Outline
24.1 Digestion of Triacylglycerols
24.2 Lipoproteins for Lipid Transport
24.3 Triacylglycerol Metabolism: An Overview
24.4 Storage and Mobilization of Triacylglycerols
24.5 Oxidation of Fatty Acids
24.6 Energy from Fatty Acid Oxidation
24.7 Ketone Bodies and Ketoacidosis
24.8 Biosynthesis of Fatty Acids
Goals
1. What happens during the digestion of triacylglycerols?
Be able to list the sequence of events in the digestion of dietary triacylglycerols and their
transport into the bloodstream.
2. What are the various roles of lipoproteins in lipid transport?
Be able to name the major classes of lipoproteins, specify the nature and function of the
lipids they transport, and identify their destinations.
3. What are the major pathways in the metabolism of triacylglycerols?
Be able to name the major pathways for the synthesis and breakdown of triacylglycerols
and fatty acids, and identify their connections to other metabolic pathways.
4. How are triacylglycerols moved into and out of storage in adipose tissue?
Be able to explain the reactions by which triacylglycerols are stored and mobilized, and
how these reactions are regulated.
5. How are fatty acids oxidized, and how much energy is produced by their oxidation?
Be able to explain what happens to a fatty acid from its entry into a cell until its conversion
to acetyl-CoA.
6. What is the function of ketogenesis?
Be able to identify ketone bodies, describe their properties and synthesis, and explain their
role in metabolism.
7. How are fatty acids synthesized?
Be able to compare the pathways for fatty acid synthesis and oxidation, and describe the
reactions of the synthesis pathway.
24.1 Digestion of Triacylglycerols
• The pathway of dietary triacylglycerols is
not as straightforward as that of
carbohydrates.
• Triacylglycerols are not water-soluble but
must enter an aqueous environment.
• They are packaged in lipoproteins, which
consist of droplets of hydrophobic lipids
surrounded by phospholipids and other
molecules.
• Lipoproteins are special forms of micelles.
24.1 Digestion of Triacylglycerols
24.1 Digestion of Triacylglycerols
• When food leaves the stomach, it enters
the duodenum, triggering the release of
pancreatic lipases.
• The gallbladder releases bile, a mixture of
cholesterol, phospholipids, and bile acids
that is manufactured in the liver and stored
in the gallbladder until needed.
• It is the job of bile acids and phospholipids
to emulsify the triacylglycerols by forming
micelles.
24.1 Digestion of Triacylglycerols
• The major bile acid is cholic acid.
• It resembles soaps and detergents
because it contains both hydrophilic and
hydrophobic regions.
24.1 Digestion of Triacylglycerols
• Pancreatic lipase partially hydrolyzes the
emulsified triacylglycerols, producing
mono- and diacylglycerols plus fatty acids
and a small amount of glycerol.
24.1 Digestion of Triacylglycerols
• Small fatty acids and glycerol are
absorbed through the villi that line the
small intestine, then carried by the blood
to the liver (via the hepatic portal vein).
• Water-insoluble acylglycerols and larger
fatty acids are again emulsified, then
absorbed by the cells lining the intestine.
• To enter the aqueous bloodstream for
transport, they are packaged into
lipoproteins known as chylomicrons.
24.1 Digestion of Triacylglycerols
• Chylomicrons are absorbed into the
lymphatic system through lacteals, small
vessels analogous to capillaries within villi.
• They are carried to the thoracic duct,
where the lymphatic system empties into
the bloodstream. At this point, the lipids
are ready to be used either for energy
generation or storage.
• From the thoracic duct the chylomicrons
are carried directly to the liver.
24.1 Digestion of Triacylglycerols
24.2 Lipoproteins for Lipid Transport
• The lipids used in the body’s metabolic
pathways have three sources. They enter
the pathways:
1. From the digestive tract,
2. From adipose tissue, where excess lipids
have been stored, and
3. From the liver, where lipids are synthesized.
• Whatever their source, these lipids must
eventually be transported in blood.
24.2 Lipoproteins for Lipid Transport
24.2 Lipoproteins for Lipid Transport
• Fatty acids released from adipose tissue
associate with albumin, a protein found in
blood plasma that binds up to 10 fatty acid
molecules per protein molecule.
