Lipids and their metabolism for nurses

LIPIDS AND THEIR METABOLISM
Prepared by:
Mrs. Namita Batra Guin
Associate Professor

LIPIDS
⦿It is a heterogenous group of hydrophobic
organic molecules found in the cells.
⦿Sparingly soluble in water, but soluble in
organic solvents.

CLASSIFICATION
⦿SIMPLE LIPIDS
⦿COMPOUND LIPIDS
⦿DERIVED LIPIDS

SIMPLE LIPIDS
⦿Esters of fatty acids with alcohol.
⦿Includes neutral fats and waxes.
⦿Neutral fats and oils: Mixture of triglycerides
whose fatty acid composition may vary with
source.
⦿Neutral fats are obtained from animal sources,
while oils from the plant sources.
⦿Neutral fats have more number of saturated
fatty acids. Have higher melting point.
⦿Neutral oils are rich in unsaturated fatty acids
and have low melting point.
⦿A wax is a simple lipid which is an ester of a
long-chain alcohol and a fatty acid.

COMPOUND LIPIDS
⦿Comprise of fatty acids, alcohol and amphipathic
group.
⦿Phospholipids :Lipids conjugated with phosphoric
acid.
⦿Glycolipids: lipids with a carbohydrate attached by
a glycosidic bond. They are generally components of
cell membrane.
⦿Lipoproteins: contains both proteins and lipids ,
bound to the proteins , which allow fats to move
through the water inside and outside cells.

PHOSPHOLIPIDS
⦿Contains one or more phosphoric acid residues
and a polar group that may be nitrogenous
base, an amino acid or a polyhydroxy-alcohol.
⦿Also contain one or two long chain fatty acids.
⦿Amphipathic in nature. i.e. hydrophilic head
and long hydrophobic tail.
⦿Hydrophilic domain- interacts with the
aqueous environment and contains a
phosphate group and an alcohol.
⦿Hydrophobic- form non aqueous environment
and contains a long chain fatty acid.

PHOSPHOLIPIDS
⦿Types:
⦿Glycerophospholipids
⦿Sphingolipids
⦿Glycerophospholipids: derivatives of glycerol. Also
called as phosphoglycerides. E.g. lecithins,
cephalins, phosphatidylinostols, plasmalogens.
⦿Lecithin: are surface active agents and help in
emulsification of fats. Widely distributed in
brain cells, nerve cells, sperm and egg yolk.
⦿Cephalins: Present in erythrocytes membrane,
brain and many other tissues.

PHOSPHOLIPIDS
⦿Phosphatidylinostols: phosphoglycerides
containing inositol instead of nitrogenous
base. Found mainly in brain.
⦿Plasmalogens: Contains glycerol and
unsaturated fatty acids linked by ether
linkage. Present in cardiac and skeletal
muscles and semen.

PHOSPHOLIPIDS
⦿Types:
⦿Glycerophospholipids
⦿Sphingolipids
⦿Sphingolipids: are a class of lipids containing
a backbone of sphingoid bases, a set of
aliphatic amino alcohols that includes
sphingosine.
⦿Myelin sheath of nerve axons are rich in
sphingomyelin.

PHOSPHOLIPIDS
⦿Sphingolipids
⦿Types: Cerebrosides - contain ceramide
attached to sugar residue such as glucose.
Majorly found in white matter.
⦿Gangliosides: complex glycolipids. Present
in large amount in ganglion cells of the
central

PHYSIOLOGICAL ROLE OF
PHOSPHOLIPIDS
⦿They are part of cell membrane.
⦿Functions as reservoir for intracellular
messengers
⦿Serves as anchor for some proteins
⦿Components of lung surfactants
⦿Essential component of bile and help in
regulation of serum cholesterol.

LIPOPROTEINS
⦿A lipoprotein is a biochemical assembly that
contains both proteins and lipids ,bound to the
proteins , which allow fats to move through the
water inside and outside cells.
⦿They are compound lipids.
⦿Globular micelle like particles consisting of
non-polar core of triacylglycerols and
cholesterol esters, which are surrounded by the
amphiphilic coating that consists of proteins,
cholesterol and phospholipids.
⦿Also known as protein lipid complexes or
proteolipids.

LIPOPROTEINS
⦿Are classified as:
⦿Chylomicrons
⦿Very low density Lipoprotein
⦿Low density Lipoprotein
⦿High density Lipoprotein

CLASSIFICATION
ACCORDING TO SIZE

LIPOPROTEINS- CHYLOMICRONS
⦿Chylomicrons: Very large particles secreted
into lymphatics by the mucosal cells of
small intestine.
⦿90% of their mass is triglycerides esterified
with cholesterol and fat soluble vitamin.
⦿Surface layer is made up of free
cholesterol, phospholipids and apoproteins.

