Download Chapter Twenty Five Lipid Metabolism

Chapter Twenty Five
Lipid Metabolism
Outline
► 25.1 Digestion of Triacylglycerols
► 25.2 Lipoproteins for Lipid Transport
► 25.3 Triacylglycerol Metabolism: An Overview
► 25.4 Storage and Mobilization of Triacylglycerols
► 25.5 Oxidation of Fatty Acids
► 25.6 Energy from Fatty Acid Oxidation
► 25.7 Ketone Bodies and Ketoacidosis
► 25.8 Biosynthesis of Fatty Acids
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25.1 Digestion of Triacylglycerols
► Triacylglycerols (TAGs) pass through the mouth
unchanged and enter the stomach. The heat and
churning action of the stomach break lipids into
smaller droplets.
► The presence of lipids in consumed food slows down
the rate at which the mixture of partially digested
foods leaves the stomach because they take longer to
digest.
► When partially digested food leaves the stomach, it
enters the upper end of the small intestine (the
duodenum), where its arrival triggers the release of
pancreatic lipases, enzymes for the hydrolysis of
lipids. The gallbladder simultaneously releases bile.
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Bile contains bile acids and cholesterol, which are
steroids, and phospholipids. Cholic acid is the major
bile acid. These molecules use their hydrophilic and
hydrophobic regions to emulsify the lipid droplets so
they can be acted on by the pancreatic lipases.
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Pancreatic lipase partially hydrolyzes the emulsified
triacylglycerols, producing mainly mono- and
diacylglycerols, plus fatty acids and a small amount
of glycerol.
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► Smaller fatty acids and
glycerol are water-soluble and
are absorbed directly through
the surface of the villi that
line the small intestine and
enter the bloodstream through
capillaries.
► The insoluble acylglycerols
and larger fatty acids within
the intestine packaged into
the lipoproteins known as
chylomicrons. Too large to
enter through capillary walls,
they are absorbed into the
lymphatic system through
lacteals within the villi.
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Summary of pathways of lipids through the villi and
into the transport systems of the bloodstream and the
lymphatic system.
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25.2 Lipoproteins for Lipid Transport
► Lipids enter metabolism from three different sources:
- (1) the diet
- (2) storage in adipose tissue
- (3) synthesis in the liver
► Whatever their source, these lipids must eventually
be transported in blood.
► To become water-soluble, fatty acids released from
adipose tissue associate with albumin, a very large
protein that binds up to 10 fatty acid molecules. All
other lipids are carried by lipoproteins of various
types.
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► A lipoprotein: A
lipoprotein contains a
core of neutral lipids,
including
triacylglycerols and
cholesteryl esters.
► Surrounding the core is
a layer of phospholipids
in which varying
proportions of proteins
and cholesterol are
embedded.
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► Lipids are less dense than proteins, the density of
lipoproteins depends on the ratio of lipids to proteins.
► Chylomicrons, which are the only lipoproteins
devoted to transport of lipids from the diet, are the
lowest-density lipoproteins (specific gravity < 0.95 ).
► Very-low-density lipoproteins (VLDLs) carry TAGs
from the liver to peripheral tissues for storage or
energy generation (0.96 < s. g. < 1.006).
► Intermediate-density lipoproteins (IDLs) carry
remnants of the VLDLs from peripheral tissues back
to the liver for use in synthesis (1.006 < s. g. < 1.019).
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► Low-density lipoproteins (LDLs) transport
cholesterol from the liver to peripheral tissues, where
it is used in cell membranes or for steroid synthesis.
LDL cholesterol can also cause formation of arterial
plaque (1.019 < s. g. < 1.063).
► High-density lipoproteins (HDLs) transport
cholesterol from dead or dying cells back to the liver,
where it is converted to bile acids. The bile acids are
then available for use in digestion or are excreted
when in excess (1.063 < s. g. < 1.210).
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25.3 Triacylglycerol Metabolism:An
Overview
► Triacylglycerols undergo hydrolysis to fatty acids
and glycerol.
