Lipid

Chemistry and Metabolism

 Cont.
• Lipids constitute a heterogeneous group of
compounds of biochemical importance. Lipids
may be defined as compounds which are
relatively insoluble in water, but freely soluble
in nonpolar organic solvents like benzene,
chloroform, ether, hot alcohol, acetone, etc.
 Functions
• Storage form of energy (triglycerides)
• Structural components of biomembranes
(phospholipids and cholesterol)
• Metabolic regulators (steroid hormones and
prostaglandins)
• Act as surfactants, detergents and
emulsifying agents (amphipathic lipids)
• Act as electric insulators in neurons
 Cont.
• Provide insulation against changes in
external temperature (subcutaneous fat)
• Give shape and contour to the body Protect
internal organs by providing a cushioning
effect (pads of fat)
• Help in absorption of fat soluble vitamins
(A, D, E and K)
• Improve taste and palatability of food.
 CLASSIFICATION
• Based on the chemical nature, lipids are classified as
Simple lipids. They are esters of fatty acids with
• glycerol or other higher alcohols.
• Compound lipids. They are fatty acids esterified
• with alcohol; but in addition they contain other groups.
• a. Phospholipids, containing phosphoric acid.
• b. Non-phosphorylated lipids.
• Derived lipids. They are compounds which are derived
from lipids or precursors of lipids, e.g. fatty acids,
steroids.
 Fatty acids
• The most frequently used systematic
nomenclature names the fatty acid after the
hydrocarbon with the same number and
arrangement of carbon atoms, with -oic being
substituted for the final -e (Genevan system).
• Thus, saturated acids end in -anoic, eg,
octanoic acid, and unsaturated acids with
double bonds end in -enoic, eg, octadecenoic
acid (oleic acid).
 Cont.
• Carbon atoms are numbered from the carboxyl
carbon. The carbon atoms adjacent to the
carboxyl carbon (Nos. 2, 3, and 4) are also
known as the α, β, and γ carbons, respectively,
and the terminal methyl carbon is known as
the ω or n-carbon.
 Unsaturated fatty acids
• Fatty acids may be further subdivided as follows:
• (1) Monounsaturated (monoethenoid, monoenoic)
acids, containing one double bond.
• (2) Polyunsaturated (polyethenoid, polyenoic) acids,
containing two or more double bonds.
• (3) Eicosanoids: These compounds, derived from
eicosa- (20-carbon) polyenoic fatty acids, comprise the
prostanoids, leukotrienes (LTs), and lipoxins (LXs).
Prostanoids include prostaglandins (PGs),
prostacyclins (PGIs), and thromboxanes (TXs).
• PUFAs are seen in vegetable oils.
• They are nutritionally essential; and are called
Essential Fatty Acids.
• Prostaglandins, thromboxanes and leukotrienes
are produced from arachidonic acid.
• PUFAs form integral part of mitochondrial
membranes. In deficiency of PUFA, the
efficiency of biological oxidation is reduced.
 Cont.
• The carbon chains of saturated fatty acids form
a zigzag pattern when extended, as at low
temperatures. At higher temperatures, some
bonds rotate, causing chain shortening, which
explains why biomembranes become thinner
with increases in temperature.
 Cont.
• A type of geometric isomerism occurs in
unsaturated fatty acids, depending on the
orientation of atoms or groups around the axes
of double bonds, which do not allow rotation.
• If the acyl chains are on the same side of the
bond, it is cis-, as in oleic acid; if on opposite
sides, it is trans-, as in elaidic acid, the trans
isomer of oleic acid
• Trans fatty acids are present in certain foods,
arising as a by-product of the saturation of
fatty acids during hydrogenation, or
“hardening,” of natural oils in the manufacture
of margarine.
• Fatty acids with trans double bonds (Trans
fatty acids) are injurious to health. They
decrease fluidity of membranes; decrease
HDL-cholesterol, increase LDL-cholesterol
and may cause atherosclerosis.
 Digestion of lipids
• Triacylglycerols are the major fat in the human
diet because they are the major storage lipid in
the plants and animals that constitute our food
supply. Triacylglycerols contain a glycerol
backbone to which three fatty acids are
esterified.
 DIGESTION OF LIPIDS
• The major dietary lipids are triacylglycerol,
cholesterol and phospholipids.
• Digestion in Stomach
• The lingual lipase from the mouth enters
stomach along with the food. It has an
optimum pH of 2.5-5). The enzyme, therefore,
continues to be active in the stomach. It acts
on short chain triglycerides (SCT).
 Cont.
• Gastric lipase
• is acid stable, with an optimum pH around 5.4.
It is secreted by chief cells, the secretion is
stimulated by gastrin. Up to 30% digestion of
triglycerides occurs in stomach.
 Digestion in Intestines