• All other lipids are carried by lipoproteins.
• Because lipids are less dense than
proteins, the density of lipoproteins
depends on their ratio of lipids to proteins.
• Lipoproteins can be arbitrarily divided into
five major types.
24.2 Lipoproteins for Lipid Transport
• Chylomicrons are devoted to transport of lipids from the diet.
They carry triacylglycerols through the lymphatic system into
the blood and to the liver for processing. These are the
lowest-density lipoproteins.
• Very-low-density lipoproteins (VLDLs) carry triacylglycerols
from the liver (where they are synthesized) to tissues for
storage or energy generation.
• Intermediate-density lipoproteins (IDLs) carry remnants of
the VLDLs from peripheral tissues back to the liver for use in
synthesis.
• Low-density lipoproteins (LDLs) transport cholesterol from
the liver to peripheral tissues, where it is used in cell
membranes or for steroid synthesis.
• High-density lipoproteins (HDLs) transport cholesterol from
dead or dying cells back to the liver, where it is converted to
bile acids.
24.2 Lipoproteins for Lipid Transport
Lipids and Atherosclerosis
• According to the U.S. Food and Drug Administration (FDA), there is
“strong, convincing, and consistent evidence” for the connection
between heart disease and diets high in saturated fats and
cholesterol.
• A diet rich in saturated animal fats leads to an increase in bloodserum cholesterol, while a diet low in saturated fat and higher in
unsaturated fat can lower the serum cholesterol level.
• High levels of cholesterol are correlated with atherosclerosis, and an
increased risk of coronary artery disease and heart attack or stroke.
• Risk factors for heart disease: High blood levels of cholesterol and
low levels of high-density lipoproteins, cigarette smoking, high blood
pressure, diabetes, obesity, low level of physical activity, family
history of early heart disease.
• The ideal ratio of total cholesterol/HDL is considered to be 3.5. A
ratio of 4.5 indicates an average risk, and a ratio of 5 or higher
shows a high and potentially dangerous risk.
24.3 Triacylglycerol Metabolism: An Overview
24.3 Triacylglycerol Metabolism: An Overview
Dietary Triacylglycerols
• Hydrolysis occurs when chylomicrons encounter
lipoprotein lipase anchored in capillary walls.
• When energy is in good supply, they are converted
back to triacylglycerols for storage in adipose tissue.
• When cells need energy, the fatty acid carbon atoms
are activated then oxidized as acetyl-CoA.
• Acetyl-CoA generates energy via the citric acid cycle
and oxidative phosphorylation.
• Acetyl-CoA serves as the starting material for
lipogenesis, ketogenesis and the synthesis of
cholesterol, from which all other steroids are made.
24.3 Triacylglycerol Metabolism: An Overview
Triacylglycerols from Adipocytes
• When stored triacylglycerols are needed as an
energy source, lipases within fat cells are
activated by hormone level variation—low insulin
and high glucagon.
• Stored triacylglycerols are hydrolyzed to fatty
acids, and free fatty acids and glycerol are
released into the bloodstream.
• These fatty acids travel in association with
albumins (blood plasma proteins) to cells
(primarily muscle and liver cells), where they are
converted to acetyl-CoA for energy generation.
24.3 Triacylglycerol Metabolism: An Overview
Glycerol from Triacylglycerols
• Glycerol produced from triacylglycerol hydrolysis
is carried to the liver or kidneys, where it is
converted to glyceraldehyde 3-phosphate and
dihydroxyacetone phosphate (DHAP).
• DHAP enters the glycolysis/gluconeogenesis
pathways, linking lipid and carbohydrate paths.
24.3 Triacylglycerol Metabolism: An Overview
Fate of Dietary Triacylglycerols
Triacylglycerols undergo hydrolysis to fatty acids and glycerol.
Fatty acids undergo:
– Resynthesis of triacylglycerols for storage
– Conversion to acetyl-CoA
Glycerol is converted to glyceraldehyde 3-phosphate and DHAP, which
participate in:
– Glycolysis—energy generation
– Gluconeogenesis—glucose formation
– Triacylglycerol synthesis—energy storage
Acetyl-CoA participates in:
– Triacylglycerol synthesis
– Ketone body synthesis (ketogenesis)
– Synthesis of sterols and other lipids
– Citric acid cycle and oxidative phosphorylation
24.3 Triacylglycerol Metabolism: An Overview
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Fat Storage: A Good Thing or Not?