► Fatty acids undergo
- Resynthesis of triacylglycerols for storage
- Conversion to acetyl-SCoA
► Glycerol is converted to glyceraldehyde 3-phosphate
and DHAP, which participate in
- Glycolysis—energy generation
- Gluconeogenesis—glucose formation
- Triacylglycerol synthesis
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Metabolism of
triacylglycerols.
Pathways that break
down molecules
(catabolism) are shown
in light brown, and
synthetic pathways
(anabolism) are shown
in blue. Connections to
other pathways or
intermediates of
metabolism are shown
in green.
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► Acetyl-SCoA participates in
- Triacylglycerol synthesis
- Ketone body synthesis
- Synthesis of steroids and other lipids
- Citric acid cycle and oxidative phosphorylation
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25.4 Storage and Mobilization of
Triacylglycerols
► The passage of fatty acids in and out of storage in
adipose tissue is a continuous process essential to
maintaining homeostasis.
► After a meal, blood glucose levels are high and
insulin activates the synthesis of TAGs for storage.
► The metabolism of glucose is needed to supply
dihydroxyacetone phosphate that isomerizes to give
the necessary glycerol 3-phosphate because
adipocytes do not have the enzyme needed to
convert glycerol to glycerol 3-phosphate.
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► The reactants in TAG synthesis are glycerol 3phosphate and fatty acid acyl groups carried by
coenzyme A.
► TAG synthesis proceeds by transfer of first one and
then another fatty acid acyl group from coenzyme A
to glycerol 3-phosphate.
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► Next, the phosphate group is removed and the third
fatty acid group is added to give a triacylglycerol.
► When digestion of a meal is finished, blood glucose
levels are low; consequently insulin levels drop and
glucagon levels rise.
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► The lower insulin level and higher glucagon level
together activate triacylglycerol lipase, the enzyme
within adipocytes that controls hydrolysis of stored
TAGs.
► When glycerol 3-phosphate is in short supply, an
indication that glycolysis is not producing sufficient
energy, the fatty acids and glycerol produced by
hydrolysis of the stored TAGs are released to the
bloodstream for transport to energy-generating cells.
► Mobilization (of triacylglycerols): Hydrolysis of
triacylglycerols in adipose tissue and release of fatty
acids into the bloodstream.
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25.5 Oxidation of Fatty Acids
► Once a fatty acid enters the cytosol of a cell that
needs energy, three successive processes must occur.
► 1. Activation: The fatty acid must be activated by
conversion to fatty acyl-SCoA. Some energy from
ATP must initially be invested in converting the fatty
acid to fatty acyl-SCoA, a form that breaks down
more easily.
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► 2. Transport: The fatty acyl-SCoA must be
transported into the mitochondrial matrix where
energy generation will occur. Carnitine, a
transmembrane protein found only in the
mitochondrial membrane, specifically moves fatty
acyl-SCoA across the membrane into the
mitochondria.
► 3. Oxidation: The fatty acyl-SCoA must be oxidized
by enzymes in the mitochondrial matrix to produce
acetyl-SCoA plus the reduced coenzymes to be used
in ATP generation. The oxidation occurs by repeating
the series of four reactions which make up the boxidation pathway.
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► b-Oxidation refers to the oxidation of the carbon
atom b to the thioester linkage in two steps of the
pathway.
► STEP 1: The first b-oxidation: The oxidizing
agent FAD removes hydrogen atoms from the carbon
atoms a and b to the C=O group in the fatty acylSCoA, forming a carbon–carbon double bond.
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► STEP 2: Hydration: A water molecule adds across
the newly created double bond to give an alcohol
with the –OH group on the b-carbon.
► STEP 3: The second b-oxidation: NAD+ is the
oxidizing agent for conversion of the b-OH group to
a carbonyl group.
► STEP 4: Cleavage to remove an acetyl group: An
acetyl group is split off and attached to a new
coenzyme A molecule, leaving behind an acyl-SCoA
that is two carbon atoms shorter.
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The four steps of the b-oxidation pathway:
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25.6 Energy from Fatty Acid
Oxidation
► The total energy output from fatty acid catabolism is
measured by the total number of ATPs produced.
Current best estimates are that 2.5 ATPs result from
each NADH and 1.5 ATPs from each FADH2.
► The b-oxidation pathway produces 1 NADH and 1
FADH2 or 4 ATPs per cycle.
