2.

The Metabolism of Lipids and its

Alterations

Table of Contents
INTRODUCTION ............................................................................................................................... 2
DEFINITION, CLASSIFICATION, AND FUNCTIONS OF LIPIDS ........................................................... 3
Definition .................................................................................................................................. 3
Classification of Lipids ................................................................................................................ 3
Simple Lipids ............................................................................................................................. 3
Complex or Compound Lipids ...................................................................................................... 3
Derived Lipids ........................................................................................................................... 4
Functions of Lipids ..................................................................................................................... 4
DEFINITION, CLASSIFICATION, AND FUNCTIONS OF FATTY ACIDS ................................................ 5
Definition .................................................................................................................................. 5
Classification of Fatty Acids ......................................................................................................... 5
Straight-Chain Fatty Acids ........................................................................................................... 5
Branched Fatty Acids .................................................................................................................. 7
Substituted Fatty Acids ................................................................................................................ 7
Cyclic Fatty Acids ...................................................................................................................... 8
CLINICAL SIGNIFICANCE OF MONOUNSATURATED FATTY ACID AND POLYUNSATURATED
FATTY ACID .................................................................................................................................... 8
Clinical Significance of Monounsaturated Fatty Acids (MUFAs) ......................................................... 8
Clinical Significance of Polyunsaturated Fatty Acids (PUFAs) ............................................................ 9
CLINICAL SIGNIFICANCE OF ESSENTIAL FATTY ACIDS AND TRANS FATTY ACIDS ........................ 9
Essential Fatty Acids ................................................................................................................... 9
Trans Fatty Acids ..................................................................................................................... 10
DIGESTION AND ABSORPTION OF LIPIDS ..................................................................................... 11
Digestion of Lipids .................................................................................................................... 11
Digestion in Small Intestine ........................................................................................................ 11
Absorption of Lipids by Intestinal Mucosal Cells ........................................................................... 12
Transport of Dietary Lipids ........................................................................................................ 12
Abnormalities in Lipid Digestion and Absorption ........................................................................... 13
METABOLISM OF LIPIDS AND RELATED DISORDERS ................................................................... 14
Fatty Acid Oxidation ................................................................................................................. 14
Synthesis of Fatty Acids ............................................................................................................ 19
Triacylglycerol Metabolism ......................................................................................................... 19
Cholesterol Metabolism .............................................................................................................. 22
COMPOUNDS FORMED FROM CHOLESTEROL ............................................................................... 24
Steroid Hormones ..................................................................................................................... 24
Vitamin D Hormone .................................................................................................................. 24
Bile Acids ................................................................................................................................ 24
KETONE BODIES: NAME, TYPES AND SIGNIFICANCE .................................................................... 26
Name and Types of Ketone Bodies .............................................................................................. 27
Formation of Ketone Bodies ....................................................................................................... 28
Utilization of Ketone Bodies ....................................................................................................... 28
Significance of Ketone Body Formation ........................................................................................ 28
Disorders of Ketone Body Metabolism ......................................................................................... 29
LIPOPROTEINS, TYPES AND FUNCTIONS ....................................................................................... 30

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Types of Lipoproteins ................................................................................................................ 31

Functions of Lipoprotein ............................................................................................................ 32
ATHEROSCLEROSIS ....................................................................................................................... 33
Prevention of Atherosclerosis ...................................................................................................... 34
LIPID PROFILE ............................................................................................................................... 34
Total Serum Cholesterol ............................................................................................................. 35
Serum Triglycerides ................................................................................................................... 35
HDL Cholesterol ....................................................................................................................... 36
LDL Cholesterol ....................................................................................................................... 37

Unit Learning outcomes Content

2 Explain the metabolism of lipids • Definition, classification and
and its alterations functions of lipids

• Definition, classification and

functions of fatty acids

• Definition and clinical

significance of monounsaturated
fatty acids (MUFA), and
polyunsaturated fatty acids
(PUFA)

• Definition and clinical

significance of essential fatty
acids, and trans fatty acids

• Digestion, and absorption of

lipids

• Metabolism of lipids and related

disorders

• Compounds formed from

cholesterol

• Ketone bodies, name, types and

significance

• Lipoproteins, types and

functions

• Atherosclerosis

• Lipid profile

INTRODUCTION
Lipids are naturally occurring water insoluble substances. Due to predominance of hydrocarbon chains in their
structure, lipids have hydrophobic nature. Some lipids are vital energy reserves, whereas others are the primary
structural components of biological membranes. This chapter describes the structures, properties, and functions of the
major lipid classes found in living organism and their metabolism.

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DEFINITION, CLASSIFICATION, AND

FUNCTIONS OF LIPIDS
Definition
Lipids may be defined as organic substances insoluble in water but soluble in organic solvents such as chloroform,
ether, and benzene. They are esters of fatty acids with alcohol and are utilizable by the living organism.

Classification of Lipids
The most commonly used classification of lipids is as follows:

1. Simple lipids

2. Complex or compound lipids

3. Derived lipids

Simple Lipids
These are esters of fatty acids with various alcohols. Depending on the type of alcohols, these are subclassified as:

1. Neutral fats or triacylglycerol or triglycerides

2. Waxes

Neutral Fats or Triacylglycerol or Triglycerides

These are esters of fatty acids with alcohol glycerol, e.g., tripalmitin. Because they are uncharged, they are termed
neutral fat. The fats we eat are mostly triglycerides. A fat in liquid state is called oil, e.g., vegetable oils such as
groundnut oil, mustard oil, and corn oil.

Waxes
These are esters of fatty acids with higher molecular weight long-chain alcohols. These compounds have no
importance as far as human metabolism is concerned. These are widely used in pharmaceutical, cosmetic, and other
industries in the manufacture of lotions, ointments, and polishes. Examples of waxes are lanolin (from lamb's wool),
beeswax, and spermaceti oil (from whales).

Waxes also contain long-chain alcohols, aldehydes, and steroid alcohols, e.g., cholesterol ester, vitamin A ester
(retinol), and vitamin D ester.

Complex or Compound Lipids

These are esters of fatty acids, with alcohol containing additional (prosthetic) groups. These are subclassified according
to the type of prosthetic group present in the lipid as follows:

• Phospholipids

• Glycolipids

• Lipoproteins

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Phospholipids
Phospholipids are lipids containing phosphoric acid as a prosthetic group in addition to fatty acids and an alcohol.
They also have nitrogen-containing bases and other substituents. Phospholipids may be classified on the basis of the
type of alcohol present in them as glycerophospholipids and sphingophospholipids.

• In glycerophospholipids, the alcohol present is glycerol. Examples of glycerophospholipids are:

• Phosphatidyl choline (lecithin)

• Phosphatidyl ethanolamine (cephalin)

• Phosphatidyl serine

• Phosphatidylinositol

• Lysophospholipid

• Plasmalogens

• Cardiolipins

• In sphingophospholipids, the alcohol present is sphingol, e.g., sphingomyelins.

Glycolipids
A lipid containing fatty acid, alcohol sphingosine, and additional group is carbohydrates with nitrogen base. They do
not contain phosphate group. These sugar-containing sphingolipids are also called glycosphingolipids, for example,
cerebrosides and gangliosides.

Lipoproteins
Lipoproteins are formed by the combination of lipid with a prosthetic group protein, e.g.,

• Chylomicrons

• Very low–density lipoprotein (VLDL)

• Low-density lipoprotein (LDL)

• High-density lipoprotein (HDL)

Derived Lipids
Derived lipids include the products obtained after the hydrolysis of simple and compound lipids, which possess the
characteristics of lipids, e.g., fatty acids, steroids, and cholesterol.

Functions of Lipids
Lipids serve as:

• Storage form of energy: The fats and oils are used almost universally as stored forms of energy.

• Structural lipids: Lipids are major structural components of membranes, e.g., phospholipids, glycolipids, and
cholesterol.

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• Lipid acts as a thermal insulator in the subcutaneous tissues and around certain organs.

• Nonpolar lipids act as electrical insulators in neurons.

• Lipids are important dietary constituents because of the fat-soluble vitamins and essential fatty acids, which are
present in the fat of natural foods.

• Lipids help in absorption of fat-soluble vitamins (A, D, E, and K). They act as a solvent for the transport of fat-
soluble vitamins.

• Cholesterol is a precursor of steroid hormones and vitamin D.