LIPOPROTEINS- CHYLOMICRONS
⦿FUNCTIONS:
Chylomicrons transport lipids absorbed from the
intestine to: adipose, cardiac, and skeletal muscle
tissue, where their triglyceride components are
hydrolyzed by the activity of lipoprotein lipase and the
released free fatty acids are absorbed by the tissue.
When a large portion of the triacylglycerol core have
been hydrolyzed, chylomicron remnants are formed
and are taken up by the liver, hereby transferring
dietary fat also to the liver.
It transports dietary fats and cholesterol from intestines
to tissues.

LIPOPROTEINS- VLDL
⦿Very Low density Lipoproteins:
⦿Large particles, which are secreted into
blood stream, by the hepatocytes.
⦿50-60% mass in triglycerides. Contains
relative more cholesterol esters than
chylomicron.
⦿Surface contain free cholesterol,
phospholipids and single molecule of apo
B100 and other apoproteins.
⦿It is transformed into intermediate density
lipoproteins. (IDL).

LIPOPROTEINS- VLDL
⦿FUNCTIONS:
 VLDL transports endogenous triglycerides
, phospholipids, cholesterol, and cholesteryl
esters.
 It functions as the body's internal transport
mechanism for lipids.
 In addition it serves for long-range transport of
hydrophobic intercellular messengers, like the
morphogen.

LIPOPROTEINS- IDL
 It’s formed from the degradation of very low-
density lipoproteins.
 Their size is, in general, 25 to 35 nm in
diameter, and they contain primarily a range
of triacylglycerols and cholesterol esters.

LIPOPROTEINS- IDL
⦿FUNCTIONS:
 It enables fats and cholesterol to move within
the water-based solution of the bloodstream.
 Each native IDL particle consists of protein that
encircles various fatty acids, enabling, as a
water-soluble particle, these fatty acids to
travel in the aqueous blood environment as
part of the fat transport system within the body.

LIPOPROTEINS- LDL
⦿Low density Lipoproteins:
⦿Carries about 75% of the total cholesterol,
in human plasma.
⦿Sometimes also known as “bad
cholesterol”.
⦿Are the principal cholesterol and fat
transporter in human blood that carries
cholesterol from the liver to the body
tissues and cells.

LIPOPROTEINS- LDL
⦿FUNCTIONS
 In metabolism their function is mediating by cellular
uptake via receptor-mediated endocytosis followed by
lysosomal degradation, and is strongly dependent on the
lipid distribution.
 LDL particles are intimately involved in the progression of
cardiovascular diseases such as atherosclerosis or
stroke, which are among the most prevalent causes of
death.
 Raised plasma levels of LDL are linked to an increased
risk for disease.

LIPOPROTEINS- HDL
⦿High density Lipoproteins:
 HDL type is the smallest of
the lipoprotein particles.
 It is the densest because it contains the
highest proportion of protein to lipids.
 It is the most abundant apolipoproteins .

LIPOPROTEINS- HDL
⦿FUNCTIONS
⦿Protects against heart disease via their role in
reverse cholesterol transport, or the transport of
excess cholesterol out of the body.
⦿Are also part of the innate immune system due to
their ability to bind a number of toxic substances in
the blood.
⦿Are Reverse Cholesterol Transport .
⦿Aid Esterification of cholesterol, (through the
action of LCAT).
⦿Are also a reservoir of apoproteins that can be
transferred to other lipoproteins.
⦿Acceptor of cholesterol. Can accept and solubilise
the cholesterol.

METABOLISM OF LIPOPROTEINS
⦿Chylomicrons: The enzyme lipoprotein
lipase, with apolipoprotein (apo)C-II as a co-
factor, hydrolyzes chylomicron triglyceride
allowing the delivery of free fatty acids to muscle
and adipose tissue. A chylomicron remnant is
formed in the end.
⦿LDL: About 40 to 60% of all LDL are cleared by
the liver in a process mediated by apo B and
hepatic LDL receptors.
⦿The rest are taken up by either hepatic LDL or
non-hepatic non-LDL (scavenger) receptors.

 VLDL metabolism is very similar to Chylomicrons
metabolism.
 The main lipid found in VLDL is also
triacylglycerol, but in this case triacylglycerols
come from excess fatty acids on diet or an
increase in the hepatic synthesis of fatty acids as a
consequence of excess carbohydrates in diet.
 Fats coming from the hepatocytes uptake of
Chylomicrons remnants are also a source of
triacylglycerols for VLDL.

 HDL: HDLs are synthesized in the liver
and the small intestine. They are the
lipoproteins with the higher protein
content (it can reach around 50 % of the
particle total weight). When secreted,
they contain little cholesterol and no
cholesteryl esters.

