Lipid Metabolism

Prof. Dr. Senol DANE

Nile University of Nigeria
• Lipids:
– (1) neutral fat (triglycerides)
– (2) phospholipids
– (3) cholesterol
• The basic lipid moiety of triglycerides and
phospholipids is fatty acids.
• Cholesterol does not contain fatty acid, its sterol
nucleus is synthesized from portions of fatty acid
molecules, giving it many of the physical and
chemical properties of other lipids.
 BASIC CHEMICAL STRUCTURE OF
TRIGLYCERIDES

A typical structure of the

triglyceride molecule

• Three fatty acid molecules are bound with one molecule of

glycerol.
• The 3 fatty acids most commonly present in the
triglycerides:
– (1) stearic acid
– (2) oleic acid
– (3) palmitic acid
 TRANSPORT OF TRIGLYCERIDES AND OTHER LIPIDS FROM THE
GASTROINTESTINAL TRACT BY LYMPH—THE CHYLOMICRONS

• Almost all the fats in the diet are absorbed from the
intestines into the intestinal lymph.
• During digestion, triglycerides are split into
monoglycerides and fatty acids.
• While passing through the intestinal epithelial cells,
the monoglycerides and fatty acids are resynthesized
into new molecules of triglycerides.
• They enter the lymph as minute, dispersed droplets
called chylomicrons, whose diameters are 0.08-0.6 µm.
 TRANSPORT OF TRIGLYCERIDES AND OTHER LIPIDS FROM THE
GASTROINTESTINAL TRACT BY LYMPH—THE CHYLOMICRONS

• Apoprotein B is adsorbed to the outer surfaces of

the chylomicrons.
• The remainder of the protein molecules project
into the surrounding water and increase the
suspension stability of the chylomicrons in the
lymph fluid and prevent their adherence to the
lymphatic vessel walls.
• Most of the cholesterol and phospholipids
absorbed from the GIT enter the chylomicrons.
• The chylomicrons are composed of
triglycerides (87%), phospholipids (9%),
cholesterol (3%), and apoprotein B (1%).
• The chylomicrons are transported through the
thoracic duct and emptied into the venous
blood at the juncture of the jugular and
subclavian veins.
 REMOVAL OF THE CHYLOMICRONS
FROM THE BLOOD
• About 1 hour after a meal that contains fat, the
chylomicron concentration in the plasma may
rise to 1-2% of the total plasma, and because of
the large size of the chylomicrons, the plasma
appears turbid and sometimes yellow.
• The chylomicrons have a half-life of less than 1
hour, so the plasma becomes clear again within
a few hours.
Chylomicron Triglycerides are Hydrolyzed by Lipoprotein Lipase, and
Fat is Stored in Adipose Tissue