DEFINITION, CLASSIFICATION, AND

FUNCTIONS OF FATTY ACIDS
Definition
Fatty acids are carboxylic acids with hydrocarbon chains (–CH2–CH2–CH2–…). Fatty acid molecules have a variable
hydrocarbon chain length with a methyl terminus and a carboxylic acid head group (Figure 2.1). Fatty acid is
represented by a chemical formula R-COOH, where R stands for hydrocarbon chain.

Fatty acid carbon atoms are numbered starting at the carboxyl group. Carbon atoms 2 and 3 are often referred to as
α and β, respectively. The carbon atom of the methyl group, i.e., the carbon most distant from the carboxyl group is
called the ω carbon (omega, the last letter in the Greek alphabet) (Figure 2.1).

Classification of Fatty Acids

Fatty acids are classified into four major classes (Figure 2.2):

1. Straight-chain fatty acids

2. Branched fatty acids

3. Substituted fatty acids

4. Cyclic fatty acids

Straight-Chain Fatty Acids

In straight-chain fatty acids, the carbons are arranged linearly. These are subclassified into two classes:

1. Saturated fatty acids

2. Unsaturated fatty acids

Figure 2.1. Structure of fatty acid.

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Figure 2.2. Classification of fatty acids.

Saturated Fatty Acids

There is no double bond in the hydrocarbon chain of these fatty acids (Table 2.1). Saturated fatty acids are subclassified
into two classes:

1. Even carbon acids carry even number of carbons, e.g., palmitic acid and stearic acid.

2. Odd carbon acids carry odd number of carbons, e.g., propionic acid.

Unsaturated Fatty Acids

These contain double bonds in their hydrocarbon chains. These are subclassified according to the number of double
bonds present in the structure as follows (Table 2.2):

• Monounsaturated fatty acids (MUFAs) carry a single double bond in the molecule, e.g., oleic acid and palmitoleic
acid.

• Polyunsaturated fatty acids (PUFAs) contain two or more double bonds. PUFAs can be further subdivided on the
basis of the location of the first double bond relative to the methyl terminus of the chain. For example, (#-3) and
(#-6) fatty acids are two of the most biologically significant PUFA classes and have their first double bond on either
the third or sixth carbon from the methyl terminus (omega carbon), respectively (Figure 2.3).

• Naturally occurring polyunsaturated fatty acids belong to #-6 and #-3 series. For example,

• Linoleic acid (#-6) having two double bonds.

• Linolenic acid (#-3) having three double bonds.

• Arachidonic acid (#-6) having four double bonds.

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Branched Fatty Acids

These are less abundant than straight-chain acids in animals and plants, e.g., isovaleric acid and isobutyric acid.

Substituted Fatty Acids

In substituted fatty acids, one or more hydrogen atoms have been replaced by another group, e.g., lactic acid of blood
and cerebronic acid and oxynervonic acids of brain glycolipids.

Table 2.1. Some naturally occurring saturated fatty acids.

Fatty acids Number of carbon atoms

Acetic acid 2
Propionic acid 3
N-Butyric acid 4
Lauric acid 12
Myristic acid 14
Palmitic acid 16
Stearic acid 18
Arachidic acid 20
Lignoceric acid 24

Table 2.2. Some naturally occurring unsaturated fatty acids.

Fatty acids Number of carbon atoms Number of double bonds Unsaturated fatty acid
class
Monounsaturated fatty acid (MUFA)
Palmitoleic acid 16 1 #-7
Oleic acid 18 1 #-9
Nervonic acid 24 1 #-9
Polyunsaturated fatty acids (PUFA)
Linoleic acid 18 2 #-6
Linolenic acid 18 3 #-3
Arachidonic acid 20 4 #-6

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Figure 2.3. Representation of double bonds of #-3 and #-6 unsaturated fatty acids.

Cyclic Fatty Acids

Fatty acids bearing cyclic groups are present in some bacteria and seed lipids, e.g., hydnocarpic acid (chaulmoogric
acid) of chaulmoogra seed.

Functions of Fatty Acids

Fatty acids have three major physiological functions:

1. Fatty acids serve as a major fuel for most cells. They are stored in adipose tissues as triacylglycerol also called
neutral fats or triglyceride.

2. Fatty acids are the building blocks of phospholipids and glycolipids. These amphipathic molecules are important
components of biological membranes.

3. Fatty acid derivatives serve as hormones, e.g., prostaglandins and intracellular messenger such as
phosphatidylinositol.

CLINICAL SIGNIFICANCE OF
MONOUNSATURATED FATTY ACID AND
POLYUNSATURATED FATTY ACID
Clinical Significance of Monounsaturated Fatty Acids
(MUFAs)
Monounsaturated fatty acids or MUFAs are a type of unsaturated fat. “Mono,” meaning one, signifies that
monounsaturated fats have only one double bond. MUFAs are found in animal and plant-based foods. The best
sources are olive oil, nuts, and seeds. Foods that are high in unsaturated fats are usually liquid at room temperature,
whereas foods that are high in saturated fats, such as butter and coconut oil, are usually solid at room temperature.
Monounsaturated fats have various health benefits.

• High-MUFA diets may help reduce blood cholesterol and triglycerides, blood pressure, and other heart disease
risk factors, particularly if they replace some saturated fats in the diet. High blood cholesterol is a risk factor for
heart disease, as it can block arteries and lead to heart attacks or stroke.

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• High saturated fat in diet increases unhealthy bad LDL cholesterol, while the high-MUFA diet reduces LDL
cholesterol and increases “good” HDL cholesterol.

• There is also some evidence that diets rich in MUFAs may help reduce the risk of certain cancers.

• High-MUFA diets may be beneficial for improving insulin sensitivity and blood sugar control in those with and
without high blood sugar.

Clinical Significance of Polyunsaturated Fatty Acids

(PUFAs)
Polyunsaturated fatty acids (PUFAs) are fatty acids that contain more than one double bond (Table 2.2). PUFA contains
essential fatty acids. Polyunsaturated fat is found in plant and animal foods. Foods high in polyunsaturated fatty acids
include a number of plant-based oils, including soybean, corn, and sunflower. Other sources include some nuts and
seeds such as walnuts and sunflower seeds, tofu, and soybeans.

Polyunsaturated fats are usually liquid at room temperature and are referred to as “oils.” These oils are liquid at room
temperature because the double bonds allow the fat to bend and fold.

Since the human body can't produce ω-6 and ω-3 polyunsaturated fatty acids, these fatty acids are referred to
as “essential fatty acids,” meaning that we have to get them from our diet. Naturally occurring ω-6 and ω-3
polyunsaturated essential fatty acids are:

• Linoleic acid (#-6) having two double bonds

• Linolenic acid (#-3) having three double bonds.

Dietary polyunsaturated fatty acids affect a wide variety of functions. For example,

• Polyunsaturated fatty acids along with monounsaturated fatty acids are considered healthy fatty acids, as they may
reduce the risk of heart disease, especially when substituted for saturated fats.

• Polyunsaturated fatty acids can help reduce bad cholesterol levels in blood, which can lower the risk of heart disease
and stroke.

• Oils rich in polyunsaturated fats also contribute vitamin E to the diet. Vitamin E is an antioxidant vitamin.

• Oils rich in polyunsaturated fatty acids also provide essential fatty acids, such as omega-6 and omega-3 fatty acids.
Omega-6 and omega-3 fatty acids are important for many functions in the body, which are discussed under essential
fatty acids.

CLINICAL SIGNIFICANCE OF ESSENTIAL

FATTY ACIDS AND TRANS FATTY ACIDS
Essential Fatty Acids
Humans can synthesize many saturated and monounsaturated fatty acids. However, humans cannot synthesize the two
main types of polyunsaturated fatty acids, linoleic (ω-6) and α-linolenic (ω-3) acids. But plants can synthesize both.
Because they are necessary for the synthesis of other products, linoleic acid and linolenic acid are essential fatty
acids for humans and they must be obtained from the diet.

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Arachidonic acid can be synthesized from linoleic acid. Therefore, in deficiency of linoleic acid, arachidonic acid also
becomes essential fatty acids. Similarly, linolenic acid is converted to two important derivatives, eicosapentaenoic
acid (EPA) and docosahexaenoic acid (DHA).

Clinical Significance of Essential Fatty Acids

• Linoleic acid is an essential precursor for the synthesis of arachidonic acid from which prostaglandins are
produced, which have important regulatory functions.

• Similarly, linolenic acid can synthesize two important other #-3 polyunsaturated acids, eicosapentaenoic acid
(EPA) and Docosahexaenoic acid (DHA), which are important in cellular function.

• Proper development and functioning of the brain and nervous system: DHA is particularly needed for the
development of the brain and retina and may protect against heart disease, cancer, and other health problems. EPA
can reduce symptoms of depression.