Mammals store excess dietary calories as triacylglycerols in
adipocytes (fat cells, the cells that make up adipose tissue).
Excessive storage of triacylglycerols is a predictor of serious health
problems, and has been associated with increased risk of Type II
diabetes, colon cancer, heart attack, or stroke.
Leptin, a peptide hormone, is synthesized in adipocytes and acts on
the brain to stop eating—it suppresses appetite. Grehlin stimulates
intense sensations of hunger. Other hormones, including insulin, are
also apparently involved in appetite and satiety regulation.
The bodies of mammals are seemingly “programmed” to conserve
extra calories as fat against a time when calories might be scarce.
Metabolic pathways exist to convert carbohydrate and protein into
fat for storage; it is not only dietary fat that is stored.
Scientists do not yet understand all the hormonal and metabolic
connections in the storage process, but a sensible diet combined
with exercise will sustain a stable weight without fat accumulation.
24.4 Storage and Mobilization of Triacylglycerols
Triacylglycerol Synthesis
• After a meal, blood glucose levels
increase, insulin levels rise, and glucagon
levels drop.
• Glucose enters cells, the rate of glycolysis
increases, and insulin activates the
synthesis of triacylglycerols for storage.
24.4 Storage and Mobilization of Triacylglycerols
Triacylglycerol Synthesis
• The reactants in triacylglycerol synthesis are glycerol 3phosphate and fatty acid acyl groups carried by
coenzyme A.
• Triacylglycerol synthesis proceeds by transfer of first
one and then another fatty acid acyl group from
coenzyme A to glycerol 3-phosphate.
• The reaction is catalyzed by acyl transferase, and the
product is phosphatidic acid.
24.4 Storage and Mobilization of Triacylglycerols
Triacylglycerol Synthesis
• Next, the phosphate group is removed from phosphatidic
acid to produce 1,2-diacylglycerol. The third fatty acid
group is then added to give a triacylglycerol:
24.4 Storage and Mobilization of Triacylglycerols
• Adipocytes cannot synthesize glycerol 3phosphate from glycerol.
• Glycerol 3-phosphate can be synthesized
from dihydroxyacetone phosphate
(DHAP), so adipocytes can synthesize
triacylglycerols as long as there is
available DHAP.
• This pathway is called glyceroneogenesis,
and it supplies the DHAP necessary to
become glycerol 3-phosphate.
24.4 Storage and Mobilization of Triacylglycerols
• When digestion of a meal is finished, blood glucose
levels return to normal; insulin levels drop and
glucagon levels rise.
• The lower insulin level and higher glucagon level
activate triacylglycerol lipase, the enzyme that
controls hydrolysis of stored triacylglycerols.
• When glycerol 3-phosphate is in short supply, fatty
acids and glycerol produced by hydrolysis of stored
triacylglycerols are released to the bloodstream for
transport to energy-generating cells.
• Otherwise, the fatty acids and glycerol are cycled
back into new TAGs for storage.
24.4 Storage and Mobilization of Triacylglycerols
24.5 Oxidation of Fatty Acids
Activation
• The fatty acid must be activated by conversion
to fatty acyl-CoA.
• This serves the same purpose as the first few
steps in oxidation of glucose by glycolysis.
• Some energy from ATP must be invested in
converting the fatty acid to fatty acyl-CoA, a form
that breaks down more easily.
24.5 Oxidation of Fatty Acids
Transport
• Fatty acyl-CoA must be transported from the
cytosol into the mitochondrial matrix, where
energy generation will occur.
• Carnitine undergoes an ester formation
exchange reaction with the fatty acyl-CoA,
resulting in a fatty acyl-carnitine ester that
moves into the mitochondria by facilitated
diffusion.
• There, another ester formation exchange
reaction regenerates the fatty acyl-CoA and
carnitine.
24.5 Oxidation of Fatty Acids
Oxidation:
• Fatty acyl-CoA must be oxidized in the mitochondrial
matrix to produce acetyl-CoA plus the reduced
coenzymes used in ATP generation.