DERIVED LIPIDS
⦿Obtained after hydrolysis of simple and
compound lipids.
⦿They include fatty acids, glycerol, steroid
hormones etc.

FATTY ACIDS
⦿They are the carboxylic acids with long
hydrocarbon side chain which may be
saturated or unsaturated with one or more
double bonds.
⦿Major source of circulating free fatty acids is
adipose tissues.
⦿Hydrolysis of chylomicrons and VLDL gives
free fatty acids. they are important source of
energy.
⦿Since they have limited solubility in water,
they are transported with plasma albumin
which has specific binding sites for free fatty
acids.

Physical Properties of Fatty Acids
• Solubility
>Longer chains
• more hydrophobic, less soluble.
>Double bonds increase solubility.
• Melting points
• Depend on chain length and saturation
• Double bonds lead chain disorder and low melting
temperature.
• Unsaturated FAs are solids at Room Temperature.

Physical Properties of Fatty Acids
• Fatty acids in various oils react with alkali and forms
salts. These salts from various fatty acids are used as
soaps and emulsifying agents.
• Unsaturated fatty acids undergo reduction and are
converted to saturated fat. For e.g. hydrogenation of
vegetable oil results in the formation of ghee.
• Various fatty acids can be separated from a mixture by
gas chromatography.

Types of fatty acids
The Length of the Carbon Chain
 long-chain (14 or more carbons)
 medium-chain (10-14 carbons)
 short-chain (4-10 carbons)
The Degree of Unsaturation
 saturated (-anoic)
 unsaturated (-enoic)
The Location of Double Bonds
 omega-3 fatty acid
 omega-6 fatty acid

The Degree of
Unsaturation
Saturated Unsaturated
(cis or trans
configuration)
Monounsaturated Polyunsaturated

TYPES OF FATTY ACIDS
⦿Depending upon presence of double bond
they are of three types:
◼Saturated
◼Unsaturated
◼Polyunsaturated

SATURATED FATTY ACIDS
⦿All carbon atoms are joined by single bond
and each carbon atom carries hydrogen atom.
⦿These fatty acids end with “anoic”. E.g.
octadecanoic acid (stearic acid).
⦿Has relatively free rotation around each of
their C-C bond.
⦿Highly flexible
⦿General chemical formula is CnH2nO2.

UNSATURATED FATTY ACIDS
⦿Ends with “enoic”. E.g. octadecenoic acid
(Oleic acid).
⦿They are linked by double bond.
⦿They cannot pack tightly together as
saturated fatty acids due presence of kinks
because of cis double bonds.
⦿Less thermal energy is required to disturb the
interactions. Therefore they have low melting
points.

POLYUNSATURATED FATTY ACIDS
⦿Fatty acids having more than one double
bonds are called polyunsaturated fatty acids.
⦿Double usually occurs after every 3-carbon
atoms.
⦿Main sources of these fatty acids are:
soyabean oil, sunflower oil, groundnut oil etc.
⦿They are also known as essential fatty acids
as they are not synthesized in the body.
⦿E.g. linolenic acid and arachidonic acid.

PHYSIOLOGICAL ROLE OF PUFA
⦿They form essential component of diet, as
they are necessary for growth and normal
health.
⦿Important constituent of a biological
membrane.
⦿Also used for esterification of cholesterol and
thus help in transport and metabolism.
⦿Diet rich in -3fatty acids promote reduction in
plasma triacylglycerols.
⦿Arachidonic acid acts as a precursor of
eicosanoids such as prostaglandins,
thromboxanes and leukotrienes.

STEROIDS
⦿Though they do not contain fatty acids, but
they are included in lipids because of their
lipid like properties.
⦿They contain complex carbon framework of
four fused rings, three of which have six
carbon atoms and fourth one has five.
⦿Common steroids are: sterols.
⦿Sterols include cholesterol and ergosterol etc.
⦿It includes: A. Sterols B. Bile acids and salts
C. Steroid hormones D. Vitamin D
⦿Most common Steroid is cholesterol. It has 27
carbons.

CHOLESTEROL
⦿ Common sterol in animals.
⦿ Amphipathic in nature.
⦿ Blood contains cholesterol- 150-250mg/100ml.
⦿ Increase in blood may lead to its deposition, thus
causing atherosclerosis.
⦿ Importance:
◼Important component of plasma membrane
◼Acts as precursor for various substances in
mammals such as steroid hormones, vitamin D
etc.
◼Bile acid, the derivatives of cholesterol help in
emulsification of fats.

PROSTAGLANDINS
⦿Hormone like compounds.
⦿20-carbon containing fatty acids having one
or more double bond, hydroxyl or keto group
on certain carbons and a cyclopentane ring.
⦿Synthesized aerobically from polyunsaturated
fatty acids.
⦿It exist in virtually every mammalian tissue
and act as a local hormone.
⦿There are three classes: A, E and F.