► Each acetyl-SCoA produces 3 NADH, 1 FADH2 and
1 ATP or 10 ATPs per acetyl-SCoA.
► Lauric acid, CH3(CH2)10COOH, has 12 carbons.
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► After initial activation (-2 ATP), five b-oxidations
(5x4 ATP = +20 ATP) will change lauric acid into 6
acetyl-SCoA molecules (6x10 ATP = + 60 ATP). The
total energy yield is 78 ATP per lauric acid.
► 1 mole (200g) lauric acid yields 78 moles ATP
► 1 mole (180g) glucose yields 30-32 moles ATP
► Fats and oils yield 9 Calories per gram
► Carbohydrates yield 4 Calories per gram
► Each gram of glycogen can hold as much as 2 grams
of water so fats are almost 7 times more energy
dense than carbohydrates in the body.
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25.7 Ketone Bodies and Ketoacidosis
► When there is too much acetyl-SCoA for the citric
acid cycle to process, ketone bodies are formed.
► Ketone bodies: Compounds produced in the liver
that can be used as fuel by muscle and brain tissue:
- 3-hydroxybutyrate
- acetoacetate
- acetone.
► Ketogenesis: The synthesis of ketone bodies from
acetyl-SCoA.
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► In Step 1, two acetyl-SCoA molecules combine in a
reversible reaction to produce acetoacetyl-SCoA.
► In Step 2, a third acetyl-SCoA and a water molecule
react with acetoacetyl-SCoA to give 3-hydroxy-3methylglutaryl-SCoA.
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► In Step 3, removal of acetyl-SCoA from the product
of Step 2 produces the first of the ketone bodies,
acetoacetate, the precursor of the other two ketone
bodies produced by ketogenesis, 3-hydroxybutyrate
and acetone.
► In Step 4, the acetoacetate produced in Step 3 is
reduced to 3-hydroxybutyrate. (Note that 3hydroxybutyrate and acetoacetate are connected by a
reversible reaction. In tissues that need energy,
acetoacetate is produced by different enzymes than
those used for ketogenesis. Acetyl-SCoA can then be
produced from the acetoacetate.)
► Acetone is then formed in the bloodstream by the
decomposition of acetoacetate and is excreted
primarily by exhalation.
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► Under well-fed, healthy conditions, skeletal muscles
derive a small portion of their daily energy needs
from acetoacetate, and heart muscles use it in
preference to glucose.
► During the early stages of starvation, heart and
muscle tissues burn larger quantities of acetoacetate,
thereby preserving glucose for use in the brain. In
prolonged starvation, even the brain can switch to
ketone bodies to meet up to 75% of its energy needs.
► The condition in which ketone bodies are produced
faster than they are utilized (ketosis) occurs in
diabetes. It is indicated by the odor of acetone (a
highly volatile ketone) on the patient’s breath and the
presence of ketone bodies in the urine (ketonuria)
and the blood (ketonemia).
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Two of the ketone bodies are carboxylic acids.
Ketoacidosis results from increased concentrations
of ketone bodies in the blood. The blood’s buffers
are overwhelmed and blood pH drops. Ketoacidosis
causes dehydration due to increased urine flow,
labored breathing because acidic blood is a poor
oxygen carrier, depression, and ultimately, if
untreated, the condition leads to coma and death.
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25.8 Biosynthesis of Fatty Acids
► The biosynthesis of fatty acids from acetyl-SCoA, a
process known as lipogenesis, provides a link
between carbohydrate, lipid, and protein metabolism.
► Acetyl-SCoA is an end product of carbohydrate and
amino acid catabolism, using it to make fatty acids
allows the body to divert the energy of excess
carbohydrates and amino acids into storage as TAGs.
► Fatty acid synthesis and catabolism are similar in
that they both proceed two carbon atoms at a time.
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Lipogenesis, the biochemical pathway for synthesis
of fatty acids from acetyl-SCoA, is not the exact
reverse of the b-oxidation pathway. The reverse of
an energetically favorable pathway is energetically
unfavorable.