• The chylomicrons are removed from the blood

as they pass through the capillaries of various
tissues, especially adipose tissue, skeletal
muscle, and heart.
• Tissues synthesize the enzyme lipoprotein
lipase, which is transported to the surface of
capillary endothelial cells, where it hydrolyzes
the triglycerides of chylomicrons, releasing
fatty acids and glycerol.
Major pathways for metabolism of chylomicrons
and very low density lipoprotein (VLDL)
• The fatty acids released from the chylomicrons
diffuse into the fat cells of the adipose tissue
and muscle cells.
• Once inside these cells, the fatty acids can be
used for fuel or again synthesized into
triglycerides, with new glycerol.
• The lipoprotein lipase also causes hydrolysis of
phospholipids, which also releases fatty acids
to be stored in the cells.
• After the triglycerides are removed from the
chylomicrons, the cholesterol-enriched
chylomicron remnants are rapidly cleared
from the plasma.
• The chylomicron remnants bind to receptors
on endothelial cells in the liver sinusoids.
• Apolipoprotein-E on the surface of the
chylomicron remnants and secreted by liver
cells plays an important role in clearance of
plasma lipoproteins.
“Free Fatty Acids” are Transported in the Blood
in Combination with Albumin
• Fat stored in the adipose tissue can be used
elsewhere in the body to provide energy.
• It must first be transported from the adipose
tissue to the other tissue.
• It is transported in the form of free fatty acids
(FFA).
• This transport is achieved by hydrolysis of the
triglycerides back into fatty acids and glycerol.
• Two factors play roles in trygiseride hydrolysis.
• 1. When the amount of glucose in the fat cell is
inadequate, one of the glucose breakdown
products, α-glycerophosphate, is not available
in sufficient quantities.
• Because this substance is required to maintain
the glycerol portion of triglycerides, the result
is hydrolysis of triglycerides.
• 2. A hormone-sensitive lipase is activated by
several hormones, and this promotes rapid
hydrolysis of triglycerides.
• Fatty acids ionize strongly in the plasma and
the ionic portion combines immediately with
albumin.
• Fatty acids bound in this manner are called
FFAs or nonesterified fatty acids, to distinguish
them from other fatty acids in the plasma.
• FFA concentration in the plasma is about 15 mg/dl,
which is a total of 0.45 gram of FAs in the all blood.
• Their rate of “turnover” is very rapid: half the
plasma FA is replaced by new FA in 2 to 3 min.
• Conditions that increase the utilization of fat to get
energy increase the FFA concentration in the blood;
the concentration sometimes increases 4- to 8-fold.
• Increased FFA occurs in cases of starvation and in
DM; in both these conditions, the person derives
little energy from carbohydrates.
• Under normal conditions, 3 molecules of fatty
acid combine with each albumin, but as many
as 30 fatty acid molecules can combine with a
single albumin when the need for fatty acid
transport is extreme.
 Lipoproteins-Their Special Function in
Transporting Cholesterol and Phospholipids
• After all the chylomicrons have been removed,
more than 95% of all the lipids in the plasma are
in the form of lipoprotein.
• The total concentration of lipoproteins is 700
mg/dl with the following individual lipoprotein
constituents: Cholesterol 180, Phospholipids 160,
Triglycerides 160, Protein 200 mg/dl.
 Types of Lipoproteins
• Aside from the chylomicrons there are 4 major types of
lipoproteins:
– (1) very low density lipoproteins (VLDLs), which contain high
concentrations of triglycerides and moderate concentrations of both
cholesterol and phospholipids
– (2) intermediate-density lipoproteins (IDLs), which are VLDLs from which
a share of the triglycerides has been removed, so the concentrations of
cholesterol and phospholipids are increased
– (3) lowdensity lipoproteins (LDLs), which are derived from IDLs by the
removal of almost all the triglycerides, leaving an especially high
concentration of cholesterol and a moderately high concentration of
phospholipids
– (4) highdensity lipoproteins (HDLs), which contain a high concentration
of protein (50%) but much smaller concentrations of cholesterol and
phospholipids.
 Formation and Function of Lipoproteins

• Almost all the lipoproteins are formed in the

liver.
• In addition, small quantities of HDLs are
synthesized in the intestinal epithelium during
the absorption of fatty acids from the
intestines.
• The function of the lipoproteins is to transport
the lipids in the blood.
 Formation and Function of Lipoproteins

• The VLDLs transport triglycerides synthesized in

the liver mainly to the adipose tissue.
• Special problems of cholesterol transport cause
the disease atherosclerosis, which is associated
with the development of fatty lesions on the
insides of arterial walls.
 Adipose Tissue
• Large quantities of fat are stored in two major
tissues: the adipose tissue and the liver.
• A major function of adipose tissue is storage of
triglycerides until they are needed to provide
energy elsewhere in the body.
• Additional functions are to provide heat
insulation for the body and secretion of
hormones, such as leptin and adiponectin, which
affect multiple body functions (appetite and
energy expenditure).
 Fat Cells (Adipocytes) Store Triglycerides

• The fat cells are modified fibroblasts that store

almost pure triglycerides in quantities as great as
80-95% of the entire cell volume.
• Triglycerides are in a liquid form.
• When the tissues are exposed to prolonged cold,
the fatty acid chains of the cell triglycerides
become either shorter or more unsaturated,
allowing the fat to remain in a liquid state.
• Only liquid fat can be hydrolyzed and transported
from the cells.
• Fat cells can synthesize very small amounts of
fatty acids and triglycerides from
carbohydrates; this function supplements the
synthesis of fat in the liver.
https://youtu.be/egEraZP9yXQ

