Lipid Metabolism

MC 2: Biochemistry
Faisal H. Jackarain, RN, MPH, CLSSYB
Faculty, Manila Doctors College of Nursing
 Chapter Outline
1. Digestion and absorption of lipids
2. Triacylglycerol storage and mobilization
3. Glycerol metabolism
4. Oxidation of fatty acids
5. ATP production from fatty acid oxidation
6. Ketone bodies and ketogenesis
7. Biosynthesis of fatty acids: Lipogenesis
8. Relationship between lipogenesis and citric acid cycle
intermediates
9. Fate of fatty-acid-generated acetyl CoA
10. Relationships between lipid and carbohydrate
metabolism
11. B vitamins and lipid metabolism
Digestion and Absorption of Lipids
Lipid Digestion - An Introduction
•Dietary lipids contain 98% triacylglycerols (TAGs), which include
fats and oils
•Salivary enzymes (water soluble) in the mouth have no effect on lipids
(TAGs), which are water insoluble
•In the stomach, most, not all, TAGs change physically to small
globules or droplets called chyme, which floats above other material
– It is a physical, not chemical, process
Digestion and Absorption of Lipids
Lipid Digestion - The Stomach
• Starts in the stomach
– Gastric lipase enzymes hydrolyze TAG ester bonds
– About 10% of TAGs are hydrolyzed here
•High-fat foods stay in the stomach for longer time, and a high-fat meal causes a feeling of being full for
a longer period of time
Digestion and Absorption of Lipids
Lipid Digestion - The Intestinal cells
•Chyme enters into small intestine and is emulsified (stabilization of
colloidal suspension) with bile salts
•Pancreatic lipase hydrolyzes ester bond linkages between fatty acid
units and glycerol
–Normally two out of three fatty acids are hydrolyzed
•Fatty acids, monoacyglycerols, and bile salts combine into small
droplets called micelles
–Small enough to be absorbed through intestinal cell membranes
Digestion and Absorption of Lipids
Lipid Digestion - The Intestinal cells
•In the intestinal cells, monoacylglycerols and free fatty acids are
repackaged to form TAGs
•These new TAGs combine with membrane lipids (phospholipids and
cholesterol) and water- soluble proteins to form chylomicrons
– Chylomicrons: Lipoproteins that transport TAGs from intestinal cells, via the
lymphatic system, to the bloodstream
Digestion and Absorption of Lipids
Lipid Digestion - The Bloodstream
•In the bloodstream, TAGs are completely hydrolyzed by lipase enzymes
•Fatty acids and glycerol are absorbed by the cell and are either broken down to
the acetyl CoA for energy or repacked and stored as lipids
During digestion, triacylglycerols are converted by lipases to and .
a. glycerol; free fatty acids
b. diacylglycerols; free fatty acids
c. monoacylglycerols; free fatty acids
d. chylomicrons; micelles
During digestion, triacylglycerols are converted by lipases to and .
a. glycerol; free fatty acids
b. diacylglycerols; free fatty acids
c. monoacylglycerols; free fatty acids
d. chylomicrons; micelles
Triacylglycerol Storage and Mobilization
The Adipose Tissue
•Most cells have limited capability for TAG storage
•TAGs are stored in specialized cells called adipocytes found in
adipose tissue
•Adipose tissue:
–Largest cells in the body where the cytoplasm is replaced with large TAG
droplets
–Located primarily beneath the skin, especially in the abdominal region and
vital organs
–Serves as an insulator against heat loss and
protection against physical shock
Triacylglycerol Storage and Mobilization
Structural Characteristics of an Adipose Cell
Triacylglycerol Storage and Mobilization
Hydrolysis of TAGs
•Several hormones trigger the hydrolysis of TAGs via:
–Activation of cAMP (activates hormone sensitive lipase, HSL)
–Release of glycerol and fatty acids into the bloodstream, also called
triacylglycerol mobilization
•On an average, 10% of TAGs are replaced everyday
Triacylglycerol Storage and Mobilization
TAGs and Energy Reserves
•Triacylglycerol energy reserves (fat reserves) are the human body’s
major source of stored energy
–Energy reserves associated with protein, glycogen, and glucose are small to
very small when compared to fat reserves
Triacylglycerol Storage and Mobilization

Hydrolysis of triacylglycerols in adipose tissue is triggered by

hormones that stimulate production within adipose cells that
stimulate lipases in these cells.