• EFAs are necessary for the formation of healthy cell membranes: EFAs are constituent of structural lipids of
the cell and are involved in maintenance of the structural integrity of the cell membrane.

• EFAs are necessary for the regulation of blood clotting: Omega-6 fatty acids encourage blood clot formation,
whereas omega-3 fatty acids reduce clotting.

• EFAs are essential for the transport and breakdown of cholesterol: Essential fatty acids increases esterification
and excretion of cholesterol, thereby lowering serum cholesterol level.

• EFAs act as a skin and hair protector: In the skin, EFA covalently binds another Fatty acid that helps to make
the skin impermeable to water. Deficiency of EFAs causes scaly skin, eczema (in children), and loss of hair.

• EFAs are also necessary for the regulation of blood pressure

Trans Fatty Acids

Trans fatty acids are unsaturated fatty acids. In chemical terms, trans fatty acid is an fatty acid molecule that contains
one or more double bonds in trans configuration. A double bond may exhibit one of the two possible configurations:
trans or cis. The trans molecule is a straighter molecule, while the cis molecule is bent.

Trans fats are found in two forms: natural, which occurs in some meat and dairy products, and artificial, which is
formed through an industrial process that adds hydrogen to vegetable oil, which solidifies the oil at room temperature.

Trans fatty acids present in high amounts in processed foods, fast foods and bakery items and fried foods. Doctors
worry about trans fat because it increases the risk for heart attacks, stroke, and type 2 diabetes. Trans fat also has
an unhealthy effect on blood cholesterol levels. It increases LDL or bad cholesterol and decreases HDL or good
cholesterol. There are two main types of cholesterol:

• Low-density lipoprotein (LDL): Low-density lipoprotein or bad cholesterol can be deposited in the walls of the
arteries, making them hard and narrow, which can lead to heart attack, or a stroke.

• High-density lipoprotein (HDL): High-density lipoprotein or good cholesterol picks up excess cholesterol and
takes it back to liver.

Disadvantages of the use of trans fats in food are as follows:

• Trans fatty acids compete with essential fatty acids and hence aggravate essential fatty acid deficiency.

• Trans fatty acid raise the level of LDL, TAG and lower the level of HDL.

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• Consumption of trans fatty acids for long terms may raise the risk factor for cardiovascular diseases such as
atherosclerosis and coronary artery disease and diabetes mellitus.

• It also increases the body's inflammatory response.

DIGESTION AND ABSORPTION OF LIPIDS

Digestion of Lipids
Little or no digestion occurs in the mouth or stomach. The major site of lipid digestion is the small intestine, where
dietary lipid undergoes its major digestive processes using enzymes secreted by pancreas.

Digestion in Small Intestine

Overall, in adults, where the stomach pH is acidic, dietary lipids are not digested to any extent in the stomach or
in the mouth. The acidic stomach contents called chyme. Entrance of the acidic chyme from the stomach into the
duodenum stimulates the secretion of enteric hormones called secretin and cholecystokinin (pancreozymin) by
duodenal mucosa.

• Cholecystokinin stimulates the release bile and digestive enzymes containing lipase into the small intestine.

• Secretin causes the pancreas to release bicarbonate that helps to neutralize the pH of the acidic chyme and changes
the pH to the alkaline side, which is necessary for the activity of pancreatic and intestinal enzymes.

• Pancreatic juice and bile enter the duodenum. Bile salts present in bile is powerful emulsifying agent. It emulsifies
the triacylglycerols into small droplets.

Figure 2.4. Hydrolysis of triacylglycerol by lipase in intestine.

• Three lipid digestive enzymes secreted by pancreas are:

• Pancreatic lipase

• Cholesterol esterase

• Phospholipase-A2

Hydrolysis of dietary triacylglycerols: Pancreatic lipase hydrolyzes emulsified triacylglycerols. Lipase hydrolyses
triacylglycerol, to 2-monoacylglycerols and two molecules of fatty acids (Figure 2.4).

Hydrolysis of dietary phospholipids: Dietary phospholipids are digested by pancreatic phospholipase-A2. This
enzyme catalyzes the hydrolysis of phospholipids to a free fatty acid and lysophospholipid. The lysophospholipid
either enter the mucosal cells or are degraded further to glycerol and free fatty acid by lysophospholipase enzyme
secreted by intestinal cells (Figure 2.5).

Hydrolysis of cholesterol ester: Cholesterol esters are hydrolyzed by pancreatic cholesterol ester hydrolase
(cholesterol esterase), which produces cholesterol plus free fatty acid.

The primary products of dietary lipid digestion are:

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• Free fatty acids

• Free cholesterol

• 2-Monoacylglycerol

• Lysophospholipid

Figure 2.5. Hydrolysis of glycerophospholipid by phospholipase A2 in intestine.

These, together with bile salts, form mixed micelles. Fat-soluble vitamins A, D, E, and K are also packaged in these
micelles and are absorbed from the micelles along with the primary products of dietary lipid digestion.

Absorption of Lipids by Intestinal Mucosal Cells

The mixed micelles approach the brush border membrane of the intestinal mucosal cells. There the lipid components
from mixed micelles pass through and are absorbed into the mucosal cells of the jejunum and ileum by diffusion. The
net result is the transfer of monoacylglycerols, free fatty acids, cholesterol, and lysophospholipid molecules into the
cell. After absorption, the following events occur in the mucosa cell:

• 2-monoacylglycerols are reconverted to triacylglycerols. The fatty acids are required for the resynthesis of
triacylglycerols. Fatty acids are first activated to acyl-CoA by the action of thiokinase (Figure 2.6).

• The absorbed lysophospholipid and cholesterol are also converted to phospholipids and cholesterol esters by using
fatty acyl-CoA.

Bile salts of the micelles are not absorbed at this point. They are reabsorbed in the lower part of the small intestine
and return to the liver by the portal vein for resecretion into the bile, which is known as enterohepatic circulation of
bile salts.

Transport of Dietary Lipids

Triacylglycerol, phospholipid, and cholesterol esters synthesized in the intestinal mucosa and absorbed fat soluble
vitamins are transported from the mucosal cells into the lymph and then into the blood in the form of lipoprotein
known as chylomicrons (Figure 2.6).

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Figure 2.6. Absorption and transport of lipid from intestinal lumen.

(2-MAG: 2-monoacylglycerol; C: cholesterol; CE: cholesterol ester;

FA: fatty acid; LysoPL: lysophospholipid; TG: triacylglycerol)

After a meal, there is a transient elevation of blood lipids called alimentary hyperlipemia. The peak level of lipid in
blood plasma usually occurs after 1/2–3 hours and returns to normal in 5–6 hours. The chylomicrons are responsible
for the turbid or milky appearance of the plasma after a meal rich in fat.

The amounts of various lipids in blood plasma of normal adults in postabsorptive state are given in (Table 2.3).

Table 2.3. Plasma lipids of a normal adult.

Lipid mg/100 mL of plasma
Total lipid 400–590
Neutral fat (triacylglycerol) 30–200
Free fatty acids 5–10
Total cholesterol <200
Cholesterol ester 115–140
Free cholesterol 45–60
Phospholipid 150–200

Abnormalities in Lipid Digestion and Absorption

Lipid Malabsorption
Lipid malabsorption results in a loss of lipid as much as 30 g/day, including the fat soluble vitamins and essential
fatty acids in the feces. Conditions in which the feces contain large amounts of fat and fatty acids, commonly stearic

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acid, are therefore called steatorrhea (Greek, steato = fat). Steatorrhea is caused by a number of conditions. The
most common causes are:

• Bile salt deficiency occurs in liver disease or due to obstruction in the bile duct.

• Pancreatic enzyme deficiency occurs in pancreatitis or cystic fibrosis.

• Defective chylomicron synthesis occurs in congenital abetalipoproteinemia.

METABOLISM OF LIPIDS AND RELATED

DISORDERS
Fatty Acid Oxidation
Fatty acids are fuel molecules. They are stored in adipose tissues as triacylglycerol also called neutral fats or
triglyceride. Triacylglycerols of adipose tissue degraded to fatty acids and glycerol and transported to the energy
requiring tissues. Glycerol produced by lipolysis is metabolized by liver. Fatty acids mobilized from triacylglycerol
are oxidized to meet energy needs of a cell.