• The oxidation occurs by repeating four reactions,
which make up the b-oxidation pathway.
• Each repetition of these reactions cleaves a 2carbon acetyl group from the end of a fatty acid acyl
group and produces one acetyl-CoA.
• The acyl group must continue to return to the
pathway until each pair of carbon atoms is removed.
24.5 Oxidation of Fatty Acids
24.5 Oxidation of Fatty Acids
The b-Oxidation Pathway
STEP 1: The first b -oxidation
• Acyl-CoA dehydrogenase and FAD remove
hydrogen atoms from the carbon atoms a
and b to the carbonyl group in the fatty acylCoA, forming a carbon–carbon double
bond.
• These hydrogen atoms and their electrons
are passed directly from FADH2 to
coenzyme Q so that the electrons can enter
the electron transport chain.
24.5 Oxidation of Fatty Acids
The b-Oxidation Pathway
STEP 2: Hydration
• Enoyl-CoA hydratase adds a water molecule
across the newly created double bond to give
an alcohol with the —OH group on the b
carbon.
STEP 3: The second b-oxidation
• The coenzyme NAD+ is the oxidizing agent
for conversion of the b—OH group to a
carbonyl group by b-hydroxyacyl-CoA
dehydrogenase.
24.5 Oxidation of Fatty Acids
The b-Oxidation Pathway
STEP 4: Cleavage to remove an acetyl group
• An acetyl group is split off by thiolase (acyl-CoA
acetyltransferase) and attached to a new coenzyme A
molecule, leaving behind an acyl-CoA that is two carbon
atoms shorter.
• For a fatty acid with an even number of carbon atoms, all
of the carbons are transferred to acetyl-CoA molecules
through the b-oxidation spiral. Additional steps are
required to oxidize fatty acids with odd numbers of
carbon atoms and double bonds.
24.6 Energy from Fatty Acid Oxidation
• The number of acetyl-CoA molecules produced from a
fatty acid is its number of carbon atoms divided by 2.
• These acetyl-CoA molecules proceed to the citric acid
cycle, where each one yields 1 ATP, 3 NADH molecules
and 1 FADH2.
• Using the estimates of 3 ATP molecules produced for
each NADH and 2 ATP molecules produced for each
FADH2, each acetyl-CoA generates 11 ATP molecules
from reduced coenzymes.
• Adding the single ATP molecule generated in the citric
acid cycle to the 11 obtained from the reduced
coenzymes, we get a total of 12 ATP molecules per
acetyl-CoA.
24.6 Energy from Fatty Acid Oxidation
• With 2 ATP molecules produced per
FADH2 and 3 ATP molecules produced
per NADH, 5 ATP molecules are produced
for each b-oxidation.
• The number of repetitions is always one
fewer than the number of acetyl-CoA
molecules produced because the last boxidation cleaves a 4-carbon chain to give
2 acetyl-CoA molecules
• 2 ATP molecules are spent in activation of
a fatty acid.
24.6 Energy from Fatty Acid Oxidation
• Best estimates show that 1 mol of glucose
(180 g) generates 38 mol of ATP.
• 1 mol of lauric acid (200 g) generates 95
mol of ATP.
• Fatty acids yield nearly three times as
much energy per gram as carbohydrates.
• Carbohydrates yield 4 Cal/g (16.7 kJ/g),
whereas fats and oils yield 9 Cal/g (37.7
kJ/g).
24.7 Ketone Bodies and Ketoacidosis
• b-oxidation produces several acetyl-CoA from
each molecule of fatty acid, and the enzymes in
the b-oxidation pathway catalyze reactions more
rapidly than the enzymes in the citric acid cycle.
• Excess acetyl-CoA is converted by liver
mitochondria to 3-hydroxybutyrate and
acetoacetate. Acetoacetate spontaneously
decomposes to acetone.
24.7 Ketone Bodies and Ketoacidosis
• 3-hydroxybutyrate, acetoacetate, and
acetone are known as ketone bodies.
• They are water-soluble, so once formed
they are available to all body tissues.
• Ketogenesis occurs in four enzymecatalyzed steps plus the spontaneous
decomposition of acetoacetate.