a.ATP
b.cyclic AMP (cAMP)
c.NADH
d.fatty acid
Triacylglycerol Storage and Mobilization

Hydrolysis of triacylglycerols in adipose tissue is triggered by

hormones that stimulate production within adipose cells that
stimulate lipases in these cells.

a. ATP
b. cyclic AMP (cAMP)
c. NADH
d. fatty acid
Glycerol Metabolism
Glycerol, After Entering the Bloodstream
•Taken to the liver or kidney and converted to dihydroxyacetone
phosphate in two steps:
– Phosphorylation of primary hydroxyl group of the glycerol
–Oxidization of secondary alcohol group of glycerol to a ketone
 Glycerol Metabolism
Glycerol, After Entering the Bloodstream
What is the fate of the glycerol that is produced during mobilization of
triacylglycerols in adipose cells?

a. It enters the bloodstream and is transported to joints where it functions as a

lubricant.
b. It is converted to fructose-1,6-bisphosphate, which is an intermediate in
gluconeogenesis.
c. It is converted by a two-step process to dihydroxyacetone phosphate, which is an
intermediate in glycolysis and gluconeogenesis.
d. Both (b) and (c).
 Glycerol Metabolism

What is the fate of the glycerol that is produced during mobilization of

triacylglycerols in adipose cells?

a. It enters the bloodstream and is transported to joints where it functions as a

lubricant.
b. It is converted to fructose-1,6-bisphosphate, which is an intermediate in
gluconeogenesis.
c. It is converted by a two-step process to dihydroxyacetone phosphate, which is an
intermediate in glycolysis and gluconeogenesis.
d. Both (b) and (c).
Oxidation of Fatty Acids
Breakdown of Fatty Acids to Produce Energy
•This process is divided into three parts:
1. Fatty acid must be activated by binding to coenzyme A
2. Fatty acid must be transported to the mitochondrial
matrix
3. Fatty acid must be repeatedly (fatty acid spiral) oxidized to produce acetyl
CoA, FADH2, and NADH
Oxidation of Fatty Acids
Fatty Acid Activation
•Takes place in the outer mitochondrial membrane
•Fatty acids react with CoA in the presence of ATP to produce high-energy acyl
CoA
•ATP is converted to AMP
Oxidation of Fatty Acids
Fatty Acid Transport
•A shuttle mechanism is involved in the transport of acyl CoA from mitochondrial
membrane to mitochondrial matrix
Oxidation of Fatty Acids
Reactions of the β-Oxidation Pathway
•Four reactions repeatedly cleave two carbon units from the carboxyl
end of the acyl CoA molecule
•This process is also called β-oxidation pathway because the second
carbon or beta carbon from the carboxyl end of the chain is oxidized
–Removes two carbon units and converts acyl CoA to
acetyl CoA
–FADH2 and NADH are produced
Oxidation of Fatty Acids
Four Steps of the Beta-Oxidation Pathway
•Step 1: First dehydrogenation
–Hydrogen atoms are removed from the α and β carbons, creating a double
bond between these two carbon atoms
–FAD is the oxidizing agent, and an FADH2 molecule is the product
•Step 2: Hydration
–A molecule of water is added across the trans double bond, producing a
secondary alcohol at the β-carbon position
Oxidation of Fatty Acids
Four Steps of the Beta-Oxidation Pathway
•Step 3: Second dehydrogenation
+
–β-hydroxyl group is oxidized to a keto functional group with NAD serving
as the oxidizing agent
•Step 4: Thiolysis
–Fatty acid chain is broken between the α and β carbons by reaction with a
coenzyme A molecule
–The result is an acetyl CoA molecule and a new acyl CoA molecule that is
shorter by two carbon atoms than its predecessor
Oxidation of Fatty Acids
Beta-Oxidation Pathway
Oxidation of Fatty Acids
Unsaturated Fatty Acids
•Oxidation of unsaturated fatty acids requires two additional steps
compared to saturated fatty acids
–Epimerase - Changes D configuration to an L
configuration
–Cis–trans isomerase - Produces a trans-(2,3) double bond from a cis-(3,4)
double bond
 Oxidation of Fatty Acids
What is the first step in the oxidation of a fatty acid?
a. It is activated by bonding to coenzyme A.
b. It is transported into the mitochondrial matrix.
c. It is oxidized to acetyl CoA, which enters the citric acid cycle.
d. It undergoes dehydrogenation.
Oxidation of Fatty Acids
What is the first step in the oxidation of a fatty acid?
a. It is activated by bonding to coenzyme A.
b. It is transported into the mitochondrial matrix.
c. It is oxidized to acetyl CoA, which enters the citric acid cycle.
d. It undergoes dehydrogenation.
ATP Production From Fatty Acid Oxidation
Fatty Acid vs. Glucose Oxidation: A Comparison
• Fatty acid oxidation produces a net of 120 ATP molecules by oxidation of C18 atom or stearic
acid
– 2 ATP molecules are needed for activation of fatty
acids, so net ATP production is 120 molecules
• 1 stearic acid molecule (C18 atom) produces 122 molecules of ATP
ATP Production From Fatty Acid Oxidation
Fatty Acid vs. Glucose Oxidation: A Comparison
•Stoichiometric comparison:
–1.00 g Stearic acid produces 0.423 mole ATP
–1.00 g glucose produces 0.167 mole ATP
•Stearic acid produces 2.5 times more energy than glucose
ATP Production From Fatty Acid Oxidation
What is the net ATP production for a 16-carbon fatty acid?
a. 78
b. 92
c. 106
d. 120
ATP Production From Fatty Acid Oxidation
What is the net ATP production for a 16-carbon fatty acid?
a. 78
b. 92
c. 106
d. 120
Ketone Bodies and Ketogenesis

