerols?
Hormones signal the need for metabolic
energy.
Hormones epinephrine and glucagon are
secreted in response to low blood glucoselevels
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These hormones activate the enzyme adenylylcyclase in the adipocyte plasma membrane.
Results in increased amount of the secondary
messenger cAMP.
Capillary
Glucagon and epinephrine act by a
signal transduction mechanism
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cAMP activateshormone-sensitive
triacylglycerol lipase
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The fatty acids released
passed into the bloodwhere they bind to blood
protein serum albumin.
the insoluble fatty acids
are carried to tissues,
dissociated from albumin
and transported into cellsto serve as fuels.
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The products of fat mobilization
Triacylglycerols are broken down toglycerol and fatty acid
95% of the biologically available energy oftriacylglycerols resides in their long-chain
fatty acids 5% is contributed by the glycerol moiety
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Entry of glycerol into the glycolytic
pathway
The glycerol released isphosphorylated by glycerolkinase to glycerol 3-phosphate
oxidized to dihydroxyacetonephosphate
then converted toglyceraldehyde 3-phosphate,which is oxidized viaglycolysis
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Fatty acids are activated and
transported into mitochondria
FA oxidation enzymes
are located in
mitochondria Free FA cannot pass
directly through the
mitochondrialmembranes
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1. Activation of fatty acid by CoA
Acyl CoA synthase
Fatty acid + CoA + ATP fatty acyl-CoA +AMP + PPi
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2. Esterification to carnitine
Then transferred to carnitine
Fatty acyl-CoA + carnitine Fatty acyl- carnitine + CoASH
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The fatty acyl group is transferred to
carnitine by carnitine transferase I on the
outer face of the inner membrane The fatty acyl-carnitine ester then enters the
matrix through the acyl-carnitine/carnitine
transporter
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3. Esterification to CoA
The fatty acyl group is enzymatically transferred fromcarnitine to coenzyme A by carnitine acyltransferase II
Regenerates fatty acyl-CoA and free carnitine
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Mitochondrial oxidation of fatty
acids takes place in three stages
These stages result in massive ATP
production
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Stage 1. -oxidation: Oxidative removal
of successive two-
carbon units to formacetyl-CoA startingfrom carboxyl end ofthe fatty acyl chain
Also generatesNADH and FADH2
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Stage 2
Acetyl groups of
acetyl-CoA are
oxidized to CO2 in
the TCA cycle
NADH is also
generated from theTCA cycle
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Stage 3
The NADH and
FADH2produced
mitochondrialrespiratory chain
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The -oxidation of saturated
fatty acids has four basic steps
The -oxidation sequence is a
mechanism of breaking stable bondbetween methylene (-CH
2-) groups.
The first three steps create a bond that is
more easily broken.
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Step 1
Dehydrogenation of fatty acyl-CoA produces a doublebond between C-2 and C-3
This double bond is in the trans configuration
Yields FADH2
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Step 2
Hydration - water is added to the double bondto form -hydroxyacyl-CoA.
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Step 3
-hydroxyacyl-CoA is dehydrogenated(oxidized) to form ketoacyl-CoA.(yields NADH + H+)
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Step 4
ketoacyl-CoA reacts with freecoenzyme A to split off the carboxyl-
terminal two-carbon fragment of the
original FA as acetyl CoA.
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The products for one pass through -
oxidation
Palmitoyl-CoA + CoA + FAD + NAD+ + H20
myristoyl-CoA + acetyl-CoA + FADH2
+ NADH + H +
Myristate is a C14 fatty acid
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The myristoyl-CoA can go through another
set of four -oxidation reactions to yield asecond molecule of acetyl-CoA and lauryl-
CoA (C-12).
The four steps are repeated to
yield acetyl-CoA and ATP
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The complete -oxidation of
palmitate
Palmitoyl-CoA + 7CoA + 7FAD + NAD+ + 7H20
8acetyl-CoA + 7FAD2 + 7NADH + 7H+
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The fate of FADH2 and NADH
Each molecule of FADH2---2 molecules of
ATP .
Each molecule of NADHdelivers a pair of
electrons---3 molecules of ATP.
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The fate of acetyl-CoA
Each molecule of acetyl-CoA can be
oxidized to CO2and H
2O by the TCA cycle
to yield 12 molecules of ATP.
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The overall ATP yield
Palmitoyl-CoA + 23O2 + 108Pi + 131ADP
CoA + 131ATP + 16CO2 + 23H2O
Palmitoyl-CoA + 7CoA + 7FAD + NAD+ + 7H20
8acetyl-CoA + 7FAD2 + 7NADH + 7H+
becomes
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Oxidation of special fatty acids
Mono and polyunsaturated fatty acids
Odd chain fatty acids
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Oxidation of unsaturated fatty acids
requires additional reactions
Most fatty acids in triacylglycerols and phospholipids
are unsaturated. Being in the cis position these double bonds cannot
be acted upon by the -oxidation enzymes
By the action of two auxiliary enzymes such
substrates may be broken down
Oxidation of a monounsaturated
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Oxidation of a monounsaturated
fatty acid
Example: oleic acid
Requires enoyl-CoAisomerase to reposition thedouble bond.