• Emulsification is a prerequisite for digestion

of lipids. The lipids are dispersed into smaller
droplets; surface tension is reduced; and
surface area of droplets is increased. This
process is favored by:
• 1. Bile salts (detergent action)
• 2. Peristalsis (mechanical mixing)
• 3. Phospholipids
 Cont.
• Bile Salts are Important for Digestion of
Lipids
• The bile salts present in the bile (sodium
glycocholate and sodium taurocholate) lower
surface tension. They emulsify the fat
droplets. The emulsification increases the
surface area of the particles for enhanced
activity of enzymes
• The contraction of the gallbladder and
secretion of pancreatic enzymes are stimulated
by the gut hormone cholecystokinin, which is
secreted by the intestinal cells when stomach
contents enter the intestine. Bile salts act as
detergents, binding to the globules of dietary
fat as they are broken up by the peristaltic
action of the intestinal muscle.
 Lipolytic Enzymes in Intestines

• 1. Pancreatic lipase with Co-lipase

• 2. Cholesterol esterase
• 3. Phospholipase A2.
• The bile (pH 7.7) entering the duodenum
serves to neutralize the acid chyme from the
stomach and provides a pH favorable for the
action of pancreatic enzymes.
• Pancreatic lipase is secreted along with another
protein, colipase, along with bicarbonate,
which neutralizes the acid that enters the
intestine with partially digested food from the
stomach. Bicarbonate raises the pH of the
contents of the intestinal lumen into a range
(pH ~ 6) that is optimal for the action of all of
the digestive enzymes of the intestine.
• Secretin
 Co-lipase

• The binding of co-lipase to the triacylglycerol

molecules at the oil water interface is
obligatory for the action of lipase. The co-
lipase is secreted by the pancreas as an
inactive zymogen (molecular weight 11,000).
It is activated by trypsin.
• The colipase binds to the dietary fat and to the
lipase, thereby increasing lipase activity.
 Digestion of Triglycerides
• Pancreatic lipase can easily hydrolyze the
fatty acids esterified to the 1st and 3rd carbon
atoms of glycerol forming 2-monoacylglycerol
and two molecules of fatty acid
• Then an isomerase shifts the ester bond from
position 2 to 1. The bond in the 1st position is
then hydrolysed by the lipase to form free
glycerol and fatty acid.
• The major end products of the digestion of
TAG are 2-MAG (78%), 1-MAG (6%),
glycerol and fatty acids (14%). Thus digestion
of TAG is partial (incomplete).
 Cont.
• Cholesterol ester may be hydrolysed to free
cholesterol and fatty acid. The action of
phospholipase A2 produces lysophospholipid
and a fatty acid
 ABSORPTION OF LIPIDS

• Absorption of Long Chain Fatty Acids

• Long chain fatty acids (chain length more than
14 carbons) are absorbed to the lymph and not
directly to the blood.
 Mixed Micelle Formation

• The products of digestion, namely 2-

monoglycerides, long chain fatty acids,
cholesterol, phospholipids and
lysophospholipids are incorporated into
molecular aggregates to form mixed micelle.
The micelles are spherical particles with a
hydrophilic exterior and hydrophobic interior
core
• The micelles travel through a layer of water
(the unstirred water layer) to the microvilli on
the surface of the intestinal epithelial cells,
where the fatty acids, 2-monoacylglycerols,
and other dietary lipids are absorbed, but the
bile salts are left behind in the lumen of the
gut.
 Enterohepatic Circulation of Bile Salts

• The bile salts are left behind which are mostly

reabsorbed from the ileum and returned to the
liver to be re-excreted (enterohepatic
circulation). About 98% of dietary lipids are
normally absorbed.
 Re-esterification Inside the Mucosal Cell

• Once inside the intestinal mucosal cell, the

long chain fatty acids are re-esterified to form
triglycerides
• The fatty acids are first activated to fatty acyl
CoA by the enzyme, acyl CoA synthetase or
thiokinase. This needs lysis of two high energy
bonds.
• Two such activated fatty acids react with
monoacyl glycerol (MAG) to form the
triglyceride. Majority of molecules follow this
MAG pathway
 Chylomicrons

• The TAG, cholesterol ester and phospholipid

molecules along with apoproteins B48, and
apo-A are incorporated into chylomicrons. The
chyle (milky fluid) from the intestinal mucosal
cells loaded with chylomicrons are transported
through the lacteals into the thoracic duct and
then emptied into lymph circulation
 Abnormalities in Absorption of Lipids