Tissue Lipases Permit Exchange of Fat

Between Adipose Tissue and the Blood
• Large quantities of lipases are present in adipose
tissue.
• Some of them catalyze the deposition of cell
triglycerides from the chylomicrons and
lipoproteins.
• Others cause splitting of the triglycerides of the
fat cells to release free fatty acids.
• Because of the rapid exchange of fatty acids, the
triglycerides in fat cells are renewed in every 2 to
3 weeks.
 Liver Lipids
• The principal functions of the liver:
– (1) degrade fatty acids into small compounds that
can be used for energy
– (2) synthesize triglycerides, mainly from
carbohydrates, but to a lesser extent from
proteins as well
– (3) synthesize other lipids from fatty acids,
especially cholesterol and phospholipids.
• Large quantities of triglycerides appear in the
liver (1) during the early stages of starvation,
(2) in diabetes mellitus, and (3) in any other
condition in which fat instead of
carbohydrates is being used for energy.
• In these conditions, large quantities of
triglycerides are mobilized from the adipose
tissue, transported as free fatty acids in the
blood, and redeposited as triglycerides in the
liver.
• The liver may also store large amounts of lipids in
lipodystrophy, a condition characterized by
atrophy or genetic deficiency of adipocytes.
• The liver cells, in addition to containing
triglycerides, contain large quantities of
phospholipids and cholesterol, which are
continually synthesized by the liver.
• The liver cells are much more capable of
desaturating fatty acids than are other tissues,
and liver triglycerides are much more
unsaturated than the triglycerides of adipose
tissue.
• This capability of the liver to desaturate fatty
acids is important because many structural
elements of all cells contain reasonable
quantities of unsaturated fats, and their
principal source is the liver.
• This desaturation is accomplished by a
dehydrogenase in the liver cells.
 Use of Triglycerides for Energy: Formation of Adenosine
Triphosphate

• The dietary intake of fat is as little as 10-15%

of caloric intake in Asian populations to as
much as 35-50% of the calories in Western
populations.
• Many of the carbohydrates ingested are
converted into triglycerides, stored, and used
later in the form of fatty acids for energy.
 Hydrolysis of Triglycerides into Fatty Acids
and Glycerol
• The triglycerides is hydrolyzed into fatty acids
and glycerol.
• Both the fatty acids and the glycerol are
transported in the blood to the active tissues.
• Almost all cells except brain and red blood
cells can use fatty acids for energy.
• Glycerol is immediately changed into glycerol-
3-phosphate, which enters the glycolytic
pathway for glucose breakdown and is used
for energy.
• Before the fatty acids can be used for energy,
they must be processed further in the
mitochondria.
Entry of Fatty Acids into Mitochondria

• Degradation and oxidation of fatty acids occur

in the mitochondria.
• The first step is their transport into the
mitochondria.
• This carrier-mediated process uses carnitine as
the carrier substance.
• Inside the mitochondria, fatty acids split away
from carnitine and are degraded and oxidized.
 Degradation of Fatty Acids to Acetyl
Coenzyme A by Beta-Oxidation