•Acetyl CoA formed from β-oxidation pathway is further processed by

the citric acid cycle
–Adequate balance in carbohydrate and lipid metabolism is required
•Lipid–carbohydrate metabolism can be disturbed by the following
conditions:
–Dietary intake is high in fat and low in carbohydrates
–Diabetic conditions where the body cannot use glucose properly
–Prolonged fasting conditions
Ketone Bodies and Ketogenesis
Ketone Bodies
•Under low supply of oxaloacetate, the acetyl CoA will be in excess (increased
concentration)
•As a consequence, the excess acetyl CoA is converted to ketone bodies
Ketone Bodies and Ketogenesis
Ketogenesis
•Involves the synthesis of ketone bodies from acetyl CoA
•Primary site for this process is in the liver mitochondria
•The three ketone bodies produced are:
–Acetoacetate
–β-hydroxybutyrate
–Acetone
Ketone Bodies and Ketogenesis
Steps Involved in Ketogenesis
•Step 1: First condensation
–Two acetyl CoA molecules combine to produce acetoacetyl CoA, a reversal of
the last step of the β- oxidation pathway
•Step 2: Second condensation
–Acetoacetyl CoA reacts with a third acetyl CoA and water to produce
3-hydroxy-3-methylglutaryl CoA (HMG-CoA) and CoA–SH
Ketone Bodies and Ketogenesis
Steps Involved in Ketogenesis
•Step 3: Chain cleavage
–HMG-CoA is cleaved to acetyl CoA and acetoacetate
•Step 4: Hydrogenation
–Acetoacetate is reduced to β-hydroxybutyrate
Ketone Bodies and Ketogenesis
Summary of Ketogenesis
Ketone Bodies and Ketogenesis

•When the lipid-carbohydrate metabolism is upset by certain body conditions,

more acetyl CoA is produced that can be used in the citric acid cycle. This
results in the production of by a process known as .

a. glucose; gluconeogenesis
b. glycogen; glycogenesis
c. ketone bodies; ketogenesis
d. carbon dioxide; decarboxylation
Ketone Bodies and Ketogenesis

•When the lipid-carbohydrate metabolism is upset by certain body conditions,

more acetyl CoA is produced that can be used in the citric acid cycle. This
results in the production of by a process known as .