24.7 Ketone Bodies and Ketoacidosis
Steps 1 and 2 of Ketogenesis: Assembly of
6-Carbon Intermediate
• Step 1 is the reverse of the final step of b-oxidation:
two acetyl-CoA molecules combine in a reaction
catalyzed by thiolase to produce acetoacetyl-CoA.
• In Step 2, a third acetyl-CoA and a water molecule
react with acetoacetyl-CoA to give 3-hydroxy-3methylglutaryl-CoA (HMG-CoA).
24.7 Ketone Bodies and Ketoacidosis
Steps 3 and 4 of Ketogenesis: Formation of the Ketone
Bodies
• In Step 3, removal of acetyl-CoA from the product of
Step 2 produces acetoacetate.
• Acetoacetate is the precursor of 3-hydroxybutyrate and
acetone.
• In Step 4, the acetoacetate produced in Step 3 is
reduced to 3-hydroxybutyrate by 3-hydroxybutyrate
dehydrogenase.
• As acetoacetate and 3-hydroxybutyrate are synthesized,
they are released to the bloodstream. Acetone is then
formed in the bloodstream by the decomposition of
acetoacetate and is excreted primarily by exhalation.
24.7 Ketone Bodies and Ketoacidosis
24.7 Ketone Bodies and Ketoacidosis
• When energy production from glucose is
inadequate, the body must respond by
providing other energy sources, and the
production of ketone bodies accelerates.
• During the early stages of starvation, heart
and muscle burn acetoacetate, preserving
glucose for the brain.
• In prolonged starvation, the brain can
switch to ketone bodies to meet up to 75%
of its energy needs.
24.7 Ketone Bodies and Ketoacidosis
• Ketone bodies are produced faster than they are
utilized in diabetes. This is indicated by acetone
on the patient’s breath and ketone bodies in the
urine (ketonuria) and blood (ketonemia).
• Because two of the ketone bodies are carboxylic
acids, continued ketosis leads to ketoacidosis.
• The blood’s buffers are overwhelmed and blood
pH drops. Dehydration due to increased urine
flow, labored breathing (acidic blood is a poor
oxygen carrier), and depression ensue.
Untreated, the condition leads to coma and
death.
24.7 Ketone Bodies and Ketoacidosis
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The Liver, Clearinghouse for Metabolism
The liver is the largest reservoir of blood in the body and the largest
internal organ, making up about 2.5% of the body’s mass.
Blood carrying the end products of digestion enters the liver through the
hepatic portal vein before entering general circulation. The liver is
ideally situated to regulate the concentrations of substances in the
blood.
The liver synthesizes glycogen from glucose, glucose from noncarbohydrate precursors, triacylglycerols from mono- and
diacylglycerols, fatty acids, cholesterol, bile acids, plasma proteins, and
blood clotting factors, and can catabolize glucose, fatty acids, and
amino acids.
The liver stores glycogen, certain lipids and amino acids, iron, and fatsoluble vitamins; only liver cells have the enzyme needed to convert
glucose 6-phosphate to glucose that can enter the bloodstream.
A number of pathologic conditions are based on excessive
accumulation of various metabolites. One example is cirrhosis, another
is Wilson’s disease, a genetic defect in copper metabolism.
25.8 Biosynthesis of Fatty Acids
• Lipogenesis provides a link between
carbohydrate, lipid, and protein metabolism.
• Because acetyl-CoA 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 triacylglycerols.
• Fatty acid synthesis and catabolism are similar
in that they both proceed two carbon atoms at a
time and in that they are both recursive, spiral
pathways.
25.8 Biosynthesis of Fatty Acids
25.8 Biosynthesis of Fatty Acids
The stage is set for lipogenesis by two reactions:
1. Transfer of an acetyl group from acetyl-CoA to a
carrier enzyme in the fatty acid synthase complex
(S-enzyme 1) and
2. Conversion of acetyl-CoA to malonyl-CoA, followed
by transfer of the malonyl group to acyl carrier
protein (ACP) and regeneration of coenzyme A.