• The fatty acid molecule is degraded in the

mitochondria to yield acetyl coenzyme A
(acetyl-CoA).
• This process is called the beta oxidation
process for degradation of fatty acids.
Beta-oxidation of fatty acids to yield acetyl
coenzyme A
 Oxidation of Acetyl-CoA
• The acetyl-CoA molecules enter into the citric
acid cycle, combining first with oxaloacetic
acid to form citric acid, which then is degraded
into carbon dioxide and hydrogen atoms.
• The hydrogen is subsequently oxidized by the
chemiosmotic oxidative system of the
mitochondria.
The net reaction in the citric acid cycle for
each molecule of acetyl-CoA
• The final breakdown of fatty acids is the same
as that of the acetyl-CoA formed from pyruvic
acid during the metabolism of glucose.
• The extra hydrogen atoms are also oxidized by
the same chemiosmotic oxidative system,
liberating large amounts of ATP.
 Large Amounts of ATP are Formed by
Oxidation of Fatty Acids
• During the complete oxidation of 1 molecule
of stearic acid, a total of 148 molecules of ATP
are formed.
• However, two high-energy bonds are
consumed in the initial combination of CoA
with the stearic acid molecule, making a net
gain of 146 molecules of ATP.
 Formation of Acetoacetic Acid in the Liver
and its Transport in the Blood
• Most of the degradation of FAs occurs in the
liver.
• The liver uses only a small proportion of the fatty
acids for its own metabolic processes.
• When the FA chains have been split into acetyl-
CoA, two molecules of acetyl-CoA condense to
form one molecule of acetoacetic acid.
• Acetoacetic acid is transported in the blood to
the other cells to be used for energy.
Acetoacetic acid is
converted into
β-hydroxybutyric
acid, and minute
quantities are
converted into
acetone
• The acetoacetic acid, β-hydroxybutyric acid, and
acetone (ketone bodies) diffuse through the
liver cell membranes and are transported by
the blood to the peripheral tissues.
• Inside the cells, reverse reactions occur and
acetyl-CoA molecules are formed.
• They enter the citric acid cycle and are oxidized
for energy.
• Normally, the ketone bodies’ concentration in
the plasma seldom rises above 3 mg/dl.
• Despite this small concentration in the blood,
large quantities are transported.
• Their rapid transport results from their high
solubility in the membranes of the target cells,
which allows almost instantaneous diffusion
into the cells.
 Ketosis in Starvation, Diabetes, and Other
Diseases
• The increased concentrations of ketone bodies is
called ketosis.
• The three compounds are called ketone bodies.
• Ketosis occurs during starvation, in persons with
diabetes mellitus, and sometimes even when a
person’s diet is composed almost entirely of fat.
• The unavailability of carbohydrates increases
the rate of removal of FAs from adipose tissues.
• Increased secretion of glucocorticoids by the
adrenal cortex, increased secretion of glucagon
by the pancreas, and decreased secretion of
insulin by the pancreas enhance the removal of
FAs from the fat tissues.
• Large quantities of FAs are available in the
peripheral tissues to be used for energy and in
the liver cells to be converted to ketone bodies.
• The ketone bodies is carried from the liver to
to the cells.
• For several reasons, the cells are limited in the
amount of ketone bodies that can be oxidized.
• The most important reason for this limitation
is that one of the products of carbohydrate
metabolism is the oxaloacetate.
• Oxaloacetate is required to bind with acetyl-
CoA to enter into the citric acid cycle.
• Therefore, deficiency of oxaloacetate derived
from carbohydrates limits the entry of acetyl-
CoA into the citric acid cycle.
• When a simultaneous outpouring of large
quantities of ketone bodies from the liver
occurs, the blood concentrations of ketone
bodies sometimes rise to as high as 20 times
normal, thus leading to extreme acidosis.
• The acetone that is formed during ketosis is a
volatile substance, some of which is blown off
in small quantities in the expired air of the
lungs, thus giving the breath an acetone smell
that is frequently used as a diagnostic criterion
of ketosis.
 Adaptation to a High-Fat Diet
• When changing slowly from a carbohydrate diet to a
diet almost completely consisting of fat, a person’s
body adapts to use far more acetoacetic acid than
usual, and in this instance, ketosis normally does
not occur.
• For instance, in the Inuit (Eskimos), who sometimes
live mainly on a fat diet, ketosis does not develop.
• After a few weeks, even the brain cells, which
derive almost all their energy from glucose, can
derive 50-75% of their energy from fats.
 Synthesis of Triglycerides From
Carbohydrates
• Whenever a greater quantity of carbohydrates
enters the body than can be used for energy or
can be stored in the form of glycogen, the excess
is rapidly converted into triglycerides and stored
in this form in the adipose tissue.
• In humans, most triglyceride synthesis occurs in
the liver, but minute quantities are also
synthesized in the adipose tissue.
• The triglycerides formed in the liver are
transported mainly in VLDLs to the adipose tissue.
 Conversion of Acetyl-CoA into Fatty Acids

• The first step in the synthesis of triglycerides is

conversion of carbohydrates into acetyl-CoA.
• This conversion occurs during the normal
degradation of glucose by the glycolytic system.
• The synthesis of fatty acids from acetyl-CoA
occurs by the two-step process, using malonyl-
CoA and reduced nicotinamide adenine
dinucleotide phosphate (NADPH).
Synthesis of fatty acids
 Combination of Fatty Acids With
α-Glycerophosphate to Form Triglycerides
• The synthesized fatty acid chains bind with
glycerol to form triglycerides.
• The glycerol portion of triglycerides is
furnished by α-glycerophosphate, which is
another product derived from the glycolytic
scheme of glucose degradation.
Overall schema for synthesis of
triglycerides from glucose
 Efficiency of Carbohydrate Conversion Into
Fat

• During triglyceride synthesis, only about 15%

of the original energy in the glucose is lost in
the form of heat; the remaining 85 percent is
transferred to the stored triglycerides.
 Importance of Fat Synthesis and Storage

• Fat synthesis from carbohydrates is important for two

reasons:
• 1. The ability of the body to store carbohydrates in the
form of glycogen is slight; only a few hundred grams of
glycogen can be stored in the liver, the skeletal muscles,
and all other tissues.
• Many kilograms of fat can be stored in adipose tissue.
• Fat synthesis is a means to store the energy of excess
ingested carbohydrates (and proteins) for later use.
• The average person has 150 times as much energy stored
in the form of fat as stored in the form of carbohydrate.
• 2. Each gram of fat contains almost two and a
half times the calories of energy contained by
each gram of glycogen.
• A person can store several times as much
energy in the form of fat as in the form of
carbohydrate.
Failure to Synthesize Fats From Carbohydrates
in the Absence of Insulin
• When insulin is not available, as occurs in persons
with DM, fats cannot be synthesized for the
following reasons:
– 1-when insulin is not available, glucose does not enter
the fat and liver cells, the acetyl-CoA and NADPH
needed for fat synthesis can’t be derived from glucose.
– 2-lack of glucose in the fat cells reduces the availability
of α-glycerophosphate, which also makes it difficult for
the tissues to form triglycerides.
 Synthesis of Triglycerides From Proteins