a. glucose; gluconeogenesis
b. glycogen; glycogenesis
c. ketone bodies; ketogenesis
d. carbon dioxide; decarboxylation
Biosynthesis of Fatty Acids: Lipogenesis
Lipogenesis vs. Fatty Acid Degradation
Biosynthesis of Fatty Acids: Lipogenesis
The Citrate–Malate Shuttle System
•Acetyl CoA is the starting material for lipogenesis
•Acetyl CoA needed for lipogenesis is generated in mitochondria and must first
be transported to the cytosol
•Citrate–malate transport system helps transport acetyl CoA to the cytosol
indirectly
Biosynthesis of Fatty Acids: Lipogenesis
The Citrate–Malate System
Biosynthesis of Fatty Acids: Lipogenesis
ACP Complex Formation
•All intermediates in fatty acid synthesis are linked to carrier proteins (ACP–SH)
•ACP–SH can be regarded as a “giant CoA molecule”
Biosynthesis of Fatty Acids: Lipogenesis
Chain Elongation
•Four reactions constitute first step of chain elongation process:
–Step 1: Condensation—where acetyl ACP and malonyl ACP condense
together to form acetoacetyl ACP
–Step 2: Hydrogenation—where the keto group of the acetoacetyl complex is
reduced to alcohol by NADPH
–Step 3: Dehydration—where water is removed from alcohol to form an alkene
–Step 4: Hydrogenation—where hydrogen is added to alkene 3 to form
saturated butyryl ACP from NADPH
Biosynthesis of Fatty Acids: Lipogenesis
Biosynthesis of Fatty Acids: Lipogenesis
Unsaturated Fatty Acid Biosynthesis
•To produce a double bond, molecular O2 is needed
–In humans and animals, enzymes can only introduce double bond between
C4 and C5 and between C9 and C10
•Consequence - Essential unsaturated fatty acids linoleic (C18 with C9
and C12 double bonds) and linolenic (C18 with C9, C12, and C15
double bonds) cannot be biosynthesized
–Should come from diet (Plants have enzymes to
synthesize them)
Biosynthesis of Fatty Acids: Lipogenesis

•Lipogenesis occurs in the cell , where all intermediates are

bound to , resulting in a fatty acid biosynthetic pathway where the
fatty acid chain increases in length by carbons per pathway
cycle.

a. mitochondria; CoA–SH; 4
b. mitochondria; CoA–SH; 2
c. cytosol; ACP–SH; 4
d. cytosol; ACP–SH; 2
Biosynthesis of Fatty Acids: Lipogenesis

•Lipogenesis occurs in the cell , where all intermediates are

bound to , resulting in a fatty acid biosynthetic pathway where the
fatty acid chain increases in length by carbons per pathway
cycle.

a. mitochondria; CoA–SH; 4
b. mitochondria; CoA–SH; 2
c. cytosol; ACP–SH; 4
d. cytosol; ACP–SH; 2
Relationships Between Lipogenesis and Citric Acid Cycle
Intermediates
•The last four intermediates of the citric acid cycle bear the following
relationship with each other:

•The intermediate C4 carbon chains of lipogenesis bear the following

relationship with each other:
Relationships Between Lipogenesis and Citric
Acid Cycle Intermediates
Important Contrasts Between Citric Acid Cycle and Lipogenesis
Intermediates
•The citric acid intermediates involve C4 diacids, and the lipogenesis
intermediates involve C4 monoacids
•The order in which the various acid derivative types are encountered in
lipogenesis is the reverse of the order in which they are encountered in the
citric acid cycle
 Relationships Between Lipogenesis and Citric Acid Cycle
Intermediates
Identify the statement that states the relationship between
lipogenesis and citric acid intermediates?

a.The lipogenesis intermediates are four carbon monoacids, and

the citric acid intermediates are four carbon diacids.
b. The lipogenesis intermediates are four carbon diacids, and the citric acid
intermediates are four carbon monoacids.
c. The intermediates in lipogenesis and the citric acid cycle are four carbon
monoacids.
d. The intermediates in lipogenesis and the citric acid cycle are four carbon
diacids.
 Relationships Between Lipogenesis and Citric Acid Cycle
Intermediates
Identify the statement that states the relationship between
lipogenesis and citric acid intermediates?

a.The lipogenesis intermediates are four carbon monoacids, and

the citric acid intermediates are four carbon diacids.
b. The lipogenesis intermediates are four carbon diacids, and the citric acid
intermediates are four carbon monoacids.
c. The intermediates in lipogenesis and the citric acid cycle are four carbon
monoacids.
d. The intermediates in lipogenesis and the citric acid cycle are four carbon
diacids.
Fate of Fatty-Acid-Generated Acetyl CoA
Acetyl CoA After Fatty Acid Oxidation
•Further channeled in different routes:
–Further processed to obtain ATP
–Ketone body formation
–Storage in the form of TAGs
–Used as starting material for the production of lipids and other fatty
acids
•Example: Cholesterol biosynthesis occurs when the
body is in an acetyl-CoA-rich state
Fate of Fatty-Acid-Generated Acetyl CoA
Cholesterol
•Necessary component of cell membrane
•Precursor for bile salts, sex hormones, and adrenal hormone
Fate of Fatty-Acid-Generated Acetyl CoA
Biosynthesis of cholesterol occurs in the _____.
a. muscles
b. liver
c. small intestine
d. pancreas
Fate of Fatty-Acid-Generated Acetyl CoA
Biosynthesis of cholesterol occurs in the _____.
a. muscles
b. liver
c. small intestine
d. pancreas
Relationships Between Lipid and Carbohydrate
Metabolism
An Overview