⦿PG A- are alpha, beta unsaturated ketones
⦿PG E- contain beta-hydroxy ketone ring
⦿PG F- 1,3-diols.
⦿Importance:
◼Stimulate contractions of smooth muscles of
the uterus during menstruation and labour.
◼Elevate body temperature and cause
inflammation and pain in case of injury.
◼Help in formation of blood clots and
regulation of B.P.
◼Helpful in inhibiting gastric acid secretion in
patients with peptic ulcers

⦿ Prostaglandins act as local hormones.
⦿ PGs are produced in almost all the tissues.
⦿ PGs are not stored & they are degraded to
inactive products at the site of their
production.
⦿ PGs are produced in very small amounts &
have low half-lives.
Biochemical actions of prostaglandins

⦿ Regulation of blood pressure:
⦿ The prostaglandins (PGE, PGA & PGl2) are
vasodilator in function.
⦿ This results in increased blood flow and
decreased peripheral resistance to lower the
blood pressure.
⦿ PGs serve as agents in the treatment of
hypertension.

⦿ Inflammation:
⦿ PGEI & PGE2 induce the symptoms of
inflammation (redness, swelling, edema etc.)
due to arteriolar vasodilation.
⦿ PGs are natural mediators of inflammatory
reactions of rheumatoid arthritis, psoriasis,
conjunctivitis etc.
⦿ Corticosteroids are used to treat these
inflammatory reactions, since they inhibit
prostaglandin synthesis.

⦿ Reproduction:
⦿ PGE2 & PGF2 are used for the medical termination of
pregnancy & induction of Iabor.
⦿ Pain and fever:
⦿ Pyrogens (fever producing agents) promote
prostaglandin synthesis leading to the formation of
PGE2 in hypothalamus-regulation of body temperature.
⦿ PGE2 along with histamine & bradykinin cause pain.
⦿ Migraine is also due to PGE2.
⦿ Aspirin & other non-steroidal drugs inhibit PG synthesis
& thus control fever & relieve pain.

⦿ Regulation of gastric secretion:
⦿ Prostaglandins (PGE) inhibit gastric secretion.
⦿ PGs are used for the treatment of gastric ulcers.
⦿ PGs stimulate pancreatic secretion & increase
the motility of intestine which often causes
diarrhea.
⦿ Influence on immune system:
⦿ Macrophages secrete PGE which decreases the
immunological functions of B-& T-lymphocytes.

⦿ Effects on respiratory function:
⦿ PGE is a bronchodilator whereas PGF acts
as a constrictor of bronchial smooth muscles.
⦿ PGE & PGF oppose the actions of each other
in the lungs.
⦿ PGEI & PGE2 are used in the treatment of
asthma.

⦿ Influence on renal functions:
⦿ PGE increases glomerular filtration rate &
promotes urine output.
⦿ Excretion of Na+ & K+ is also increased by PGE.
⦿ Effects on metabolism:
⦿ Prostaglandins influence certain metabolic
reactions, through the mediation of cAMP.
⦿ PGE decrease lipolysis, increases glycogen
formation & promotes calcium mobilization.

⦿ Platelet aggregation & thrombosis:
⦿ The prostaglandins – prostacyclins (PGI2),
inhibit platelet aggregation.
⦿ Thromboxanes (TXA2) & prostaglandin E2
promote platelet aggregation & blood
clotting that might lead to thrombosis.

Biomedical applications of PGs
⦿ They are used in the treatment of gastric
ulcers, hypertension, thrombosis, asthma etc.
⦿ Prostaglandins are also employed in the
medical termination of pregnancy, prevention
of conception, induction of labor etc.

TRIACYLGLYCEROLS
⦿Simplest lipids constructed from fatty acids.
⦿Also called as triglycerides or neutral fats.
⦿Glycerol with one molecule of fatty acid is
called monoacylglycerol.
⦿With two it is diacylglycerol and with three it
is triacylglycerol.
⦿A molecule of triacylglycerol may contain
three similar or dissimilar fatty acids which
may be saturated or unsaturated.
⦿All natural fats and oils are mixed
triacylglycerols.

PROPERTIES OF TRIACYLGLYCEROLS
⦿It is the storage form of energy in the body.
⦿They are hydrolysed by lipases to free fatty
acids and glycerol
⦿Naturally occurring fat, particularly from
animal sources, develop unpleasant odor or
taste, if stored for a long period under moist
conditions. This is called rancidity.
⦿Unsaturated fatty acids in triacylglycerol
accepts halogens such as iodine at the double
bond. The process is termed as halogenation.

