Lipids Metabolism

CC 103: BIOCHEMISTRY FOR MLS
College of Liberal Arts, Sciences and Education

Prepared by: Dennis M. Dimaranan
Erwin R. Abrencillo, PhD
MODULE 11
LIPIDS METABOLISM
Brief Introduction or Description
This module discusses the energy-generating pathways of Lipids metabolism. When glucose supplies
are low, the body is able to draw upon lipids as an alternative energy source. Lipids are generally stored as
triglycerides and the first step in lipid metabolism is the conversion to glycerol and fatty acids which then enter
the Krebs cycle.
Lipids are fatty substances that are required for maintenance of normal bodily function. Cholesterol and
triglycerides are the major lipids that circulate in blood plasma and are transported in globules known as
lipoproteins. Cholesterol is an important component of cell membranes and is required for the synthesis of
steroid hormones and bile acids. As the daily requirement for cholesterol cannot be met from dietary intake,
the majority (80%) is derived from biosynthesis in the liver. Triglycerides are the storage form of long chain
fatty acids, derived from the diet or synthesized in the liver, which are an important source of energy and
structural fatty acids required for formation of phospholipids, an essential component of cell membranes. Both
the liver and the gut package cholesterol, triglycerides and fat-soluble vitamins into lipoproteins for delivery to
other tissues.
Learning Outcomes:
By the end of the module, you should be able to:
1 Explain how energy can be derived from fat
2. Explain the purpose and process of Fatty Acid Oxidation

3. Differentiate Fatty acid oxidation from Fatty acid synthesis
4. Explain the purpose and the process of lipogenesis and lipolysis
5. Describe the properties of lipoprotein
Pre – Assessment. Read the following questions and Encircled the correct letter
1. The acetyl CoA is produced in the mitochondria and must be transported into cytosol for synthesis of fatty
acid. Which of the following is true regarding its transport?
A. Acetyl CoA is diffused from mitochondrial membrane
B. Acetly CoA is transported by its specific transporter protein
C. Acetyl CoA is converted into pyruvate, enters into cytosol and acetyl CoA is regenerated
D. Acetyl CoA is converted into citrate, enters into cytosol and acetyl CoA is regenerated.
2. What are the most active organs in the animal body that can synthesize triacylglycerol?
A. Liver and intestines
B. Kidney and intestines
C. Gall bladder and kidneys
D. Pancreas and intestines
3. Fatty acid β-oxidation occurs in
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A. Mitochondria
B. Peroxisomes
C. Lysosomes
D. All of the above

4. What is the allosteric regulator of acetyl CoA caboxylase?
A. Fatty acid
B. ATP
C. Citrate
D. Acetly CoA
5. The conversion of acetyl CoA to malonyl CoA is the rate limiting step in fatty acid synthesis. Which of the
following enzyme catalyzes the above mentioned reaction?
A. Acetly CoA carboxylase
B. Malonyl CoA synthetase
C. Acetyl CoA decarboxylase
D. Malonyl CoA synthase
Lesson 1: Triacylglycerols—the body fuel reserve
Lipids constitute about 15-20% of the body weight in humans. Triacylglycerols (formerly triglycerides) are the
most abundant lipids comprising 85-90% of body lipids. Most of the triacylglycerols (TGs; also called neutral fat
or depot fat) are stored in the adipose tissue and serve as energy reserve of the body. This is in contrast to
carbohydrates and proteins which cannot be stored to a significant extent for energy purposes. Fat also acts as
an insulating material for maintaining the body temperature of animals.
Why should fat be the fuel reserve of the body?
Triacylglycerols are the most predominant storage form of energy. There are two main reasons for fat being
the fuel reserve of the body
1. Triacylglycerols (TGs) are highly concentrated form of energy, yielding 9 Cal/g, in contrast to carbohydrates
and proteins that produce only 4 Cal/g. This is because fatty acids found in TG are in the reduced form.
2. The triacylglycerols are non-polar and hydrophobic in nature, hence stored in pure form without any
association with water (anhydrous form). On the other hand, glycogen and proteins are polar. One gram of
glycogen combines with 2 g of water for storage.
Long chain fatty acids (of fat) are the ideal storage fuel reserves of the body. Fats can support the body’s
energy needs for long periods of food deprivation. In extreme cases, humans can fast and survive for 60–90
days, and the obese persons can survive even longer (6 months to one year!) without food.
Hibernating animals provide good example for utilizing fat reserve as fuel. For instance, bears go on
hibernation for about 7 months and, during this entire period, the energy is derived from the degradation of
fat stores.
Other important body lipids
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Phospholipids, glycolipids and cholesterol are major components of cell membranes. Cholesterol is also a
precursor for bile acids and steroid hormones. Arachidonic acid—an unsaturated fatty acid—is the substrate
for the synthesis of certain intercellular regulators— prostaglandins, thromboxanes, prostacyclins etc.
Transport of lipids
The insoluble lipids are solubilized in association with proteins to form lipoproteins in which form lipids are
transported in the blood stream. Free lipids are undetectable in blood. Chylomicrons, very low density
lipoproteins (VLDL), low density lipoproteins (LDL), high density lipoproteins (HDL) and albumin-free fatty acids
are the different lipoprotein complexes that transport lipids in the blood stream
Lesson 2: LIPOLYSIS (TRIGLYCERIDES BREAKDOWN)
To obtain energy from fat, triglycerides must first be broken down by hydrolysis into their two principal
components, fatty acids and glycerol.
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This process, called lipolysis, takes place in the cytoplasm. The resulting fatty acids are oxidized by β-
oxidation into acetyl CoA, which is used by the Krebs cycle. The glycerol that is released from triglycerides
after lipolysis directly enters the glycolysis pathway as DHAP. Because one triglyceride molecule yields three
fatty acid molecules with as much as 16 or more carbons in each one, fat molecules yield more energy than
carbohydrates and are an important source of energy for the human body. Triglycerides yield more than twice
the energy per unit mass when compared to carbohydrates and proteins. Therefore, when glucose levels are
low, triglycerides can be converted into acetyl CoA molecules and used to generate ATP through aerobic
respiration.
There are two primary lipolysis enzymes:
 Lipoprotein lipase (LPL)