•Acetyl CoA is the primary link between lipid and carbohydrate

metabolism pathways
•Acetyl CoA:
–Starting material for the biosynthesis of fatty acids, cholesterol, and ketone
bodies
–Degradation product for glucose, glycerol, and fatty acids
Relationships Between Lipid and Carbohydrate
Metabolism

What is the product of lipid and carbohydrate metabolism that enters

the citric acid cycle?
a. Pyruvate
b. ACP-SH
c. Acetyl CoA
d. Lactic acid
Relationships Between Lipid and Carbohydrate
Metabolism

What is the product of lipid and carbohydrate metabolism that enters

the citric acid cycle?
a. Pyruvate
b. ACP-SH
c. Acetyl CoA
d. Lactic acid
B Vitamins and Lipid Metabolism

•Structurally modified B vitamins function as coenzymes in lipid metabolism

•B vitamins that participate in various pathways of lipid metabolism include:
+
–Niacin (as NAD , NADH, and NADPH)
–Riboflavin (as FAD)
–Pantothenic acid (as CoA, acetyl CoA, and ACP)
–Biotin
B Vitamins and Lipid Metabolism
B Vitamin Participation in Lipid Metabolism Reactions
B Vitamins and Lipid Metabolism

Which of the following B-vitamin-containing coenzymes is needed in

the reactions associated with the conversion of fatty acids to acetyl
CoA?

a. NADP
b. FAD
c. Biotin
d. None of the above
B Vitamins and Lipid Metabolism

Which of the following B-vitamin-containing coenzymes is needed in

the reactions associated with the conversion of fatty acids to acetyl
CoA?

a. NADP
b. FAD
c. Biotin
d. None of the above
 Concept Question 1

Shortly after arriving at your place of work in a clinical laboratory, you have your blood drawn for
serum analysis. You notice your serum is milky white in appearance rather than the normal
straw color. Why is this?

a.You probably have a blood bacterial infection.

b. You had a high-fat breakfast, and the milky color is due to the presence of high levels of chylomicron, a
lipoprotein that transports triacylglycerols from the small intestine to the bloodstream.
c. You had a high-fat breakfast, and the milky color is due to the presence of high levels of low-density
lipoprotein, a lipoprotein that transports triacylglycerols from the small intestine to the bloodstream.
d.You had a high-fat breakfast, and the milky color is due to the presence of high levels of high-density
lipoprotein, a lipoprotein that transports triacylglycerols from the small intestine to the bloodstream.
 Concept Question 1

Shortly after arriving at your place of work in a clinical laboratory, you have your blood drawn for
serum analysis. You notice your serum is milky white in appearance rather than the normal
straw color. Why is this?

a.You probably have a blood bacterial infection.

b. You had a high-fat breakfast, and the milky color is due to the presence of high levels of chylomicron, a
lipoprotein that transports triacylglycerols from the small intestine to the bloodstream.
c. You had a high-fat breakfast, and the milky color is due to the presence of high levels of low-density
lipoprotein, a lipoprotein that transports triacylglycerols from the small intestine to the bloodstream.
d.You had a high-fat breakfast, and the milky color is due to the presence of high levels of high-density
lipoprotein, a lipoprotein that transports triacylglycerols from the small intestine to the bloodstream.
 Concept Question 2

Besides cholesterol being an important cell membrane component,

what other function does cholesterol serve?

a.It is a precursor for various classes of steroid hormones.

b. It can be converted to glucose during gluconeogenesis when high levels of
energy are required.
c. It is converted to steroid hormones, bile acids, and Vitamin K.
d. It has no other function and any excess is deposited in arteries, increasing the
risk of heart disease.
 Concept Question 2

Besides cholesterol being an important cell membrane component,

what other function does cholesterol serve?

a. It is a precursor for various classes of steroid hormones.

b. It can be converted to glucose during gluconeogenesis when high levels of
energy are required.
c. It is converted to steroid hormones, bile acids, and Vitamin K.
d. It has no other function and any excess is deposited in arteries, increasing the
risk of heart disease.