IMPORTANCE
⦿Adipocytes stores large amount of
triacylglycerols as fat droplets.
⦿Stored as oil in the seeds of many types of
plants, provides energy and act as
biosynthetic precursors during seed
germination.
⦿Serves as a shock absorbing cushion around
the eye balls, kidneys and gonads.

DIGESTION OF
TRIACYLGLYCEROL
It is initiated in mouth with chewing and by the
action of lingual lipase.
By the action of gastric lipase in stomach, nearly
30% of the dietary triglycerides get degraded into
di-glycerides and free fatty acids within 2-3 hrs.
Contents then passes to small intestine. Where it
stimulates the release of two hormones i.e.
cholecystokinin (CCK) and secretin from duodenal
cells.
CCK signals the gall bladder to contract and release
bile, down the bile duct and into the duodenum.

DIGESTION OF
TRIACYLGLYCEROL
Bile contains large quantity of bile salts and
lecithin.
Secretin signals pancreas to release
pancreatic juice rich in pancreatic lipase.
Bile emulsifies fat and breaks fat globules
into small pieces and keep them suspended in
solution.
It increases the total surface area for the
action of pancreatic lipase.

DIGESTION OF
TRIACYLGLYCEROL
Pancreatic lipase hydrolyzes all accessible
triglycerides, within minutes into
monoglycerides and free fatty acids.
Bile salts surrounds the hydrolyzed products of
fat and form water soluble globules with fatty
core- micelles
Micelles transport monoglycerides and free
fatty acids to the brush border of the intestinal
mucosal cells for absorption.
Similarly phospholipase hydrolyze phospholipids
and release monoglycerides, free fatty acids,
phosphate and a nitrogenous substance.

ABSORPTION OF TRIACYLGLYCEROL
Most fat absorption takes place in the duodenum
or jejunum of small intestine.
Micelles carry monoglycerides and long chain fatty
acids to the surface of micro villi and diffuses into
intestinal cells.
Unabsorbed bile salts returns to the interior of
small intestine to transport more triglycerides and
fatty acids .
This recycling pathway for bile is called
enterohepatic circulation.

ABSORPTION OF TRIACYLGLYCEROL
As monoglycerides and fatty acids pass into
intestinal cells, they reform triglycerides.
Most of the triglycerides, cholesterol and
phospholipids combine with apoproteins and form
chylomicrons.
They enter into lymph system to be propelled
through the thoracic duct and emptied into vein
in the neck.
Glycerol and medium and short fatty acids are
absorbed directly into blood.

DIGESTION, MOBILIZATION AND
TRANSPORT OF LIPIDS
In stomach
Lipids are broken down into triglycerides
(gastric lipase).
Bile salts emulsify the fats in small intestine.
In intestine
Degraded into triacylglycerol (intestinal lipase)
Free fatty acids and other breakdown products
are taken up by the intestinal mucosa and
converted to triacylglycerols.

⦿Through blood stream, they are taken up by
the cells i.e. adipocytes, where they either
oxidized as fuel or stored.
⦿Various lipids are transported into blood in
association with the lipoproteins.
⦿Bile salts emulsify the dietary fats in small
intestine, forming mixed micelles.

TRANSPORT MECHANISM
⦿Lipids are transported by lipoproteins in
following way:
◼Chylomicrons are involved movement of high
proportion triacylglycerols from intestine to other
tissues.
◼Triacylglycerol is acted upon by lipoproteins
lipase, releasing free fatty acids to adipose and
muscle tissues and chylomicron remnants to liver.
◼In liver these remnants release their cholesterol
and degraded in lysosomes.
◼The cholesterol and triacylglycerol are packaged
with specific apoproteins to VLDL.

FATE OF GLYCEROL
⦿Glycerol is phosphorylated by glycerol kinase
and resulting glycerol 3- phosphate is
oxidized to dihydroxyacetone phosphate.
⦿The glycolytic enzyme triose phosphate
isomerase converts this compound to
glyceraldehyde -3-phosphate which is further
oxidized via glycolysis.

FATE OF FATTY ACIDS
⦿Fatty acids are oxidized to acetyl CoA to meet
the energy requirements of the body.
⦿The acetyl CoA enters citric acid cycle to
produce CO2.
⦿In liver acetyl CoA may be converted to
ketone bodies, which is transported to brain
and other tissues when glucose is not
available.

BETA OXIDATION OF FATTY ACIDS
⦿As long chained fatty acids cannot enter the
mitochondria, so they are first activated and
then undergo the oxidation.
⦿In beta oxidation, there is successful removal
of two carbon units.
⦿Long chain fatty acids are oxidized to yield
acetyl residues in the form of acetyl CoA.

ACTIVATION OF FATTY ACIDS
⦿It occurs in outer membrane of mitochondria.
⦿Activation requires coenzyme A, Mg2+, ATP
and presence of Acyl CoA.