 Hormone-sensitive lipase (HSL)
Despite performing the same function, at the adipose level, the enzymes are primarily active for
seemingly opposite reasons. In the fed state, LPL on the endothelium of blood vessels cleaves lipoprotein
triglycerides into fatty acids so that they can be taken up into adipocytes, for storage as triglycerides, or
myocytes where they are primarily used for energy production. This action of LPL on lipoproteins is shown in
the two figures below.
HSL is an important enzyme in adipose tissue, which is a major storage site of triglycerides in the body. HSL
activity is increased by glucagon and epinephrine ("fight or flight" hormone), and decreased by insulin. Thus, in
hypoglycemia (such as during a fast) or a "fight or flight" response, triglycerides in the adipose are cleaved,
releasing fatty acids into circulation that then bind with the transport protein albumin. Thus, HSL is important
for mobilizing fatty acids so they can be used to produce energy. The figure below shows how fatty acids can
be taken up and used by tissues such as the muscle for energy production.
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We are not going to focus on glycerol, but it does have two metabolic fates.
 It can be broken down in glycolysis

 It can be used to synthesize glucose (gluconeogenesis)
Lesson 3: FATTY ACID OXIDATION ( β – oxidation)

The metabolic process by which fatty acids and their lipidic derivatives are broken down is called β-
oxidation. This process bears significant similarity to the mechanism by which fatty acids are synthesized,
except in reverse. In brief, the oxidation of lipids proceeds as follows: two-carbon fragments are removed
sequentially from the carboxyl end of the fatty acid after dehydrogenation, hydration, and oxidation to form a
ketoacid, which is then cleaved by thiolysis. The acetyl-CoA molecule liberated by this process is eventually
converted into ATP through the TCA cycle.
β-oxidation can be broken down into a series of discrete steps:
1. Activation: Before fatty acids can be metabolized, they must be “activated. ” This activation step
involves the addition of a coenzyme A (CoA) molecule to the end of a long-chain fatty acid, after which
the activated fatty acid (fatty acyl -CoA) enters the β-oxidation pathway.
2. Oxidation: The initial step of β-oxidation is catalyzed by acyl-CoA dehydrogenase, which oxidizes the
fatty acyl-CoA molecule to yield enoyl-CoA. As a result of this process, a trans double bond is
introduced into the acyl chain.
3. Hydration: In the second step, enoyl-CoA hydratase hydrates the double bond introduced in the
previous step, yielding an alcohol (-C-OH).
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4. Oxidation: Hydroxyacyl-CoA dehydrogenase oxidizes the alcohol formed in the previous step to a
carbonyl (-C=O).
5. Cleavage: A thiolase then cleaves off acetyl-CoA from the oxidized molecule, which also yields an acyl-
CoA that is two carbons shorter than the original molecule that entered the β-oxidation pathway.
This cycle repeats until the fatty acid has been completely reduced to acetyl-CoA, which is fed through the
TCA cycle to ultimately yield cellular energy in the form of ATP.
Oxidation of fatty acids and metabolic water