Fatty acids are oxidized mainly by a process called β-oxidation, in which two carbon units are removed from fatty
acid in the form of acetyl-CoA. It is called #-oxidation because oxidation of fatty acids occurs at the #-carbon atom.
#-oxidation pathway occurs in mitochondria. It involves following three steps:

1. Activation of fatty acid to fatty acyl-CoA

2. Transfer of acyl-CoA from cytosol into mitochondria by carnitine transport system

3. Reactions of #-oxidation

Activation of Fatty Acid

Before being catabolized, free fatty acids are converted to an active form called fatty acyl-CoA. It occurs in the cytosol
in the presence of ATP, coenzyme-A (CoA-SH), and the enzyme acyl-CoA synthetase (Figure 2.7). Subsequent steps
of #-oxidation occur in the mitochondria of the liver and other tissue cells.

Transfer of Acyl-CoA from Cytosol into Mitochondria by Carnitine

Transport System
Activation of fatty acids occurs in the cytosol, whereas they are oxidized in the mitochondrial matrix. The
mitochondrial inner membrane is impermeable to fatty acids. So a special carnitine transport mechanism is needed.
Activated long-chain fatty acids are carried across the inner mitochondrial membrane by carnitine. This occurs in
four steps (Figure 2.8).

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Figure 2.7. Activation of fatty acid.

Figure 2.8. Transport of fatty acid into mitochondria by carnitine transport system.

(CAT-I: carnitine acyl transferase-I; CAT-II: carnitine acyl transferase-II)

1. The acyl group of acyl-CoA is transferred to the carnitine to form acyl-carnitine. This reaction is catalyzed by
carnitine acyltransferase (CAT)-I, which is located on the cytosolic face of the inner mitochondrial membrane.

2. Acyl-carnitine is then transported across the inner mitochondrial membrane by an enzyme translocase.

3. The acyl group is transferred back to CoA in the mitochondrial matrix by the enzyme carnitine acyl transferase-
II (CAT-II), located on the inside of the inner mitochondrial membrane.

4. Fatty acyl-CoA is reformed in the mitochondrial matrix with liberation of carnitine, which is returned to the cytosolic
side by the translocase in exchange for an incoming acyl-carnitine.

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Reactions of #-Oxidation of Fatty Acid

After the penetration of the fatty acyl-CoA into mitochondria, it undergoes #-oxidation. A saturated fatty acyl-CoA is
degraded by a repeated sequence of four reactions (Figure 2.9).

1. Oxidation by FAD

2. Hydration

3. Oxidation by NAD

4. Cleavage

1. Oxidation by FAD: The first reaction is the oxidation of fatty acyl-CoA by an acyl-CoA dehydrogenase to give
α, β unsaturated fatty acyl-CoA (a double bond between α carbon and β carbon) and generates FADH2.

2. Hydration: The next step is the hydration (addition of water) of the double bond by enoyl-CoA hydratase to form
#-hydroxy acyl-CoA.

3. Oxidation by NAD: The #-hydroxy acyl-CoA undergoes second oxidation reaction catalyzed by β-hydroxy acyl-
CoA dehydrogenase to form #-keto acyl-CoA and generates NADH.

4. Cleavage: Finally, #-ketoacyl-CoA is split at the #-carbon by thiolase to yield acetyl-CoA and fatty acyl-CoA,
which is shorter by two carbon atoms than the original fatty acyl-CoA that underwent oxidation. The fatty acyl-
CoA, containing two carbons less than the original, re-enters the #-oxidation pathway.

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Figure 2.9. #-Oxidation of fatty acids.

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The process continues till the fatty acid degraded completely to acetyl-CoA. For example, after seven cycles, the
C16 fatty acid, palmitic acid, would be converted to eight acetyl-CoA molecules. The overall result of #-oxidation
of 16-carbon palmitic acid is shown in Figure 2.10. Acetyl-CoA can be oxidized to CO2 and H2O via citric acid
cycle in mitochondria and thus oxidation of fatty acids is completed.

Energy Yield from the #-Oxidation of Fatty Acids

Complete #-oxidation of palmitoyl-CoA (16-carbon acid) occurs through 7 cycles of #-oxidation yielding finally 8
acetyl-CoA, 7 FADH2, and 7 NADH (Figure 2.10).

• 2.5 ATP molecules are generated when each of these NADH is oxidized by mitochondrial respiratory chain.

• 1.5 ATP molecules are formed for each FADH2.

• The oxidation of acetyl-CoA by the citric acid cycle yields 10 ATPs. Therefore, the number of ATPs formed in
the oxidation of palmitoyl-CoA is:

• 10.5 ATPs from the 7 FADH2

• 17.5 ATPs from the 7 NADH

• 80 ATPs from the oxidation of 8 molecules of acetyl-CoA in TCA cycle

• Total of 108 ATPs

• In the activation of fatty acid palmitate, the equivalents of two high-energy phosphate bonds are consumed in which
a molecule of ATP is split into AMP and PPi.

• Thus the net yield from the complete oxidation of palmitate is 108 ATPs minus 2ATPs = 106 ATPs.

Regulation of #-Oxidation
• Rate-limiting step in the #-oxidation pathway is the formation of acyl-carnitine which is catalyzed by carnitine-
acyl transferase-I (CAT-I):

• Insulin inhibits CAT-I and leads to decrease in fatty acid oxidation.

• Glucagon stimulates CAT-I and leads to increase in fatty acid oxidation.

Oxidation of a Fatty Acid with an Odd Number of Carbon Atoms

Fatty acids, having an odd number of carbon atoms, are oxidized by the pathway #-oxidation described above
producing acetyl-CoA until a 3-carbon propionyl-CoA residue remains. Thus in the oxidation of odd carbon fatty
acids, the propionyl-CoA and acetyl-CoA, rather than two molecules of acetyl-CoA are produced in the final round
of degradation. Propionyl-CoA is converted to succinyl-CoA a constituent of citric acid cycle. Odd carbon fatty acid
propionyl-CoA is the only one glucogenic fatty acid.

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Figure 2.10. Overall process of #-oxidation of palmitic acid.

Synthesis of Fatty Acids

The majority of fatty acids required by the body are supplied by the diet. Fatty acids are synthesized whenever there
is a caloric excess in the diet. Excess amounts of carbohydrate and protein obtained from the diet can be converted
to fatty acids, which are stored as triacylglycerol.

• In humans, fatty acid synthesis occurs mainly in the liver and lactating mammary glands and, to a lesser extent,
in adipose tissue, kidney, and brain.

• Fatty acids are both synthesized from acetyl-CoA and oxidized to acetyl-CoA. Fatty acid oxidation takes place
in mitochondria. In contrast, fatty acid biosynthesis takes place in the cytosol. Some important features of the
pathways for the biosynthesis and degradation of fatty acids are listed in Table 2.4.

• Acetyl-CoA is the immediate substrate for fatty acid synthesis. The initial two carbons incorporated into fatty acids
are in the form of acetyl-CoA, which becomes carbon atoms 15 and 16 of palmitic acid. All other carbon atoms are
donated by malonyl-CoA formed from acetyl-CoA. The synthesis of palmitate C-16 saturated fatty acid requires 8
molecules of acetyl-CoA, 14 NADPH, 7 ATP, and fatty acid synthase enzyme.

Triacylglycerol Metabolism
Triacylglycerols are the simplest lipids, also referred to as triglycerides, fats, or neutral fats. These are esters of
fatty acids with glycerol. Triacylglycerol is the major storage and transport forms of fatty acids.

• Triacylglycerol are composed of three fatty acids, which are esterified with a single glycerol through their carboxyl
groups, resulting in a loss of negative charge and formation of neutral fat (Figure 2.11). As the polar hydroxyl
groups of glycerol and polar carboxyl groups of the fatty acids are bound in ester linkages, triacylglycerols are
nonpolar, hydrophobic, and neutral (in charges) molecules, and insoluble in water.

Functions of Triacylglycerols
Triacylglycerol serves as the body's major energy storage reserve. Triacylglycerols are highly concentrated storage
form of energy. Fatty acids are stored in the adipose tissue in the form of triacylglycerol.

Obese persons may have 15 or 20 kg of triacylglycerol deposited in their adipocytes, sufficient to supply energy needs
for months. In contrast, the human body can store carbohydrates less than a day's energy supply in the form of glycogen.

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Table 2.4. Difference between biosynthesis and degradation pathways of fatty acid.