• Many amino acids can be converted into

acetyl-CoA.
• The acetyl-CoA can be synthesized into
triglycerides.
• When people have more proteins in their diets
than their tissues can use as proteins, a large
share of the excess is stored as fat.
 Carbohydrates are Preferred over Fats for Energy
When Excess Carbohydrates are Available
• If excess carbohydrates are available, they are used
preferentially over triglycerides for energy.
• This is called “fat-sparing” effect of carbohydrates.
• Fats in adipose tissue are present in two forms: stored
triglycerides and FFA. They are in constant equilibrium
with each other.
• If excess quantities of α-glycerophosphate are present, it
binds the free fatty acids to form triglycerides.
• Because α-glycerophosphate is a product of glucose
metabolism, the availability of glucose inhibits the use of
fatty acids for energy.
• If carbohydrates are available in excess, fatty
acids are synthesized more rapidly than they
are degraded.
• This effect is caused partially by the large
quantities of acetyl-CoA formed from the
carbohydrates and by the low concentration
of free fatty acids in the adipose tissue.
• An even more important effect that promotes
the conversion of carbohydrates to fats is the
following:
• The first step in the synthesis of fatty acids is
carboxylation of acetyl-CoA to form malonyl-
CoA.
• The rate of this reaction is controlled primarily
by the enzyme acetyl-CoA carboxylase.
• Thus, an excess of carbohydrates in the diet
not only acts as a fat-sparer but also increases
fat stores.
• In fact, all the excess carbohydrates not used
for energy or stored in the small glycogen
deposits of the body are converted to fat for
storage.
 Acceleration of Fat Utilization for Energy
in the Absence of Carbohydrates
• All the fat-sparing effects of carbohydrates are
lost and reversed if carbohydrates are not
available.
• The equilibrium shifts in the opposite
direction, and fat is mobilized from adipose
cells and used for energy in place of
carbohydrates.
• Also important are several hormonal changes
that promote rapid fatty acid mobilization
from adipose tissue.
• Among the most important of these hormonal
changes is a decrease in pancreatic secretion
of insulin.
• This decrease not only reduces the rate of
glucose utilization but also decreases fat
storage.
Hormonal Regulation of Fat Utilization