Fatty acid oxidation (even other forms of aerobic respiration) is accompanied by the production of water,
referred to metabolic water.
For instance, when one molecule of palmitic acid is oxidized, it releases 16 molecules of water. This metabolic
water has great significance in some animals. Camel can store lipids in its hump which is good source of water,
besides energy supply. For this reason, camel can travel in deserts for long periods even without food and
water supply. Kangaroo rat is a small animal that is believed to live indefinitely without water. It consumes
only oil rich seeds, and the metabolic water produced is adequate to meet its water needs. It may however, be
noted that the use of metabolic water is an adaptation, and is accompanied by reduced output of urine.
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Lesson 4 – KETOGENESIS
The synthesis of ketone bodies occurs in the liver. The enzymes for ketone body synthesis are located in the
mitochondrial matrix. Acetyl CoA, formed by oxidation of fatty acids, pyruvate or some amino acids, is the
precursor for ketone bodies. Ketogenesis
occurs through the following reactions
(Fig.14.11).
1. Two moles of acetyl CoA condense to form
acetoacetyl CoA. This reaction is catalyzed by
thiolase, an enzyme involved in the final step of
β-oxidation. Hence, acetoacetate synthesis is
appropriately regarded as the reversal of
thiolase reaction of fatty acid oxidation.
2. Acetoacetyl CoA combines with another
molecule of acetyl CoA to produce β--hydroxy -
β-methyl glutaryl CoA (HMG CoA). HMG CoA
synthase, catalysing this reaction, regulates the
synthesis of ketone bodies.
3. HMG CoA lyase cleaves HMG CoA to produce
acetoacetate and acetyl CoA.
4. Acetoacetate can undergo spontaneous
decarboxylation to form acetone.
5. Acetoacetate can be reduced by a
dehydrogenease to - β-hydroxybutyrate. The
carbon skeleton of some amino acids
(ketogenic) is degraded to acetoacetate or
acetyl CoA and, therefore, to ketone bodies,
e.g. leucine, lysine, phenylalanine etc.
Utilization of ketone bodies
The ketone bodies, being water-soluble, are
easily transported from the liver to various
tissues. The two ketone bodies—acetoacetate
and β -hydroxybutyrate serve as important sources of energy for the peripheral tissues such as skeletal
muscle, cardiac muscle, renal cortex etc. The tissues which lack mitochondria (e.g. erythrocytes) however,
cannot utilize ketone bodies. The production of ketone bodies and their utilization become more significant
when glucose is in short supply to the tissues, as observed in starvation, and diabetes mellitus.
Starvation : Starvation is accompanied by increased degradation of fatty acids (from the fuel reserve
triacylglycerol) to meet the energy needs of the body. This causes an overproduction of acetyl CoA which
cannot be fully handled by citric acid cycle. Furthermore, TCA cycle is impaired due to deficiency of
oxaloacetate, since most of it is diverted for glucose synthesis to meet the essential requirements (often
unsuccessful) for tissues like brain. The result is an accumulation of acetyl CoA and its diversion for
overproduction of ketone bodies.
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During prolonged starvation, ketone bodies are the major fuel source for the brain and other parts of central
nervous system. It should be noted that the ability of the brain to utilize fatty acids for energy is very limited.
The ketone bodies can meet 50-70% of the brain’s energy needs. This is an adaptation for the survival of the
organism during the periods of food deprivation.
Diabetes mellitus is associated with insulin deficiency. This results in impaired carbohydrate metabolism and
increased lipolysis, both of them ultimately leading to the accumulation of acetyl CoA and its conversion to
ketone bodies. In severe diabetes, the ketone body concentration in blood plasma may reach 100 mg/dl and
the urinary excretion may be as high as 500 mg/day.
When the rate of synthesis of ketone bodies exceeds the rate of utilization, their concentration in blood
increases, this is known as ketonemia. Ketonemia is predominantly due to increased production of ketone
bodies rather than the deficiency in their utilization. The term ketonuria represents the excretion of ketone
bodies in urine. The overall picture of ketonemia and ketonuria is commonly referred to as ketosis. Smell of
acetone in breath is a common feature in ketosis. Ketosis is most commonly associated with starvation and
severe uncontrolled diabetes mellitus
Regulation of ketogenesis
The ketone body formation (particularly overproduction) occurs primarily due to no availability of
carbohydrates to the tissues. This is an outcome of excessive utilization of fatty acids to meet the energy
requirements of the cells. The hormone glucagon stimulates ketogenesis whereas insulin inhibits. The
increased ratio of glucagon/insulin in diabetes mellitus promotes ketone body formation. This is due to
disturbances caused in carbohydrate and lipid metabolisms in diabetes,
After they are synthesized in the liver, ketone bodies are released into circulation where they can travel to the
brain. The brain converts the ketone bodies to acetyl- CoA that can then enter the citric acid cycle for ATP
production, as shown below.
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If there are high levels of ketones secreted, it results in a condition known as ketosis or ketoacidosis. The high
level of ketones in the blood decreases the blood’s pH, meaning it becomes more acidic. It is debatable
whether mild ketoacidosis is harmful, but severe ketoacidosis can be lethal. One symptom of this condition is
fruity or sweet smelling breath, which is due to increased acetone exhalation.
Lesson 5: Fatty Acids Synthesis