Biosynthesis of fatty acids Degradation of fatty acids

Occurs in cytosol Occurs in mitochondrial matrix
Intermediates are linked to the an acyl carrier protein Intermediates are linked to the coenzyme-A
(ACP)
Enzymes are joined in a single polypeptide chain to form Enzymes do not seem to be associated
a multienzyme complex called fatty acid synthase
Reducing agent is NADPH Oxidizing agents are NAD+ and FAD
Fatty acids are synthesized by addition of acetyl-CoA Fatty acids are degraded by sequential by removal of
sequentially acetyl-CoA
Participation of CO2 occurs No participation of CO2
Isomeric form of hydroxyl acyl intermediate is D Isomeric form of hydroxyl acyl is L

Figure 2.11. Structure of triacylglycerol.

Synthesis of triacylglycerols

In both liver and adipose tissue, triacylglycerols are synthesized. The precursors for the synthesis of triacylglycerol
are fatty acyl-CoA (active form of fatty acid) and glycerol-3-phosphate (Figure 2.12).

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Mainly glycerol-3-phosphate is derived from the glycolytic intermediate dihydroxyacetone phosphate (DHAP) by
glycerol-3-phosphate dehydrogenase in liver.

Figure 2.12. Synthesis of triacylglycerol.

A small amount of glycerol-3-phosphate is also formed from the phosphorylation of glycerol by glycerol kinase in
liver. Adipose tissue lacks glycerol kinase and can produce glycerol-3-phosphate only from glucose via DHAP.

The other precursor of triacylglycerols is fatty acyl-CoAs, formed from fatty acids by acyl-CoA synthetases, the
same enzyme responsible for the activation of fatty acids for #-oxidation.

• First reaction in the biosynthesis of triacylglycerol is activation of fatty acids to acyl-CoA.

• Then two molecules of acyl-CoA combine with glycerol-3-phosphate to form 1,2-diacylglycerol phosphate.

• Dephosphorylation of 1,2-diacylglycerol phosphate produces diacylglycerol.

• A further molecule of acyl-CoA is esterified with diacylglycerol to form triacylglycerol.

Degradation of triacylglycerol formed in liver and adipose tissue

• The triacylglycerol stored in adipose tissue are continually undergoes lipolysis (hydrolysis) and resynthesis re-
esterification. The triacylglycerol stored in adipose tissue undergoes hydrolysis by a hormone-sensitive lipase to
form free fatty acids and glycerol.

• Some of the fatty acids released by lipolysis of triacylglycerol in adipose tissue pass into the bloodstream, and
remainder are used for the resynthesis of triacylglycerol.

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• Some of the fatty acids released into the blood are taken up by several tissues, including muscle, where it is oxidized
to provide energy and some are taken up by the liver.

• Much of the fatty acid taken up by liver is not oxidized but is recycled to triacylglycerol and exported again into the
blood in the form of VLDL back to adipose tissue and re-esterified into triacylglycerol.

• The glycerol, released in adipose tissue, cannot be metabolized by adipose tissue because they lack glycerol kinase.
Rather, glycerol is transported through the blood to the liver in the liver it is phosphorylated to glycerol phosphate.
The resulting glycerol phosphate can be used to form triacylglycerol in the liver or to be converted to DHAP.

Regulation of triacylglycerol metabolism

The rate of the biosynthesis and degradation of triacylglycerols depends on the metabolic resources and requirements
of the moment. The rate of triacylglycerol biosynthesis is regulated by the action of hormones.

• Insulin stimulates the conversion of dietary carbohydrates and proteins to triacylglycerol and inhibits the breakdown
of triacylglycerol.

• The hormones glucagon and epinephrine stimulates the breakdown of triacylglycerol from adipose tissue.

Cholesterol Metabolism
Cholesterol is the animal sterol. It is the major sterol in animal tissues. It is a major structural constituent of the cell
membranes and plasma lipoproteins. Cholesterol is widely distributed in all the cells of the body, but particularly
in nervous tissue. It occurs in animal fats, but not in the plant fats.

Cholesterol is amphipathic, with a polar head, the hydroxyl group at C3 and a nonpolar, the steroid nucleus and
alkyl hydrocarbon side chain at C17 (Figure 2.13). Most of the cholesterol in the body exists as a cholesterol ester,
with an fatty acid attached to the hydroxyl group at C3.

The major source of dietary cholesterol is egg yolk and meat, particularly liver. An abnormality in either cholesterol
metabolism or transport through the plasma appears to be related to the development of atherosclerosis that can lead
to myocardial infarction or stroke.

Figure 2.13. The structure of cholesterol.

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Biosynthesis of Cholesterol
Cholesterol is synthesized by a pathway that occurs in most cells of the body. Liver and intestine are major sites of
cholesterol synthesis.

All 27 carbon atoms of cholesterol are derived from the acetyl-CoA. The enzyme system of cholesterol synthesis
presents in cytosolic and endoplasmic reticulum fractions. The reactions of cholesterol biosynthesis occur into five
stages (Figure 2.14). The first two stages take place in the cytoplasm and next three in the endoplasmic reticulum.
The five stages are as follows:

1. Condensation of 3-molecules of acetyl-CoA to mevalonate.

2. Conversion of mevalonate to activated isoprene units.

3. Polymerization of six isoprene units to form squalene.

4. Cyclization of squalene to form parent steroid nucleus lanosterol.

5. Formation of cholesterol from lanosterol.

Figure 2.14. Five stages of cholesterol biosynthesis.

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Transport of Cholesterol
• Dietary cholesterol is transported from intestine to the liver in the form of chylomicrons.

• LDL is the major carrier of cholesterol from liver to peripheral tissues. Low-density lipoprotein cholesterol is called
bad cholesterol, because it transports cholesterol from liver to the peripheral tissue (for excretion cholesterol must
enter the liver). The risk of coronary heart disease (CHD) is related to plasma levels of total cholesterol and LDL
cholesterol.

• HDL transports cholesterol from the peripheral tissues to the liver where it is degraded or excreted in the bile.
The process of transport of cholesterol from tissues to the liver is known as reverse cholesterol transport. HDL
cholesterol is considered to be the good cholesterol, because it removes excess cholesterol from peripheral tissues
and transports it to the liver where it is degraded or excreted in the bile. HDL thus tends to lower blood cholesterol
level.

COMPOUNDS FORMED FROM CHOLESTEROL

Cholesterol serves as the precursor for a variety of biologically important products (Figure 2.15). These are described
in the following sections:

Steroid Hormones
Cholesterol is the precursor of the five major classes of steroid hormones (Figure 2.16):

• Glucocorticoids, hormones synthesized in the cortex of the adrenal gland; they regulate glucose metabolism.

• Mineralocorticoids and aldosterone are hormones synthesized in the adrenal gland; they regulate salt and water
balance.

• Testosterone, the male sex hormone, is produced in the testes.

• Estrogen, one of the female sex hormones, is produced in ovaries and placenta.

Vitamin D Hormone
Vitamin D3 or cholecalciferol is formed from cholesterol by the action of ultraviolet light from sunlight on 7-
dehydrocholesterol (Figure 2.17). Vitamin D3 regulates calcium and phosphorus metabolism.

Bile Acids
Bile acids are the principle components of bile. The bile acids required for the emulsification of the dietary lipids and
facilitate the enzymatic digestion and absorption of dietary lipids. Conversion of cholesterol into bile acid in the liver
prevents the body from becoming overloaded with cholesterol. As steroidal ring of cholesterol cannot be degraded in
the body, the excretion of bile salts serves as a major route for removal of the steroid ring from the body.

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Figure 2.15. Compounds formed from cholesterol.

Figure 2.16. Formation of steroid hormones from cholesterol.

Formation of bile acids: The primary bile acids, cholic acid and chenodeoxycholic acid, are synthesized in the liver
from cholesterol (Figure 2.18).

• The 7#-hydroxylation of cholesterol is the first step in the biosynthesis of bile acids and is catalyzed by cholesterol
7α-hydroxylase (Figure 2.18).

• The primary bile acids synthesized in the liver from cholesterol are cholic acid (found in largest amount) and
chenodeoxycholic acid.

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Figure 2.17. The formation of vitamin D3 from cholesterol.

Figure 2.18. Synthesis of bile acid and its regulation.

Before the bile acids leave the liver, they are conjugated to a molecule of either glycine or taurine to form bile
salts: glycocholic or glycochenodeoxycholic acids and taurocholic or taurochenodeoxycholic acids. In alkaline
bile, the bile acids and their conjugates are assumed to be in a salt form, hence the term “bile salts.”

• Primary bile acids are further metabolized in the intestine by the activity of the intestinal bacteria, producing
secondary bile acids: deoxycholic acid and lithocholic acid.