STEPS OF OXIDATION
⦿Dehydrogenation: fatty acyl CoA is
dehydrogenated to yield beta-unsaturated
fatty acylCoA. FAD acts as electron acceptor.
⦿Hydration: water is added to the double bond
of alpha, beta unsaturated fatty acyl CoA to
form beta hydroxyacyl CoA in presence of
enoyl CoA hydratase.
⦿Dehydrogenation: beta hydroxyacyl CoA is
dehydrogenated to form beta ketoacyl CoA.
NAD+ is electron acceptor.

⦿Thiolysis: it promotes reaction of beta-
ketoacyl CoA with a molecule of free
coenzyme A split off the carboxyl terminal as
acetyl CoA.

BIOSYNTHESIS OF FATTY ACIDS
⦿A saturated chain, 16 carbon containing fatty
acid i.e. palmitic acid is synthesized, which is
subsequently changed to other fatty acids.
⦿The process of fatty acid synthesis is called
de novo synthesis.
⦿Fatty acid synthesis occurs primarily in
cytosol, in liver, lactating mammary glands
and to lesser extent in the adipose tissues.

DE NOVO SYNTHESIS
⦿Acetyl CoA, which is produced in
mitochondria, first comes out of mitochondria
to the cytosol, where fatty acid synthesis
occurs.
⦿First step of fatty acid synthesis is the
transfer of acetate units from mitochondria
to the cytosol.
⦿For this purpose acetyl CoA condenses with
oxaloacetate and forms citrate.

⦿Citrate is then translocated from
mitochondria to the cytosol, where it is
cleaved by the enzyme ATP citrate lyase and
releases acetyl CoA and oxaloacetate in the
cytosol.
⦿In cytosol, acetyl CoA is carboxylated to
malonyl CoA by a biotin containing enzyme,
referred to as acetyl CoA carboxylase. It
requires 1ATP and CO2.

STEPS OF FATTY ACID SYNTHESIS
⦿It starts with the transfer of acetyl group to
cysteinyl-SH group of beta-ketoacyl-ACP
synthetase to form Acetyl-S-ACP. The reaction
is catalysed by Acetyl CoA- ACP
transacetylase.
⦿At the same time, malonyl group of malonyl-
CoA is transferred to the –SH group of ACP in
the presence of malonyl-CoA-ACP transferase.

⦿Malonyl group looses CO2 and transfers the
acetyl group, by beta ketoacyl ACP syntehtase
domain of fatty acid synthetase, which causes
condensation of two acetyl groups on the
CYS-SH and forms a 4-carbon acetoacetyl unit
that is attached to ACP.
⦿Acetoacetyl undergoes reduction of carbonyl
group to form beta-hydroxybutyryl-S-ACP,
catalysed by fatty acid synthase.
⦿Beta- hydroxybutyryl-ACP is then dehydrated
to yield alpha, beta unsaturated acyl-S-ACP.
In presence of fatty acid synthetase.

⦿Alpha, beta unsaturated acyl-S-ACP is
reduced in the presence of fatty acid
synthetase to form butyryl-S-ACP.
⦿As a result of the reactions, 4 carbon
compound is formed whose three terminal
carbons are fully saturated and remain
attached to ACP.
⦿These steps are gain repeated, with the
transfer of butyryl chain to the CYS-SH. This
is repeated five more times, each time
incorporating two carbon units that are
derived from malonyl CoA.

⦿When the chain length reaches 16 carbons,
the process is terminated with the formation
of palmitoyl-S-ACP.
⦿Thereafter palmitoyl thioesterase cleaves
the thioster bond and releases palmitate.

REGULATION OF FATTY ACID
SYNTHESIS
⦿Rate limiting step is conversion of acetyl CoA
to malonyl CoA. This reaction is catalysed by
the enzyme acetyl CoA carboxylase, which is
stimulated by citrate.
⦿Insulin also stimulates the activity of this
enzyme.
⦿A high carbohydrate diet increases production
of acetyl CoA, which in turn increases the
citrate pool.

⦿Glucagon inhibits the fatty acid synthesis. It
promotes release of fatty acids from the
adipose tissues.
⦿High fat diet, fasting and glucagon decrease
fatty acid synthase enzyme activity.

ROLE OF LIVER IN LIPID
METABOLISM
⦿Liver is primary tissue for de novo synthesis of
fatty acids.
⦿It is also plays important role in synthesis of
triglycerides.
⦿Hepatocytes secrete bile, which helps in
emulsification of fats.
⦿It also acts as a site for synthesis of fatty
acids from acetyl CoA.
⦿Helps in synthesis of lipoproteins particularly
VLDL.
⦿Helps in beta-oxidation of fatty acids.