Fatty acid production is controlled by enzymes, metabolites, end products, hormones and dietary
manipulations
Acetyl CoA carboxylase : This enzyme controls a committed step in fatty acid synthesis. Acetyl CoA carboxylase
exists as an inactive protomer (monomer) or an active polymer. Citrate promotes polymer formation, hence
increases fatty acid synthesis. On the other hand, palmitoyl CoA and malonyl CoA cause depolymerization of
the enzyme and, therefore, inhibit fatty acid synthesis.
Hormonal influence : Hormones regulate acetyl CoA carboxylase by a separate mechanism—phosphorylation
(inactive form) and dephosphorylation (active form) of the enzyme. Glucagon, epinephrine and
norepinephrine inactivate the enzyme by cAMPdependent phosphorylation. Insulin, on the other hand,
dephosphorylates and activates the enzyme. Thus, insulin promotes fatty acid synthesis while glucagon
inhibits.
Dietary regulation : Consumption of high carbohydrate or fat-free diet increases the synthesis of acetyl CoA
carboxylase and fatty acid synthase, which promote fatty acid formation. On the other hand, fasting or high
fat diet decreases fatty acid production by reducing the synthesis of these two enzymes.
Page 9 of 13
Lesson 6 – Lipoprotein
Lipoproteins are molecular complexes that consist of
lipids and proteins (conjugated proteins). They
function as transport vehicles for lipids in blood
plasma. Lipoproteins deliver the lipid components
(cholesterol, triacylglycerol etc.) to various tissues for
utilization.
Structure of lipoproteins
A lipoprotein basically consists of a neutral lipid core
(with triacylglycerol and/or cholesteryl ester)
surrounded by a coat shell of phospholipids,
apoproteins and cholesterol (Fig.14.33). The polar
portions (amphiphilic) of phospholipids and cholesterol
are exposed on the surface of lipoproteins so that
lipoprotein is soluble in aqueous solution.
Classification of lipoproteins
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Five major classes of lipoproteins are identified in human plasma, based on their separation by electrophoresis
(Fig.14.34).
1. Chylomicrons : They are synthesized in the intestine and transport exogenous (dietary) triacylglycerol to
various tissues. They consist of highest (99%) quantity of lipid and lowest (1%) concentration of protein. The
chylomicrons are the least in density and the largest in size, among the lipoproteins.
2. Very low density lipoproteins (VLDL) : They are produced in liver and intestine and are responsible for the
transport of endogenously synthesized triacylglycerols.
3. Low density lipoproteins (LDL) : They are formed from VLDL in the blood circulation. They transport
cholesterol from liver to other tissues.
4. High density lipoproteins (HDL) : They are mostly synthesized in liver. Three different fractions of HDL (1, 2
and 3) can be identified by ultracentrifugation. HDL particles transport cholesterol from peripheral tissues to
liver (reverse cholesterol transport).
5. Free fatty acids—albumin : Free fatty acids in the circulation are in a bound form to albumin. Each molecule
of albumin can hold about 20-30 molecules of free fatty acids. This lipoprotein cannot be separated by
electrophoresis
Lesson 7 – De Novo Synthesis of Fatty Acids (Lipogenesis)

De novo in Latin means “from the beginning.” Thus, de novo lipogenesis is the synthesis of fatty acids,
beginning with acetyl-CoA. Acetyl-CoA has to first move out of the mitochondria, where it is then converted to
malonyl-CoA (3 carbons). Malonyl-CoA then is combined with another acetyl-CoA to form a 4 carbon fatty acid
(1 carbon is given off as CO2). The addition of 2 carbons is repeated through a similar process 7 times to
produce a 16 carbon fatty acid1.
Learning Tasks
A. My Role. Identify the role of the following biochemical substance in the process of lipid metabolism
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1. beta (β)-hydroxybutyrate
2. beta (β)-oxidation
3. bile salts:
4. cholecystokinin (CCK)
5. chylomicrons
6. fatty acid oxidation
7. hydroxymethylglutaryl CoA (HMG CoA
8. ketone bodies
9. lipogenesis
10. lipolysis
11. monoglyceride molecules
12. pancreatic lipases
13. triglycerides
14. acetoacetate
15. Acetyl CoA carboxylase
16. Malonyl - CoA
17. HMG CoA lyase
18. Lipoprotein lipase (LPL)
19. Hormone-sensitive lipase (HSL)
20. Hydroxyacyl-CoA dehydrogenase
B. Essay Questions. Answer the following answer and Explain your answer briefly but concisely (5 pts each)
1. Describe the digestion and absorption of dietary lipids.