Converting the cis isomer
to a trans isomer, a normalintermediate in -oxidation
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Oxidation of a polyunsaturated
fatty acid
Example, linoleic
acid
The first step is the
same as that
described above
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Complete oxidation requiresa second auxiliary enzyme, a
NADPH dependent reductasethat removes an unsaturated
bond
The isomerase is required toconvert the double bondsfrom a cis to a transconfiguration
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Complete oxidation of odd-
number fatty acids
Odd numbered lipids are present in
plants and marine organisms
Oxidized as even chain but end up
withproprionyl-CoA
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Proprionate metabolism
Proprionyl-CoA is
carboxylated toform D-methyl-
malonyl-CoA
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D-methyl-malonyl-CoA is epimerized to
its L-stereoisomer
L-methyl-malonyl-
CoA is converted to
succinyl-CoA, which
can enter TCA cycle.
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Fatty acid oxidation is tightly
regulated
Fatty acid oxidation is regulated so it
occur only when the need for energy
requires it
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Two pathways fatty acyl-CoA in liver
The pathway taken
depends on the rate
of transfer of long-
chain fatty acyl-CoAinto the
mitochondria
Cytosol Mitochondria
Triacylglycerols
and
phospholipids
Fatty
acid
oxidation
Fatty acid
Carnitine
transporter
Fatty acid
synthesis
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Malonyl-CoA initiates fatty acid synthesis
Malonyl-CoA is the first
intermediate in the cytosolicbiosynthesis of long-chain
fatty acids from acetyl-CoA
Excess glucose that cannotbe oxidized or stored as
glycogen is converted in the
cytosol into FA for storage
as triacylglycerols
Glycerol-P
Triacylglycerol
Fatty acyl CoA
Malonyl CoA
Acetyl CoA
Glucose
Pyruvate
TCA cycle
M l l C A i hibit iti t f I
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Malonyl-CoA inhibits carnitine transferase I
Cytosol Mitochondria
Triacylglycerols
and
phospholipids
Fatty
acid
oxidation
Fatty acid
Carnitine
transporter
Fatty acidsynthesis
Malonyl-CoA
F d
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Fed state
Glycerol-P Glycerol
Triacylglycerol
Fatty acyl CoA Fatty acid
Malonyl CoA
Acetyl CoA
Glucose
Pyruvate
TCA cycleInsulin, citrate
Carnitine
transporter
S d
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Starved state
Glucagon/
epinephrine
Malonyl CoA
Glycerol-P Glycerol
Triacylglycerol
Fatty acyl CoA Fatty acid
Acetyl CoA
Glucose
Pyruvate
TCA cycle
g
lucon
eogene
si
s
Ketone bodies
Carnitine
transporter
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Ketone bodies
The acetyl-CoA formed in the
liver during -oxidation can
have two fates:
1. Enter the TCA cycle
2. Converted to ketone bodies
acetone, acetoacetone and
-hydroxybutyrate forexport to other tissues
Ketone bodies formed in the liver
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Ketone bodies formed in the liver
1. Condensation of twomolecules of acetyl-CoA,
2. The resulting
acetoacetyl-CoAcondenses with acetyl-CoA to form -hydroxy- -methylglutaryl-CoA(HMG-CoA)
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3. Cleavage of HMG-CoA yields acetyl-CoAand acetoacetate.
4. Reduction of acetoacetate yields D- -hydroxybutyrate (do not confuse with L-
-hydroxybutyrate of the b-oxidationpathway).
5. Acetoacetate is easily decarboxylated (maybe spontaneously or enzymatically) toacetone and CO2.
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Ketone bodies are exported to
other organs Acetone, produced in smaller quantities
than the other ketone bodies, is exhaled
Acetoacetate and -hydroxybutyrate aretransported in the blood to tissues other than
the liver
K b di f l
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Ketone bodies as fuels
-hydroxybutyrate maybe converted to acetyl-
CoA.
The acetyl-CoA is
Oxidized in the TCA
cycle to provide much of
the energy required bytissues
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Ketone bodies are used under
starvation conditions
The brain, which preferentially uses glucose as fuel, can
adapt to the use ofacetoacetate or -hydroxybutyrateunder starvation conditions, when glucose is
unavailable
I i l i hi d i i
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Intertissue relationships during starvation
S f li id t b li
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Summary of lipid metabolism
Sources of triacylglycerols diet and stored inadipocytes
Route taken by dietary triacylglycerols to muscle or
fat cells
Mobilization of triacylglycerols is initiated by
hormones epinephrine and glucagon
The products of mobilization are free fatty acid and
glycerol, both are used for energy production
S mmar of lipid metabolism
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Summary of lipid metabolism
Carnitine transporter mediates entry of fatty acidsinto mitochondria
-oxidation of fatty acids has four basic steps essentially fatty acid synthesis in reverse
-oxidation generates acetyl-CoA, NADH andFADH
2ATP
Ketone bodies serve as fuel molecules under
starvation conditions