FATTY LIVER
⦿Vacuoles of triglycerides accumulate in liver cells via
process of steatosis
⦿Eating fatty food does not produce fatty liver. But
ingestion of too much of alcohol, overweight people
have high risk of developing it.
⦿Usually a result of defective lipoprotein synthesis which
is caused due to pathological or physiological
conditions.
⦿The patient may have enlarged liver or minor elevation
of liver enzymes tests.
⦿Simple fatty liver may not require treatment. As
treatment is related to cause. The underlying cause has
to be treated, as disease is self limiting

⦿Physiological fatty liver can result from an
excess supply of fatty acids to the liver which
occurs in starvation, DM or excess hormone
release.
⦿The fatty acids are either metabolised or
used for the synthesis of triglycerides which
are exported as lipoproteins.
⦿Due to lack of other components of
lipoproteins, they tend to accumulate and
lead to the production of Fatty Liver.
⦿Pathological conditions include ethanol,
carbon tetrachloride, chloroform and several
other compounds.

⦿Eliminating alcohol intake can improve fatty
liver.
⦿Controlling blood sugar may reduce the
severity of fatty liver in patients with
diabetes.

SYNTHESIS OF TRIACYLGLYCEROLS
⦿Process is called as lipogenesis.
⦿Occurs mainly in liver and adipose tissues.
⦿Requires activation of free fatty acids and
alpha-glycerolphosphate and the re-
esterification of glycerolphosphate.

STEPS
⦿Activation of fatty acid: free fatty acid in
the presence of ATP and CoA, is activated to
fatty acyl CoA by the enzyme fatty acyl CoA
synthetase.
⦿Synthesis of glycerol phosphate: there are
two pathways for the production of glycerol
phosphate. In the liver and adipose tissue, L-
alpha- glycerol-3-phosphate is formed by
reduction of dihydroxyacetonephosphate, an
intermediate in glycolytic pathway. The
reaction is catalyzed by glycerol-3-phosphate
dehydrogenase.

⦿In tissues such as liver, lactating mammary
glands kineys etc, glycerol is converted
directly to L-alpha- glycerol-3-phosphate by
enzyme glycerol kinase.
⦿Synthesis of triacylglycerol: after
activateion, triacylglycerol is synthesized by
the re-esterification of L-alpha
glycerolphosphate.

⦿Firstly a molecule of acyl CoA is combines
with alpha glycerolphosphate and forms 1-
acylglycerol-3-phosphate. The reactions is
catalyzed by glycerol-3-phosphate
acyltransferase.
⦿1-acylglycerol-3-phosphate is converted to
1,2-diacylglycerolphosphate by enzyme 1-
acylglycerol-3-phosphate acyltransferase.
⦿Phosphatidic acid is then hydrolysed to 1,2-
diacylglycerol by the enzyme phosphatidic
acid phosphohydrolase also called as
phosphatidic acid phosphatase.

⦿Finally, diacylglycerol is esterified to form
triacylglycerol. The reaction is catalysed by
the enzyme diacylglycerol acyltransferase.
⦿Generally, palmitic acid is present at position
1, while oleic acid may be found at positions
2 and 3 of the triacylglycerol in a adipose
tissue, in human beings.

FORMATION OF KETONE BODIES
⦿Known as Ketogenesis.
⦿ Normal concentration of ketones-
<3mg/100ml Blood (Adult)
⦿In conditions like prolonged starvation,
diabetes mellitus; ketone bodies
concentration increases.
⦿As increased acetyl CoA production, which
cannot be fully utilized by Kreb’s cycle, gets
converted to ketone bodies.

⦿Clinical condition resulting from increased
synthesis of ketone bodies – ketosis.
⦿Formation of ketone bodies occurs in
mitochondria, in the liver.
⦿STEPS.
◼2 molecules of acetyl CoA condenses and forms
acetoacetyl CoA.
◼Acetoacetyl reacts with another acetoacetyl CoA
to form HMG CoA.
◼HMG CoA lyase splits HMG CoA to acetyl CoA and
acetoacetate.
◼Acetoacetate is the parent ketone body, which is
synthesised first.

⦿Part of acetoacetate is reduced to
hydroxybutyrate by NADH dependent
hydroxybutyrate dehydrogenase.
⦿Both acetoacetate and beta-hydroxybutyrate
are strong acids.
⦿They slowly deplete the alkali reserves of the
body and cause metabolic acidosis.
⦿Condition is called ketoacidosis.
⦿Occurs in severe diabetes, starvation and
person on high fat diet.