KETONE BODIES: NAME, TYPES AND

SIGNIFICANCE
The acetyl-CoA formed in fatty acid oxidation enters the citric acid cycle only if fat and carbohydrate degradation is
appropriately balanced. However, if fat breakdown predominates, acetyl-CoA in the liver undergoes a different fate.

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The reason is that the entry of acetyl-CoA into citric acid cycle depends on the availability of oxaloacetate for the
formation of citrate. Oxaloacetate is normally formed from pyruvate, the product of glucose degradation in glycolysis.
If carbohydrate is unavailable, the concentration of oxaloacetate is lowered and acetyl-CoA cannot enter the citric
acid cycle.

In fasting or in diabetes, oxaloacetate is used to form glucose by gluconeogenic pathway and hence is unavailable for
the first step of the citric acid cycle (condensation of oxaloacetate with acetyl-CoA). Under these conditions, acetyl-
CoA undergoes to the formation of acetoacetate and β-hydroxybutyrate.

Name and Types of Ketone Bodies

• Acetoacetate, β-hydroxybutyrate, and acetone, these three substances are collectively known as ketone bodies
(Figure 2.19). Acetoacetate and acetone are true ketones, while #-hydroxybutyrate does not possess a keto group.
The term “bodies” is an historical tag.

• These are water-soluble energy yielding substances. Acetone is, however, an exception, since it cannot be
metabolized and is readily exhaled through lungs. Acetone is a waste product as it is volatile.

• Acetoacetate and #-hydroxybutyrate are interconverted by the mitochondrial enzyme β-hydroxybutyrate

dehydrogenase. Acetoacetate continually undergoes spontaneous nonenzymatic decarboxylation to yield acetone
(Figure 2.20).

• The concentration of total ketone bodies in the blood of well-fed condition does not normally exceed 0.2 mmol/L.

Figure 2.19. Name and types of ketone bodies.

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Figure 2.20. Interconversion of ketone bodies.

Formation of Ketone Bodies

Formation of ketone bodies occurs in the liver and transferred to other organs as fuel. Enzymes responsible for ketone
body formation are associated mainly with the mitochondria. Acetoacetate, #-hydroxybutyrate, and acetone are formed
from acetyl-CoA (Figure 2.21).

Utilization of Ketone Bodies

The site of production of ketone bodies is exclusively the liver. But the liver cannot utilize ketone bodies because it
lacks the particular enzyme CoA-transferase that is required for the activation of ketone bodies.

Acetoacetate, #-hydroxybutyrate, and acetone diffuse from the liver mitochondria into the blood and are transported
to peripheral tissues. In peripheral tissues, the #-hydroxybutyrate is converted to acetoacetate and the acetoacetate is
then activated to acetoacetyl-CoA that is then cleaved to yield acetyl-CoA, which can be oxidized in the citric acid
cycle to H2O and CO2 (Figure 2.21).

Significance of Ketone Body Formation

• The production and transfer of ketone bodies from the liver to extrahepatic tissues allows continued oxidation of
increasing quantities of fatty acids in the liver when acetyl-CoA is not being oxidized in the citric acid cycle. During
starvation, intermediates of citric acid cycle are being drain off for glucose synthesis by gluconeogenesis slows
oxidation of acetyl-CoA by citric acid cycle diverting them to ketone body formation.

• During deprivation of carbohydrate as in starvation and diabetes mellitus, acetoacetate and #-hydroxybutyrate serve
as an alternative source of energy for extrahepatic tissues such as skeletal muscle, heart muscle, and renal cortex.

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Figure 2.21. Formation and fate of ketone bodies.

• In prolonged starvation, 75% of the energy needs of the brain are supplied by ketone bodies reducing its need for
glucose.

• Ketone bodies can be regarded as water-soluble transportable form of derivatives of acetyl-CoA. Therefore, they
do not need to be incorporated into lipoproteins or carried by albumins as do the other lipids.

• Acetoacetate also has a regulatory role in lipid metabolism. High levels of acetoacetate in the blood specify an
abundance of acetyl units and lead to a decrease in the rate of lipolysis in adipose tissue.

Disorders of Ketone Body Metabolism

Ketosis
Normally, the concentration of ketone bodies in blood is very low (<0.2 mmol/L), but in fasting and in diabetes
mellitus, it may reach extremely high levels. During fasting or in diabetes mellitus, when glucose is unavailable, insulin
secretion is inhibited. Decreased insulin concentration causes increased lipolysis and therefore increased production
of free fatty acids; hence, the production of ketone bodies is increased (Figure 2.22).

• When the rate of formation of the ketone bodies by liver exceeds the capacity of the peripheral tissues to use them
up, their levels begin to rise in blood. An increase in the concentration of ketone bodies in blood is called ketonemia

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and eventually leads to excretion of ketone bodies into the urine called ketonuria. The overall condition (ketonemia
and ketonuria) is called ketosis.

• In addition to #-hydroxybutyrate and acetoacetate, the blood of diabetics also contains acetone. Acetone is very
volatile and is present in the breath of diabetics, to which it gives sweet fruity odor.

Figure 2.22. Increased formation of ketone bodies in diabetes or prolonged starvation.

Ketoacidosis
Since acetoacetate and #-hydroxybutyrate are moderately strong acids, increased levels of these ketone bodies decrease
the pH of the blood and cause metabolic acidosis. The acidosis caused by over production of ketone bodies is termed
ketoacidosis.

Acetoacetate and #-hydroxybutyrate acids when present in high concentration in blood are buffered by HCO–3
(alkali) fraction of bicarbonate buffer. The excessive use of HCO–3 depletes the alkali reserve causing ketoacidosis.
Ketoacidosis is seen in type I diabetes mellitus, whereas in type II diabetes ketoacidosis is relatively rare.

LIPOPROTEINS, TYPES AND FUNCTIONS

Fat absorbed from the diet and fat synthesized by the liver and adipose tissue must be transported between the
various tissues and organs for utilization and storage. Since lipids (triacylglycerol, cholesterol, cholesterol esters, and
phospholipids) are insoluble in water, the problem arises to transport them in an aqueous environment of the blood
plasma. The lipoproteins solve the problem of transporting fats in the plasma. Lipids are transported in the bloodstream
as lipoproteins.

Lipoproteins are large water-soluble complexes formed by a combination of lipid and protein. Lipoproteins transport
insoluble lipids through the blood between different organs and tissues.

Lipoproteins consist of a lipid core containing nonpolar triacylglycerol and cholesterol ester surrounded by a
single layer of amphipathic phospholipids and free cholesterol molecules with some proteins (apoprotein) (Figure

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2.23). The protein components are referred to as an apoprotein or apolipoprotein. There are four major types of
apolipoproteins designated by letters A, B, C, and E.

Types of Lipoproteins
Lipoproteins have been categorized into four major classes according to their physical and chemical properties. The
lipoproteins can be separated by ultracentrifugation. The main types of lipoproteins are:

1. Chylomicrons

2. Very low–density lipoproteins (VLDL)

3. Low-density lipoproteins (LDL)

4. High-density lipoproteins (HDL)

These lipoprotein complexes contain different proportions of lipids and proteins. The density of these lipoproteins is
inversely proportional to triacylglycerol content. As the concentration of triacylglycerol decreases, density increases.
As the density increases, the diameter of the particle decreases as shown in Figure 2.24.

• Chylomicrons containing about 2% protein and 98% triacylglycerol have the lowest density.

Figure 2.23. Structure of lipoprotein.

(CE: cholesterol ester; TG: triacylglycerol)

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Figure 2.24. Diagrammatic representation of lipoprotein with increasing densities.

• Whereas HDL containing 55% of protein and 45% of lipid has the highest density.

• Triacylglycerol is the predominant lipid in chylomicrons and VLDL.

• Cholesterol is the predominant lipid in LDL, whereas phospholipid is the predominant lipid in HDL.

Functions of Lipoprotein
Each class of lipoprotein has a specific function, depending on their site of synthesis, lipid composition, and
apolipoprotein content. The site of synthesis of the four main lipoproteins and their functions are summarized in Table
2.5:

1. Chylomicrons are synthesized from dietary fats in the small intestine. They carry dietary triacylglycerol,
cholesterol, and other lipids from the intestine to the peripheral tissues.

2. Very low–density lipoprotein (VLDL) is synthesized in liver. It transports triacylglycerol from liver to peripheral
tissues.

3. Low-density lipoprotein (LDL) is synthesized from plasma VLDL. It is the major carrier of cholesterol in blood.
The role of LDL is to transport cholesterol from liver to peripheral tissues and regulate cholesterol biosynthesis.
LDL cholesterol is called bad cholesterol.