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► The stage is set for lipogenesis by two reactions:
- (1) transfer of an acetyl group from acetyl-SCoA
to an acyl carrier protein (ACP)
- (2) conversion of acetyl- SCoA to malonyl-SCoA
in a reaction that requires investment of energy
from ATP. The malonyl-SCoA is then transferred
to the acyl carrier protein (ACP).
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► Fatty acids with up to 16 carbon atoms (palmitic
acid) are produced by a series of 4 reactions that
lengthen the growing fatty acid chain by 2 C atoms
with each repetition.
► STEP 1: Condensation: The malonyl group from
malonyl-SACP transfers to acetyl-SACP with the
loss of CO2.
► STEPS 2–4: Reduction, Dehydration, and
Reduction: These three reactions accomplish the
reverse of Steps 3, 2, and 1 in b oxidation of fatty
acids. The carbonyl group is reduced to an –OH
group, dehydration yields a C=C double bond, and
the double bond is reduced by addition of hydrogen.
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The result of
the first
cycle in fatty
acid
synthesis is
the addition
of 2 C atoms
to an acetyl
group to
give a 4carbon acyl
group.
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► The next cycle then adds two more carbon atoms to
give a 6-carbon acyl group.
► After seven trips through the elongation spiral, a 16carbon palmitoyl group is produced. Larger fatty
acids are synthesized from palmitoyl-SCoA with the
aid of specific enzymes.
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Chapter Summary
► Triacylglycerols (TAGs) from the diet are broken
into droplets in the stomach and enter the small
intestine, where they are emulsified by bile acids.
► Pancreatic lipases partially hydrolyze the TAGs,
small fatty acids and glycerol from TAG hydrolysis
are absorbed directly into the bloodstream at the
intestinal surface.
► Insoluble hydrolysis products are carried to the
lining in micelles, where they are absorbed,
reassembled into TAGs, then assembled into
chylomicrons (which are lipoproteins) and absorbed
into the lymph system for transport to the
bloodstream.
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Chapter Summary Cont.
► VLDLs carry TAGs synthesized in the liver to
peripheral tissues for energy generation or storage.
LDLs transport cholesterol from the liver to
peripheral tissues for cell membranes or steroid
synthesis. HDLs transport cholesterol from peripheral
tissues back to the liver for conversion to bile acids.
► The fatty acids undergo b oxidation to acetyl-SCoA or
resynthesis into TAGs for storage. Acetyl-SCoA can
participate in lipogenesis, ketogenesis, steroid
synthesis, or energy generation via the citric acid
cycle and oxidative phosphorylation. Glycerol can
participate in glycolysis, gluconeogenesis, or TAG
synthesis.
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Chapter Summary Cont.
► Synthesis of TAGs for storage is activated by insulin
when glucose levels are high. Glycerol 3-phosphate
adds fatty acyl groups one at a time to yield TAGs.
Hydrolysis of TAGs stored in adipocytes is activated
by glucagon when glucose levels drop.
► Fatty acids are activated (in the cytosol) by
conversion to fatty acyl-CoA, a reaction that requires
the equivalent of two ATPs, transported into the
mitochondrial matrix and oxidized two carbon atoms
at a time to acetyl-SCoA by repeated trips through
the b-oxidation spiral.
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Chapter Summary Cont.
► The ketone bodies are 3-hydroxybutyrate,
acetoacetate, and acetone. They are produced from
acetyl-SCoA when the citric acid cycle cannot keep
pace with the quantity of acetyl-SCoA available.
► This occurs during the early stages of starvation and
in unregulated diabetes. The ketone bodies are watersoluble and can travel unassisted in the bloodstream
to tissues where acetyl-SCoA is produced from
acetoacetate and 3-hydroxybutyrate. In this way,
acetyl-SCoA is made available for energy generation
when glucose is in short supply.
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Chapter Summary Cont.
► Fatty acid synthesis (lipogenesis), like b oxidation,
proceeds two carbon atoms at a time in a four-step
pathway. The pathways utilize different enzymes and
coenzymes. In synthesis, the initial two carbons are
transferred from acetyl-SCoA to the malonyl carrier
protein.
► Each additional pair of carbons is then added to the
growing chain bonded to the carrier protein, with the
final three steps of the four step synthesis sequence
the reverse of the first three steps in b oxidation.
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End of Chapter 25
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