• At least seven hormones have significant

effects on fat utilization.
• The most dramatic increase in fat utilization is
observed during heavy exercise.
• This increase results from release of
epinephrine and norepinephrine by the
adrenal medullae during exercise, as a result
of sympathetic stimulation.
• These two hormones directly activate hormone-
sensitive triglyceride lipase, causing rapid
breakdown of triglycerides and mobilization of
fatty acids.
• Sometimes the FFA concentration in the blood
of an exercising person rises as much as
eightfold, and the use of fatty acids by the
muscles is increased.
• Other types of stress that activate the
sympathetic nervous system can also increase
FA mobilization and utilization in a similar
manner.
• Stress also causes corticotropin to be released
by the anterior pituitary gland, which causes
the adrenal cortex to secrete glucocorticoids.
• Both corticotropin and glucocorticoids activate
the hormone-sensitive triglyceride lipase.
• When corticotropin and glucocorticoids are
secreted in excessive amounts for long
periods, fats are mobilized to such a great
extent that ketosis results.
• This abnormality is called Cushing’s syndrome,
• Corticotropin and glucocorticoids have a
ketogenic effect.
• Growth hormone has an effect similar to but
weaker in activating hormone-sensitive lipase.
• GH have a mild ketogenic effect.
• Thyroid hormone increases rate of energy
metabolism in all cells.
• The resulting reduction in acetyl-CoA and other
intermediates of both fat and carbohydrate
metabolism is a stimulus to fat mobilization.
Obesity—Excess Deposition of Fat
• Obesity is caused by the ingestion of greater
amounts of food than can be used by the body
for energy.
• The excess food, whether fats, carbohydrates,
or proteins, is stored as fat in the adipose
tissue.
• In hereditary obesity, the obesity is caused by
ineffective mobilization of fat from the
adipose tissue by tissue lipase.
• There is progressive enhancement of the fat
stores and severe obesity.
• Multiple genetic factors that influence brain
feeding centers can cause hereditary obesity.
• However, monogenic (single gene) causes of
human obesity are rare.
 Phospholipids
• The major types of body phospholipids are
lecithins, cephalins, and sphingomyelin.
• Phospholipids contain one or more fatty acid
molecules and one phosphoric acid radical.
• They are lipid soluble, transported in
lipoproteins, and used throughout the body
for various structural purposes, such as in cell
membranes.
Phospholipids
 Formation of Phospholipids
• They are synthesized in all cells.
• Probably 90% are formed in liver cells;
substantial quantities are also formed by the
intestinal epithelial cells during lipid absorption
from the gut.
• When triglycerides are deposited in the liver,
the rate of phospholipid formation increases.
 Formation of Phospholipids
• Some specific substances are needed for the
formation of some phospholipids.
• Choline, either obtained in the diet or
synthesized in the body, is necessary for the
formation of lecithin, because choline is the
nitrogenous base of the lecithin molecule.
• Inositol is necessary for the formation of some
cephalins.
 Specific Uses of Phospholipids
• 1. Phospholipids are a constituent of lipoproteins
in the blood and are essential for the formation
and function of lipoproteins; in the absence of
phospholipids, serious abnormalities of transport
of cholesterol and other lipids can occur.
• 2. Thromboplastin, which is necessary to initiate
the clotting process, is composed mainly of one
of the cephalins.
 Specific Uses of Phospholipids
• 3. Large quantities of sphingomyelin are present
in the nervous system; an electrical insulator in
the myelin sheath around nerve fibers.
• 4. Phospholipids are donors of phosphate
radicals when these radicals are necessary for
different chemical reactions in the tissues.
• 5. The most important function of phospholipids
is participation in the formation of structural
elements-mainly membranes.
 Cholesterol
• Cholesterol is present in the normal diet, and it
can be absorbed slowly from the GIT into the
intestinal lymph.
• It is highly fat soluble and slightly soluble in
water.
• It is capable of forming esters with fatty acids.
• 70% of the cholesterol in the lipoproteins of the
plasma is in the form of cholesterol esters.
Cholesterol
 Formation of Cholesterol
• Besides the cholesterol absorbed each day from
the gastrointestinal tract (exogenous cholesterol),
an even greater quantity is formed in the cells of
the body (endogenous cholesterol).
• All the endogenous cholesterol in the lipoproteins
of the plasma is formed by the liver, but all other
cells of the body form at least some cholesterol.
• Many of the membranous structures of all cells
are partially composed of cholesterol.
• The basic structure of cholesterol is a sterol
nucleus, which is synthesized entirely from
multiple molecules of acetyl-CoA.
• In turn, the sterol nucleus can be modified by
various side chains to form (1) cholesterol; (2)
cholic acid, which is the basis of the bile acids
formed in the liver; and (3) many important
steroid hormones secreted by the adrenal
cortex, the ovaries, and the testes.
 Factors that Affect Plasma Cholesterol
Concentration-Feedback Control of Body Cholesterol