4. High-density lipoprotein (HDL) synthesized in the liver and small intestine. It transports cholesterol from
peripheral tissues to the liver where it can be catabolized and excreted. HDL cholesterol is called good cholesterol.
The process of transport of cholesterol from tissues to the liver is known as reverse cholesterol transport.

Good Cholesterol and Bad Cholesterol

• HDL cholesterol is considered to be the good cholesterol, because it removes excess cholesterol from
peripheral tissues and transports it to the liver where it is degraded or excreted in the bile. HDL thus tends
to lower blood cholesterol level.

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• On the other hand, LDL cholesterol is called bad cholesterol, because it transports cholesterol from liver to
the peripheral tissue (for excretion cholesterol must enter the liver). The risk of coronary heart disease (CHD)
is related to plasma levels of total cholesterol and LDL cholesterol.

ATHEROSCLEROSIS
High level of serum cholesterol results in atherosclerosis. The atherosclerosis is characterized by hardening and
narrowing of the arteries due to deposition of cholesterol and other lipids in the inner arterial wall. Deposition of
cholesterol and other lipids in the inner arterial wall leads to the formation of plaque (sticky deposit) and results in
the endothelial damage and narrowing of the arterial lumen (Figure 2.25).

Table 2.5. The four main lipoproteins and their site of synthesis and function.

Lipoprotein Site of synthesis Function

Chylomicrons Intestine Transport of dietary lipids from
intestine to peripheral tissues
VLDL Liver Transport of triacylglycerol from
liver to peripheral tissues
LDL Plasma VLDL Transport of cholesterol from liver to
peripheral tissues. LDL cholesterol is
called bad cholesterol
HDL Liver and intestine Transport of free cholesterol from
peripheral tissues to the liver
(reverse cholesterol transport). HDL
cholesterol is called good cholesterol
(HDL: high-density lipoprotein; LDL: low-density lipoprotein; VLDL: very low-density lipoprotein)

Figure 2.25. Narrowing of blood vessel due to formation of plaque.

The hardening and narrowing of coronary arteries result in coronary heart disease (CHD).

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HDL cholesterol (good cholesterol) has protective effect against atherosclerosis. HDL transports cholesterol from
peripheral cells to the liver for excretion. The higher the levels of HDL, the lower are the risk of atherosclerosis. Low
level of HDL cholesterol is associated with atherosclerosis.

Factors responsible for development of atherosclerosis:

• Age: Aging brings about changes in the blood vessel wall due to decreased metabolism of cholesterol. As age
advances, the elasticity of the vessel wall decreases and leads to a turbulent flow of blood causes mechanical injury
of the arterial wall.

• Sex: Males are affected more than females, female incidence increases after menopause. Sex incidence is equal
after age 65 years, suggesting that male sex hormone might be atherogenic or conversely that female sex hormones
might be protective.

• Hyperlipidemia: Hyperlipidemia is the major risk factor in patients under 45 years of age.

• Genetic factor: Hereditary genetic derangement of lipoprotein metabolism leads to high blood lipid level.

• Level of HDL: Low level of HDL is associated with atherosclerosis. HDL has protective effect against
atherosclerosis. HDL participates in reverse transport of cholesterol, i.e., it transports cholesterol from cells to the
liver for excretion in the bile. The higher the level of HDL, the lower is the risk of ischemic heart disease.

• Hypertension: Hypertension is the major risk factor in patients over 45 years of age. It acts probably by mechanical
injury of the arterial wall due to increased blood pressure.

• Cigarette smoking: Cigarette smoke reduces the level of HDL and accumulating carbon monoxide that may cause
endothelial cell injury.

• Diabetes mellitus: The risk is due to the obesity, hypertension, and hyperlipidemia.

• Minor or soft risk factors: The risk is due to increased LDL and decreased HDL levels. These include lack
of exercise, stress, obesity, high caloric intake, diet containing large quantities of saturated fats, use of oral
contraceptive, alcoholism, and hyperuricemia.

Prevention of Atherosclerosis
• The most important preventive measure against the development of atherosclerosis is to eat a low-fat diet that
contains mainly unsaturated fat with low cholesterol content.

• Natural antioxidants, such as vitamins E, C, or #-carotene may decrease the risk of cardiovascular disease by
protecting LDL against oxidation.

• Moderate consumption of alcohol and exercise appears to have a slightly beneficial effect by raising the level of
HDL.

• Drug therapy, e.g., lovastatin, clofibrate, and cholestyramine, which inhibit cholesterol synthesis.

LIPID PROFILE
Lipid profile tests or lipid panel are used to estimate increased risk of cardiovascular disease. A lipid profile test is
performed to measure:

• Total serum cholesterol levels

• Serum TGs levels

• HDL cholesterol (good cholesterol)

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• LDL cholesterol (bad cholesterol).

Blood should be collected after a 12-hour fast (no food or drink, except water).

Total Serum Cholesterol

Blood cholesterol is estimated by enzymatic method.

Normal Values and Interpretation of Cholesterol

• The normal range for healthy young adults is <200 mg/dL.

• It may be lower in children.

• The concentration increases with age.

• The concentration in the women is generally somewhat lower than in men up to the time of menopause but then
increase and may exceed that in men of the same age.

Increased Concentration of Cholesterol

• The total concentration is increased in:

• Hypothyroidism

• Uncontrolled diabetes mellitus

• Extrahepatic obstruction of the bile ducts

• Various hyperlipidemias

• Nephrotic syndrome

• Long-time elevated cholesterol concentration (>240 mg/dL) is a high-risk factor for the development of coronary
artery disease.

• Lowering of plasma cholesterol concentration reduces the incidence of coronary heart diseases.

• National Cholesterol Education Program (NCEP) defined the levels of serum cholesterol believed to be desirable,
tolerable, or a high-risk factor for development of coronary artery disease. The report classifies total cholesterol
concentration (Table 2.6), which is applicable to all individuals over 20 years of age and sex.

Serum Triglycerides
Serum triglyceride (TG) is estimated by enzymatic method.

Normal Value and Clinical Interpretation

The normal range of serum triglycerides is 40–145 mg/dL. Mean values rise slowly with age after the third decade.

Increased Concentration of Serum Triglycerides

• Elevated concentration is often found in disturbances of lipid metabolism and in atherosclerosis and coronary
artery disease. The classification of triglyceride concentration according to the National Cholesterol Education
Program (NCEP) is listed in Table 2.6.

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• The serum triglyceride concentration is greatly elevated in hyperlipoproteinemia. The cause of hyperlipoproteinemia
is a genetic origin, but hypertriglyceridemia occur commonly secondary to the following pathologic conditions:

Table 2.6. Classification of serum cholesterol and serum triglycerides concentration

according to the National Cholesterol Education Program (NCEP).
Category Serum cholesterol (mg/ Serum triglycerides (mg/ Serum LDL cholesterol
dL) dL) (mg/dL)
Normal (desirable, safer Below 200 Below 200 Below 130
side)
Borderline high risk 200–240 200–400 130–160
High risk Above 240 400–1,000 Above 160

• Hypothyroidism

• Nephrotic syndrome

• Alcoholism

• Obstructive liver diseases

• Acute pancreatitis

• Uncontrolled diabetes mellitus

• Glycogen storage disease (type I)

Decreased Concentration of Triglycerides

The plasma triglyceride concentration is low in the rare disease, abetalipoproteinemia (absence of low density
lipoproteins).

HDL Cholesterol
High density lipoprotein cholesterol is estimated by commercial kits.

Normal Values and Clinical Significance of HDL Cholesterol

• Serum level of HDL cholesterol for:

• Men is 30–60 mg/dL.

• Women is 40–80 mg/dL, which is 20–30% higher than men.

• Studies have indicated that when the HDL cholesterol value is <45 mg/dL in men and <55 mg/dL in women there
is an increased risk for heart disease and the relative risk increases with lower HDL cholesterol concentrations.

• Higher HDL cholesterol concentrations may be associated with decreased risk of coronary disease. Thus HDL
cholesterol levels are inversely related to the risk of cardiovascular disease. High-density lipoprotein cholesterol
level above 60 mg/dL indicates very low risk for coronary artery disease (CAD). High-density lipoprotein below
35 mg/dL increases the risk of CAD.

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• The ratio of total cholesterol to HDL cholesterol gives a more accurate and definite assessment of heart disease
risk (Table 2.7).

• Decreased levels that are associated with stress, obesity, androgens, cigarette smoking, and diseases such as diabetes
mellitus augment the risk of coronary artery disease.