KETOACIDOSIS
⦿Under normal condition, acetone formation is
negligible, but when acetoacetate accumulates
such as in severe Diabetic ketoacidosis, amount
of acetone increases in the blood to the extent
that it can be detected in breath of a patient.
⦿Diabetic Ketoacidosis is a common feature in
patients with insulin-dependent DM.
⦿This is due to severe deficiency of insulin with
excessive glucagon and other hyperglycaemic
hormones such as epinephrine, cortisol etc.
⦿There is marked hyperglycaemia, ketonemia,
ketonuria and water and electrolyte
imbalance.

KETOACIDOSIS
⦿Plasma free fatty acid concentration is
increased.
⦿This in turn leads to increased production of
ketone bodies by the liver.
⦿Various features of the disease can be
corrected by insulin administration.

KETOLYSIS
⦿Acetoacetate and beta-hydroxybutyrate
that are produced by liver are excellent
source of energy in kidney and muscles.
⦿During starvation brain also utilizes the
ketone bodies which are transported
from liver to the extra hepatic tissues.
⦿Process of oxidation of keno bodies is
called as Ketolysis.

KETOLYSIS
⦿Mitochondrial enzyme – hydroxybutyrate
dehydrogenase oxidizes hydroxybutyrate to
acetoacetate.
⦿Acetoacetate is oxidised after its activation to
acetoaectyl CoA,reacts with succinyl CoA in the
presence of enzyme transacylase and is converted to
acetoacetyl CoA.
⦿Acetoacetyl is hydrolysed to two molecules of acetyl
CoA, by the enzyme thiolase.
⦿Acetone is slowly oxidised through lungs. Can be
converted t acetoacetate by the reversal of
decarboxylation

BIOSYNTHESIS OF CHOLESTEROL
⦿Cholesterol is derived from diet as well as in
various tissues of the body.
⦿50% of the normal intake is absorbed by the
small intestine while rest is excreted in the
faeces.
⦿More than 80% is esterified in the internal
mucosa and is transported with the
lipoproteins.
⦿Ingested cholesterol is absorbed with other
lipids and is incorporated into chylomicrons
and VLDL.

BIOSYNTHESIS OF CHOLESTEROL
⦿Large quantity of cholesterol is sythesized in
extra-mitochondrial compartment of the cell.
⦿Important sites for the cholesterol synthesis
are liver, skin, intestine, adrenal cortex and
reproductive tissues including ovaries, testes
and placenta.
⦿All the carbon atoms of cholesterol are
derived from acetate (acetyl CoA) which is
obtained from several sources.

⦿ De novo synthesis of cholesterol takes place in
the body as:
⦿ Two molecules acetyl CoA condense to form
acetoacetyl CoA. This reaction is catalyzed by
enzyme acetoacetyl CoA thiolase.
⦿ In the presence of the enzyme beta-hydroxy-
beta-methylglutaryl CoA synthase (HMG CoA
synthase), acetyl CoA further condenses with
another molecule of acetyl CoA and forms beta-
hydroxy-beta methylglutaryl CoA. (HMG CoA).
⦿ NADPH independent enzyme HMG CoA reductase,
converts HMG CoA to mevalonic acid. This us the
regulatory step.

⦿There is stepwise transfer of two gamma-
phosphate groups form two molecules of ATP.
The reactions are catalyzed by two kinases
called mevalonate kinase (I) and
phosphomevalonate kinase(II).
⦿Decarboxylation takes place by the enzyme
decarboxylase. Thus, phosphorylation and
decarboxylation of mevalonic acid forms
isopentenyl pyrophosphate which is also
called active isoprenoid unit.
⦿Isoprenoid unit is isomerized to another
isoprenoid unit designated as 3,3-
dimethylallylpyrophosphate, by the enzyme
isopentenylpyrophosphate ismerase.

⦿Stepwise condensation of the three
isoprenoid units leads to the formation of a
15- carbon unit called farnesylpyrophosphate
(15C).
⦿Fusion of two molecules of
farnesylpyrophosphate forms 30 carbon
compound called squalence (30C)
⦿By ring closure and removal of the three
methyl groups squalene is converted to
cholesterol which has 27 carbons.

REGULATION OF CHOLESTEROL
SYNTHESIS
⦿De novo synthesis of cholesterol is inversely
related to the amount of dietary cholesterol.
⦿When dietary cholesterol intake is reduced,
synthesis is increased.
⦿Cholesterol inhibits its own synthesis by
feedback inhibition.
⦿Liver removes cholesterol by different
processes.

⦿Esterification of cholesterol: both HDL and
lecithin –cholesterol acyltransferase are
important for the removal of cholesterol from
the body.
⦿Plasma enzyme LCAT form the cholesterol
ester which diffuses into the core of HDL
particle, where they are transported from
tissues and plasma to liver where it gets
metabolised and excreted.
⦿Free cholesterol as well as bile acids are
excreted in the bile.

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