• Defective digestion: In steatorrhea, daily excretion

of fat in feces is more than 6 g per day. (Greek
word, "stear", means fat). It is due to chronic
diseases of pancreas. In such cases, unsplit fat is
seen in feces.
• Defective absorption: On the other hand, if the
absorption alone is defective, most of the fat in feces
may be split fat, i.e. fatty acids and monoglycerides.
Defective absorption may be due to diseases.
• Celiac disease, sprue, Crohn's disease.
• Surgical removal of intestine.
• Obstruction of bile duct: This may be due to
gall stones, tumors of head of pancreas,
enlarged lymph glands
 Oxidation
• Adipose tissue triacylglycerols are derived
from two sources; dietary lipids and
triacylglycerols synthesized in the liver. The
major fatty acids oxidized are the long-chain
fatty acids, palmitate, oleate, and stearate,
because they are highest in dietary lipids and
are also synthesized in the human.
• Between meals, a decreased insulin level and
increased levels of insulin counter-regulatory
hormones (e.g., glucagon) activate lipolysis,
and free fatty acids are transported to tissues
bound to serum albumin.
 Oxidation
• BETA OXIDATION OF FATTY ACIDS
• This process is known as beta oxidation,
because the oxidation and splitting of two
carbon units occur at the beta-carbon atom.
The oxidation of the hydrocarbon chain occurs
by a sequential cleavage of two carbon atoms
• Fatty acids are activated to their co-enzyme A
(CoA) derivative. This activation is taking
place in cytoplasm. ATP is hydrolysed to AMP
and Ppi and the energy from hydrolysis of PPi
drives the reaction forward. Thus two high
energy bonds are utilized in this reaction.
• Fatty acids are activated in the cytoplasm; but
the beta oxidation is in mitochondria. So
transport of fatty acids through the
mitochondrial membrane is essential. The long
chain fatty acyl CoA cannot pass through the
inner mitochondrial membrane.
• Therefore a transporter, carnitine is involved in
transfer of fatty acids.
• The enzyme carnitine acyl transferase-I (CAT-
I) will transfer the fatty acyl group to the
hydroxyl group of carnitine to form acyl
carnitine. The reaction occurs on the cytosolic
side of inner mitochondrial membrane.
• A protein translocase will carry the acyl
carnitine across the membrane to the matrix of
mitochondria. On the matrix side of the
membrane another enzyme, carnitine acyl
transferase-II (CAT-II) will transfer the acyl
group back to co-enzyme A molecule.
Carnitine is returned to the cytosolic side by
the translocase.
• Medium chain and short chain fatty acids do
not require carnitine for transport across the
inner mitochondrial membrane. So medium
chain and short chain fatty acids are easily
oxidised.
• Carnitine deficiency is reported in preterm
infants, in whom impaired fatty acid oxidation
is noticed. So more glucose is utilised,
resulting in episodes of hypoglycemia.
• Inherited CPT-I deficiency affects only the
liver, resulting in reduced fatty acid oxidation
and ketogenesis, with hypoglycemia. CPT-II
deficiency affects primarily skeletal muscle
and, when severe, the liver.
• The sulfonylurea drugs (glibenclamide and
tolbutamide), used in the treatment of type 2
diabetes mellitus, reduce fatty acid oxidation
and, therefore, hyperglycemia by inhibiting
CPT-I.
 Regulation of Beta Oxidation

• The availability of free fatty acid (FFA) regulates

the net utilisation through beta oxidation.
• The level of FFA, in turn, is controlled by
glucagon:insulin ratio. Glucagon increases FFA
level and insulin has the opposite effect.
• CAT-I is the regulator of entry of fatty acid into
mitochondria. Malonyl CoA inhibits CAT-I
activity. Thus during de novo synthesis of fatty
acid, the beta oxidation is inhibited.
 Peroxisomal oxidation
• Liver peroxisomes contain the enzymes for
the oxidation of very-long-chain fatty acids
such as C24:0 and phytanic acid, for the
cleavage of the cholesterol side chain
necessary for the synthesis of bile salts, for a
step in the biosynthesis of ether lipids, and for
several steps in arachidonic acid metabolism.
Peroxisomes also contain catalase and are
capable of detoxifying hydrogen peroxide.
• Very-long-chain fatty acids of C20 to C26 or
greater are activated to CoA derivatives by
very-long-chain acyl CoA synthetase present
in the peroxisomal membrane. The very-long-
chain acyl CoA derivatives are then oxidized
in liver peroxisomes to the 8-carbon octanoyl
CoA level.
• In contrast to mitochondrial beta-oxidation, the
first enzyme in peroxisomal beta-oxidation
introduces a double bond and generates
hydrogen peroxide instead of FAD(2H).
 XENOBIOTICS
• The liver uses the pathways of fatty acid
metabolism to detoxify very hydrophobic and
lipid-soluble xenobiotics that, like fatty acids,
either have carboxylic acid groups or can be
metabolized to compounds that contain
carboxylic acids. Benzoate and salicylate are
examples of xenobiotics that are metabolized
in this way.
• Salicylic acid and benzoate are similar in size
to medium-chain-length fatty acids and are
activated to an acyl CoA derivative by
MMFAE . The acyl group is then conjugated
with glycine, which targets the compound for
urinary excretion. The glycine derivatives of
salicylate and benzoate are called salicylurate
and hippurate, respectively.