• 1. An increase in the amount of cholesterol ingested

each day may increase the plasma concentration
slightly.
• However, when cholesterol is ingested, the rising
concentration of cholesterol inhibits endogenous
synthesis of cholesterol, providing an intrinsic feedback
control system to prevent an excessive increase in
plasma cholesterol concentration.
• As a result, plasma cholesterol concentration is not
changed more than ±15 percent by altering the amount
of cholesterol in the diet.
• 2. A diet high in saturated fat increases blood
cholesterol concentration 15-25%, especially when
this diet is associated with excess weight gain and
obesity.
• This increase in blood cholesterol results from
increased fat deposition in the liver, which then
provides increased quantities of acetyl-CoA in the
liver cells for the production of cholesterol.
• Therefore, to decrease the blood cholesterol
concentration, maintaining a diet low in saturated
fat and a normal body weight is even more
important than maintaining a diet low in
cholesterol.
• 3. Ingestion of fat containing highly
unsaturated fatty acids usually depresses the
blood cholesterol concentration.
• 4. Lack of insulin or thyroid hormone increases
the blood cholesterol concentration, whereas
excess thyroid hormone decreases the
concentration.
• 5. Genetic disorders of cholesterol metabolism
may increase plasma cholesterol levels.
• For example, mutations of the LDL receptor
gene prevent the liver from removing the
cholesterol-rich LDLs from the plasma.
• This phenomenon causes the liver to produce
excessive amounts of cholesterol.
• Mutations of the gene that encodes
apolipoprotein B also cause excessive
cholesterol production by the liver.
 Specific Uses of Cholesterol
• The most non-membranous use of cholesterol is to
form cholic acid in the liver.
• 80% of cholesterol is converted into cholic acid.
• Cholic acid is conjugated with other substances to form
bile salts, which promote digestion and absorption of
fats.
• A small quantity of cholesterol is used by (1) the
adrenal glands to form adrenocortical hormones, (2)
the ovaries to form progesterone and estrogen, and (3)
the testes to form testosterone.
• A large amount of cholesterol is precipitated in the
corneum of the skin.
• Cholesterol and other lipids make the skin
resistant to the absorption of water-soluble
substances and to the action of many chemical
agents because cholesterol and the skin lipids are
highly inert to acids and to many solvents that
might penetrate the body.
• Also, lipids help prevent water evaporation from
the skin; without this protection, the amount of
evaporation can be 5 to 10 liters per day (as occurs
in patients with burns who have lost their skin)
instead of the usual 300 to 400 milliliters.
 Atherosclerosis
• Atherosclerosis is a disease of the large and
intermediate-sized arteries in which fatty
lesions called atheromatous plaques develop
on the inside surfaces of the arterial walls.
• Arteriosclerosis, in contrast, is a general term
that refers to thickened and stiffened blood
vessels of all sizes.
• Atherosclerosis cause damage to the vascular
endothelium.
• This damage increases the expression of
adhesion molecules on endothelial cells and
decreases their ability to release nitric oxide
and other substances that help prevent
adhesion of macromolecules, platelets, and
monocytes to the endothelium.
• After damage to the vascular endothelium
occurs, circulating monocytes and lipids (mostly
LDLs) begin to accumulate at the site of injury.
• The monocytes cross the endothelium, enter the
intima of the vessel wall, and differentiate to
become macrophages, which then ingest and
oxidize the accumulated lipoproteins, giving the
macrophages a foamlike appearance.
• These macrophage foam cells then aggregate on
the blood vessel and form a visible fatty streak.
Attachment of a monocyte to an
adhesion molecule on a damaged
endothelial cell of an artery.
The monocyte then migrates
through the endothelium
into the intimal layer of the arterial
wall and is transformed into a
macrophage.
The macrophage then ingests and
oxidizes lipoprotein molecules,
becoming a macrophage foam cell.
The foam cells release substances
that cause inflammation and
growth of the intimal layer.
• With time, the fatty streaks grow larger and
coalesce, and the surrounding fibrous and smooth
muscle tissues proliferate to form larger and larger
plaques.
• Also, the macrophages release substances that
cause inflammation and further proliferation of
smooth muscle and fibrous tissue on the inside
surfaces of the arterial wall.
• The lipid deposits plus the cellular proliferation can
become so large that the plaque bulges into the
lumen of the artery and greatly reduces blood
flow, sometimes completely occluding the vessel.
Additional accumulation
of macrophages and
growth of the intima
cause the plaque to
grow larger and
accumulate lipids.
Eventually, the plaque
may occlude the vessel
or rupture, causing the
blood in the artery to
coagulate and form a
thrombus.
• Even without occlusion, the fibroblasts of the
plaque eventually deposit extensive amounts of
dense connective tissue; sclerosis (fibrosis)
becomes so great that the arteries become stiff.
• Still later, calcium salts often precipitate with the
cholesterol and other lipids of the plaques,
leading to bony-hard calcifications that can
make the arteries rigid tubes.
• Both of these later stages of the disease are
called “hardening of the arteries.”
• Atherosclerotic arteries lose most of their
distensibility, and because of the degenerative
areas in their walls, they are easily ruptured.
• Also, where the plaques protrude into the
flowing blood, their rough surfaces can cause
blood clots to develop, with resultant
thrombus or embolus formation, leading to a
sudden blockage of all blood flow in the
artery.
• Almost half of all deaths in the United States
and Europe are due to vascular disease.
• About two thirds of these deaths are caused
by thrombosis of one or more coronary
arteries.
• The remaining one third are caused by
thrombosis or hemorrhage of vessels in other
organs of the body, especially the brain
(causing strokes), but also the kidneys, liver,
gastrointestinal tract, limbs, and so forth.
 Roles of Cholesterol and Lipoproteins
in Atherosclerosis
• Increased Low-Density Lipoproteins:
• An important factor in causing atherosclerosis is a high
blood plasma concentration of cholesterol in the form
of LDLs.
• The plasma concentration of these high-cholesterol
LDLs is increased by several factors, especially by
eating highly saturated fat in the daily diet, obesity,
and physical inactivity.
• To a much lesser extent, eating excess cholesterol may
also raise plasma levels of LDLs.
• Familial Hypercholesterolemia:
• Familial hypercholesterolemia is a disease in which
the person inherits defective genes for the formation
of LDL receptors on the membrane surfaces of the
body’s cells.
• In the absence of these receptors, the liver cannot
absorb either IDL or LDL.
• Without this absorption, the cholesterol machinery
of the liver cells goes on a rampage, producing new
cholesterol; it is no longer responsive to the
feedback inhibition of too much plasma cholesterol.
• As a result, the number of VLDLs released by the
liver into the plasma increases immensely.
• Patients with full-blown familial hypercholesterolemia
may have blood cholesterol concentrations of 600 to
1000 mg/dl, levels that are four to six times normal.
• If untreated, many of these people die before age 30
years because of myocardial infarction or other
sequelae of atherosclerotic blockage of blood vessels
throughout the body.
• Heterozygous familial hypercholesterolemia is
relatively common and occurs in about 1 in 500
people.
• The more severe form of this disorder caused by
homozygous mutations is much rarer, occurring in only
about one of every million births on average.
 Role of High-Density Lipoproteins in
Preventing Atherosclerosis
• HDLs absorb cholesterol crystals deposited in
arterial walls.
• HDL protects against atherosclerosis by means
of inhibition of oxidative stress and prevention
of inflammation in blood vessels.
• A person has a high ratio of HDL to LDL, the
likelihood of developing atherosclerosis is
greatly reduced.
Other Major Risk Factors for Atherosclerosis