LDL Cholesterol
The value of LDL cholesterol may be calculated, if the concentrations of total and HDL cholesterol and triglycerides are
measured. In practice, LDL can be measured indirectly by use of Friedewald equation assuming that total cholesterol
is composed primarily.

Total cholesterol = Cholesterol in (VLDL + LDL + HDL).

LDL cholesterol = Total cholesterol - [HDL cholesterol + 1/5 × Triglyceride (TG)].

The concentrations of all constituents should be expressed in the same units such as mg/dL or mg/L. 1/2.22 × TG
is used when LDL cholesterol is expressed in mmol/L. The factor 1/5 × TG is an estimate of the VLDL cholesterol
concentration.

Table 2.7. Ratio of total/HDL cholesterol and LDL/HDL cholesterol for the assessment of
risk of coronary artery disease.
Total/HDL cholesterol LDL/HDL cholesterol
Category Men Women Men Women
Safer side 3.40 3.25 1.00 1.45
Borderline high risk 4.95 4.45 3.50 3.20
High risk 9.50 7.00 6.25 5.00

Normal Values and Clinical Interpretation

• The LDL cholesterol in women is somewhat lower than in men but increases after menopause.

• Low levels of LDL cholesterol lower the risk.

• Values above 160 mg/dL indicate high risk.

• Values between 130 and 160 mg/dL are in borderline risk.

• Values below 130 mg/dL are safer side (Table 2.6).

Thus the risk of cardiovascular disease is correlated directly with a high concentration of LDL cholesterol. The highest
correlations have been obtained as a risk factor by the ratio of LDL cholesterol to HDL cholesterol (Table 2.7).

Nursing Implication

• A lipid profile screening is one of the most complete, accurate and trusted screening performed. A lipid profile
screening is used to identify lipid levels including total cholesterol, HDL cholesterol (good cholesterol), and
LDL cholesterol (bad cholesterol) and triacylglycerol in blood.

• Abnormal lipid profile levels are strong indications of risk of heart disease including heart attack, stroke or
death. Unfortunately abnormal lipid profile levels show no symptoms. Unlike many diseases abnormal lipid

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profile levels may be silent. Lipid profile is a simple and accurate way to determine the risk of developing
heart disease, stroke or sudden death.

• A professional nurse will take a few drops of blood sample from a fingertip and place it into blood analyzer.
In just a few minutes a patient will know lipid levels including total cholesterol, HDL cholesterol (good), and
LDL cholesterol (bad) and triacylglycerol in blood.

• High levels of LDL or bad cholesterol, high levels of triacylglycerol, low levels of HDL or good cholesterol
are all considered abnormal and may be life threatening.

Lipid profile levels

Total cholesterol Below 200- Desirable

200-240-Border line

Above 240-High risk

HDL 60 or above- Low risk of heart disease

40-60 Near optimal

40 or below high risk of heart disease

LDL 100 or Low risk of heart disease
Triglyceride 150 or below Low risk of heart disease

ASSESSMENT QUESTIONS

Long-Answer Questions

1. 1. Define lipids, classify lipids with suitable examples, and mention their functions.

2. 2. Define fatty acids, classify fatty acids with suitable examples, and mention their functions.

3. 3. Describe major stages of cholesterol biosynthesis, and compounds formed from of cholesterol.

4. 4. Describe #-oxidation of palmitic acid, regulation and energetics.

5. 5. Describe digestion and absorption of lipids.

6. 6. Define lipoproteins. Write its different types and functions.

7. 7. Describe formation and breakdown of ketone bodies.

8. 8. Describe synthesis and degradation of triglyceride with its regulation.

Short Notes

1. 1. Cholesterol.

2. 2. PUFA.

3. 3. Lipoproteins.

4. 4. Triacylglycerol.

5. 5. Ketosis.

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6. 6. Atherosclerosis.

7. 7. Good cholesterol and bad cholesterol.

Very Short Answers

1. 1. What is triacylglycerol?

2. 2. Do LDL and HDL carry out the same function? If the answer is no, write the functions of both.

3. 3. Name essential fatty acids.

4. 4. Write any two significances of PUFA.

5. 5. What is chylomicron?

6. 6. What is cholesterol? Name any two compounds formed from cholesterol.

7. 7. Name ketone bodies.

8. 8. Which are the different types of lipoproteins?

9. 9. Enumerate the parameters of lipid profile tests.

10. 10. Define atherosclerosis. Give any two causes of it.

MULTIPLE CHOICE QUESTIONS (MCQs)

1. 1. Triacylglycerols are transported from liver to extra hepatic tissues by which of the following
lipoproteins?

a. Chylomicrons

b. VLDL

c. LDL

d. HDL

2. 2. Triacylglycerols are:

a. Energy rich compounds

b. Nonpolar in nature

c. Can be stored in adipose tissues

d. All of the above

3. 3. All are essential fatty acids, except:

a. Linoleic

b. Linolenic

c. Arachidonic acid

d. Stearic acid

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4. 4. Which out of the following fatty acids is a precursor of prostaglandins?

a. Stearic acid

b. Arachidonic acid

c. Palmitic acid

d. Acetic acid

5. 5. A fatty acid which is not synthesized in the body and has to be supplied in the diet is:

a. Palmitic acid

b. oleic acid

c. Linolenic acid

d. Palmitoleic acid

6. 6. Cholesterol is a precursor of all, except:

a. Bile salts

b. Prostaglandins

c. Steroids

d. Vitamin D

7. 7. An example of a saturated fatty acid is:

a. Palmitic acid

b. Oleic acid

c. Linoleic acid

d. Linolenic acid

8. 8. Which of the following statements about cholesterol is true?

a. It is amphipathic

b. It contains 27-carbon atom

c. It is an animal sterol

d. All of the above

9. 9. The precursor for vitamin D is:

a. Cholesterol

b. Arachidonic acid

c. Triacylglycerol

d. Phospholipids

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10. 10. The lipoprotein particles that have the highest concentration of triacylglycerol are:

a. VLDL

b. HDL

c. LDL

d. Chylomicrons

11. 11. All of the following statements about lipid are true, except:

a. They are esters of fatty acids

b. They are poor soluble in water

c. They are a source of energy

d. They are polyhydroxy aldehydes

12. 12. Ketone bodies are formed in:

a. Kidney

b. Liver

c. Heart

d. Intestines

13. 13. Which one of the following transfers fatty acids from cytosol to mitochondria?

a. Carnitine

b. Creatine

c. Citrate

d. ACP

14. 14. Number of #-oxidation cycles undergoes a 14 carbon saturated fatty acid:

a. 8

b. 7

c. 6

d. None of the above

15. 15. Which of the following is not true for #-oxidation of fatty acids?

a. Produces ATP

b. Produces acetyl-CoA

c. Occurs in the mitochondria

d. Degrades fatty acids into CO2 and H2O

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16. 16. How many ATPs are produced when palmitoyl-CoA, a 16 carbon saturated fatty acid is oxidized
completely to CO2 and H2O?

a. 96

b. 131

c. 106

d. 135

17. 17. Which of the following statements is correct for fatty acid synthesis?

a. Occurs in cytosol

b. Requires NADPH

c. Requires acetyl-CoA

d. All of the above

18. 18. This lipoprotein called good cholesterol:

a. HDL

b. VLDL

c. IDL

d. Chylomicrons

19. 19. The form in which dietary lipids are transported from intestinal mucosal cells is:

a. VLDL

b. HDL

c. Chylomicrons

d. LDL

20. 20. This lipoprotein called bad cholesterol:

a. HDL

b. VLDL

c. IDL

d. Chylomicrons

21. 21. The triacylglycerol present in liver is hydrolysed by:

a. Lipoprotein lipase

b. Pancreatic lipase

c. Phospholipase 42
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d. None of the above

22. 22. Bile acids are derived from:

a. Phospholipids

b. Triacylglycerol

c. Fatty acids

d. Cholesterol

23. 23. The following are the ketone bodies, except:

a. Acetoacetyl-CoA

b. #-hydroxy butyrate

c. Acetone

d. Acetoacetate

24. 24. Which of the following enzyme is required for digestion of lipid in intestine?

a. Pancreatic Lipase

b. #-Amylase

c. Pepsin

d. Trypsin

25. 25. Neutral fat is stored in:

a. Kidney

b. Pancreas

c. Adipose tissue

d. Brain

Answers

1. b 2. d 3. d 4. b 5. c 6. b 7. c 8. b 9. a 10. d
11. d 12. b 13. a 14. c 15. d 16. c 17. d 18. a 19. c 20. c
21. d 22. d 23. a 24. a 25. c

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