25.8 Biosynthesis of Fatty Acids
25.8 Biosynthesis of Fatty Acids
• The result of the first cycle in fatty acid synthesis is
the addition of two carbon atoms to an acetyl group
to give a 4-carbon acyl group still attached to the
carrier protein in fatty acid synthase.
• The next cycle adds two more carbon atoms to give
a 6-carbon acyl group by repeating the four steps of
chain elongation shown here up to sixteen carbon
palmitoyl groups.
Chapter Summary
1. What happens during the digestion of
triacylglycerols?
• Triacylglycerols from the diet are broken into droplets in
the stomach and enter the small intestine, where they are
emulsified by bile acids and form micelles.
• Pancreatic lipases partially hydrolyze the triacylglycerols
in the micelles. Small fatty acids and glycerol from
triacylglycerol 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 and reassembled into
triacylglycerols.
• These triacylglycerols are then assembled into
chylomicrons (which are lipoproteins) and absorbed into
the lymph system for transport to the bloodstream.
Chapter Summary, Continued
2. What are the various roles of lipoproteins in lipid
transport?
• In addition to chylomicrons, which carry triacylglycerols
from the diet into the bloodstream, there are VLDLs
(very-low-density lipoproteins), which carry
triacylglycerols synthesized in the liver to peripheral
tissues for energy generation or storage; LDLs (lowdensity lipoproteins), which transport cholesterol from
the liver to peripheral tissues for cell membranes or
steroid synthesis; and HDLs (high-density
lipoproteins), which transport cholesterol from
peripheral tissues back to the liver for conversion to
bile acids that are used in digestion or excreted.
Chapter Summary, Continued
3. What are the major pathways in the metabolism of
triacylglycerols?
• Dietary triacylglycerols carried by chylomicrons in the
bloodstream undergo hydrolysis to fatty acids and
glycerol by enzymes in capillary walls. Triacylglycerols
in storage are similarly hydrolyzed within adipocytes.
• The fatty acids from either source undergo b-oxidation
to acetyl-CoA or resynthesis into triacylglycerols for
storage. Acetyl-CoA can participate in resynthesis of
fatty acids (lipogenesis), formation of ketone bodies
(ketogenesis), steroid synthesis, or energy generation
via the citric acid cycle and oxidative phosphorylation.
• Glycerol can participate in glycolysis, gluconeogenesis,
or triacylglycerol synthesis.
Chapter Summary, Continued
4. How are triacylglycerols moved into and out
of storage in adipose tissue?
• Synthesis of triacylglycerols for storage is
activated by insulin when glucose levels are
high.
• The synthesis requires dihydroxyacetone
phosphate (from glycolysis or glycerol) for
conversion to glycerol 3-phosphate, to which
fatty acyl groups are added one at a time to yield
triacylglycerols.
• Hydrolysis of triacylglycerols stored in adipocytes
is activated by glucagon when glucose levels
drop.
Chapter Summary, Continued
5. How are fatty acids oxidized, and how much
energy is produced by their oxidation?
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Fatty acids are activated (in the cytosol) by
conversion to fatty acyl coenzyme A, a reaction
that requires the equivalent of two ATPs in the
conversion of ATP to AMP.
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The fatty acyl-CoA molecules are transported
into the mitochondrial matrix and are then
oxidized two carbon atoms at a time to acetylCoA by repeated trips through the b-oxidation
spiral.
Chapter Summary, Continued
6. What is the function of ketogenesis?
• The ketone bodies are 3-hydroxybutyrate,
acetoacetate, and acetone. They are produced from
two acetyl-CoA molecules.
• Their production is increased when energy generation
from the citric acid cycle cannot keep pace with the
quantity of acetyl-CoA available. This occurs during the
early stages of starvation and in unregulated diabetes.
• The ketone bodies are water-soluble and can travel
unassisted in the bloodstream to tissues where acetylCoA is produced from acetoacetate and 3hydroxybutyrate.
• In this way, acetyl-CoA is made available for energy
generation when glucose is in short supply.
Chapter Summary, Continued
7. How are fatty acids synthesized?
• Fatty acid synthesis (lipogenesis), like boxidation, proceeds two carbon atoms at a
time in a four-step pathway. The pathways
utilize different enzymes and coenzymes.
• In synthesis, the initial four carbons are
transferred from acetyl-CoA 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.