2. Give an account of β – oxidation of saturated even carbon fatty acid (Palmitic acid) along with its
energetics and regulation.
3. Describe denovo synthesis of saturated long chain fatty acid and its regulation.
4 .Enumerate the ketone bodies. Describe the formation and fate of ketone bodies.
5. Give an account of synthesis, transport and functions of HDL, LDL and chylomicrons.
6. Explain denovo synthesis of cholesterol and its regulation. Add a note on cholesterol lowering drugs.
7. Explain the differences between fatty acid synthesis and fatty acid oxidation
8. How does ketone bodies affects starvation and diabetes milletus?

C. Case Analysis: Read and Analyze the following case situation and answer the guide questions.
Case 1
On examination ,the patient was in no acute distress with normal vital sign. His lungs were clear to auscultation
bilateally and his heart had a regular rate and rhythm with no murmurs. An Electrocardiogram revealed a slight ischemic
changes. The blood chemistry raised serum total cholesterol and LDL cholesterol level. The patient was placed on a low
fat diet and Lovastatin Therapy. He was without complaints was feeling well on his subsequent follow up visit. On repeat
serum cholesterol screening. A decrease in cholesterol level was noted.
1. What is the mechanism of action of this drug?

2. What are the alternative options to treat the patient?
Page 12 of 13
Case 2
A teenage girl was brought to the medical center because of her complaints that she used to get too
tired when to ask to participate in gymnastic classes. A consulting neurologist found muscle weaknesses in girl
arms and legs. When no obvious could be made, biopsies of her muscles were taken for test. Biochemistry
revealed greatly elevated amount of triglycerides esterified with primary long fatty acids. Pathology reported
the presence of significant numbers of lipid vacuoles in the muscle biopsy. A Chest X-ray showed moderate
enlargement of her heart. Her liver was moderately enlarge and palpable. She was slight hypoglycemic and her
non –esterified fatty acids were slightly higher than would be expected for an overnight fast. Ketone bodies
were not detectable.
1. What is the probable diagnosis?
2. What might be the cause of her symptoms?
References:
Biochemistry and Agricultural Chemistry Division. (2009). Lecture Booklet in Biochemistry. Los Baños, Laguna:
UPLB Institute of Chemistry.
Chua, J.M.T (2022). Biological chemistry. Lorimar Publishing House Inc.
Satyanarayana U and Chakrapani U. (2013). Biochemistry. New Delhi, India: Elsevier.
Stoker, S. H (207). General, Organic and Biochemistry. Houghton Mifflin College Div; 4th edition
https://slideplayer.com/slide/5090011/
https://www.andrew.cmu.edu/course/03-231/MCQF05/MCQLec32.htm
https://www.google.com/search?q=cell+signaling+regulation+of+metabolism+harvey
https://www.researchgate.net/figure/Overview-of-the-major-metabolic-pathways-in-pluripotent-stem-cells-and-
their_fig2_339573392
https://bio.libretexts.org/Courses/Lumen_Learning/Book%3A_Anatomy_and_Physiology_II_(Lumen)/10%3A_Module_8
-_Metabolism_and_Nutrition/10.02%3A_Overview_of_Metabolic_Reactions
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Lipids Metabolism

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CC 103: BIOCHEMISTRY FOR MLS

College of Liberal Arts, Sciences and Education

2. Explain the purpose and process of Fatty Acid Oxidation

D. All of the above

Lesson 2: LIPOLYSIS (TRIGLYCERIDES BREAKDOWN)

 Lipoprotein lipase (LPL)

 It can be broken down in glycolysis

Lesson 3: FATTY ACID OXIDATION ( β – oxidation)

Oxidation of fatty acids and metabolic water

Lesson 5: Fatty Acids Synthesis

Lesson 7 – De Novo Synthesis of Fatty Acids (Lipogenesis)

1. Describe the digestion and absorption of dietary lipids.

8. How does ketone bodies affects starvation and diabetes milletus?

1. What is the mechanism of action of this drug?

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