• Predisposing factors to atherosclerosis:

– (1) physical inactivity and obesity
– (2) diabetes mellitus
– (3) hypertension
– (4) hyperlipidemia
– (5) cigarette smoking.
• Hypertension increases the risk for atherosclerotic
coronary artery disease by at least twofold.
• A person with diabetes mellitus has more than a twofold
increased risk of developing coronary artery disease.
 Other Major Risk Factors for Atherosclerosis

• When hypertension and diabetes mellitus occur

together, the risk for coronary artery disease is
increased by more than eightfold.
• When hypertension, diabetes mellitus, and
hyperlipidemia are all present, the risk for
atherosclerotic coronary artery disease is increased
almost 20-fold.
• In many overweight and obese patients, these three
risk factors occur together, greatly increasing their risk
for atherosclerosis, which in turn may lead to heart
attack, stroke, and kidney disease.
• Men are more likely to develop atherosclerosis
than are women, suggesting that male sex
hormones is atherogenic or that female sex
hormones is protective.
• Some of these factors cause atherosclerosis by
increasing the concentration of LDLs in the
plasma.
• Others, such as hypertension, lead to
atherosclerosis by causing damage to the vascular
endothelium and other changes in the vascular
tissues that predispose to cholesterol deposition.
• Excess blood levels of iron can lead to
atherosclerosis, perhaps by forming free
radicals in the blood that damage the vessel
walls.
• About one quarter of all people have a special
type of LDL called lipoprotein(a), containing an
additional protein, apolipoprotein(a), that
almost doubles the incidence of
atherosclerosis.
 Prevention of Atherosclerosis
• The most important measures to protect against the
development of atherosclerosis and its progression to
serious vascular disease:
– (1) maintaining a healthy weight, being physically active, and
eating a diet that contains mainly unsaturated fat with a low
cholesterol content
– (2) preventing hypertension by maintaining a healthy diet and
being physically active, or effectively controlling blood pressure
with antihypertensive drugs if hypertension does develop
– (3) effectively controlling blood glucose with insulin treatment
or other drugs if diabetes develops
– (4) avoiding cigarette smoking.
• Most of the cholesterol formed in the liver is converted into
bile acids and secreted into the duodenum; then, more
than 90% of these same bile acids is reabsorbed in the
terminal ileum and used over and over again in the bile.
• Any agent that combines with the bile acids in the
gastrointestinal tract and prevents their reabsorption can
decrease the total bile acid pool in the circulating blood.
• As a result, far more of the liver cholesterol is converted
into new bile acids.
• Thus, simply eating oat bran, which binds bile acids and is a
constituent of many breakfast cereals, increases the
proportion of liver cholesterol that forms new bile acids.
• Resin agents can also be used to bind bile acids in the gut
and increase their fecal excretion.
• Another group of drugs called statins
competitively inhibits hydroxymethylglutaryl-
coenzyme A (HMG-CoA) reductase, a rate-
limiting enzyme in the synthesis of cholesterol.
• This inhibition decreases cholesterol synthesis
and increases LDL receptors in the liver,
usually causing a 25 to 50 percent reduction in
plasma levels of LDLs.
• The statins may also have other beneficial
effects that help prevent atherosclerosis, such
as attenuating vascular inflammation.
• These drugs are now widely used to treat
patients who have increased plasma
cholesterol levels.
• In general, studies show that for each 1 mg/dl
decrease in LDL cholesterol in the plasma,
there is about a 2 percent decrease in
mortality from atherosclerotic heart disease.