Lipid Metabolism

• Fatty acids are a class of compounds containing a long

hydrocarbon chain and a terminal carboxylate group.
• Fatty acids have four major physiological roles-
1. Building blocks of components of biological membrane
2. Their derivatives serve as a hormones and intracellular
messenger.
3. Help in protein transport
4. As a fuel molecules.
• Unsaturated fatty acids have a lower melting point than the
saturated fatty acids.
• Chain length also affect the melting point.
• Thus short chain length and unsaturation enhances the
fluidity of fatty acids and their derivatives.
 Digestion , Mobilization and Transport of
fats
• Cells can obtain fatty acid fuels from three sources: fats
consumed in the diet, fats stored in cells as lipid droplets, and
fats synthesized in one organ for export to another.
• Some species use all three sources under various
circumstances, others use one or two.
• Vertebrates, for example, obtain fats in the diet, mobilize fats
stored in specialized tissue (adipose tissue, consisting of cells
called adipocytes ), and, in the liver, convert excess dietary
carbohydrates to fats for export to other tissues.
• Fats are stored as Triacylglycerols.
• They are uncharged esters of glycerol.
• Also called as neutral fats or triglycerides.
• Triacylglycerols provide more than half the energy
requirements of some organs, particularly the liver,
heart, and resting skeletal muscle.
• Stored triacylglycerols are virtually the sole source of
energy in hibernating animals and migrating bird.
• Protists obtain fats by consuming organisms lower in
the food chain, and some also store fats as cytosolic
lipid droplets.
• Vascular plants mobilize fats stored in seeds during
germination, but do not otherwise depend on fat for
energy.
Dietary Fats are Absorbed in the SmaIl lntestine

• In vertebrates, before ingested triacylglycerols can be

absorbed through the intestinal wall they must be
converted from insoluble macroscopic fat particles to
finely dispersed microscopic micelles.
• This solubilization is carried out by bile salts, such as
taurocholic acid, which are synthesized from
cholesterol in the liver, stored in the gallbladder, and
released into the small intestine after ingestion of a
fatty meal.
• Bile salts are amphipathic compounds that act as
biological detergents, converting dietary fats into
mixed micelles of bile salts and triacylglycerol
• Triacylglycerols packaged with dietary
cholesterol and specific proteins into
lipoprotein aggregates called chylomicrons .
• Apolipoproteins are lipid-binding proteins in
the blood, responsible for the transport of
triacylglycerols, phospholipids,cholesterol,and
cholesteryl esters between organs.
• Apolipoproteins ("apo" means "detached“ or
"separate,"designating the protein in its lipid-
free
form) combine with lipids to form several
classes of lipoprotein particles, spherical
aggregates with hydrophobic lipids at the core
and hydrophilic protein side chains and lipid
head groups at the surface.
 Triacylglycerol that enter the liver may be oxidized
to provide energy or to provide precursors for the
synthesis of ketone bodies.
• When the diet contains more fatty acids than are
needed immediately for fuel or as precursors, the
liver converts them to triacylglycerols, which are
packaged with specific apolipoproteins into
VLDLs.
• The VLDLs are transported in the blood to
adipose tissues, where the triacylglycerols are
removed and stored in lipid droplets within
adipocytes.
Hormones triggers Mobilization of stored
Triacylglycerols
 Lipase
Triacylglycerol + 3H2O Fatty acid + Glycerol + 3H+

• About 95% of the biologically available energy of

triacylglycerols resides in their three long-chain fatty
acids; only 5% is contributed by the glycerol moiety.
• The glycerol released by lipase action is
phosphorylated by glycerol kinase, and the resulting
glycerol 3-phosphate is oxidized to dihydroxyacetone
phosphate.
• The glycolytic enzyme triose phosphate isomerase
converts this compound to glyceraldehyde 3-
phosphate, which is oxidized via glycolysis.
 Fatty Acids are Activated and Transported into
Mitochondria

• The enzymes of fatty acid oxidation in animal cells are

located in the mitochondrial matrix.
• Fatty acids with long chain cannot pass directly through
the mitochondrial membranes-they must first undergo
the three enzymatic reactions of the carnitine shuttle.
• The first reaction is catalyzed by a family of Isozymes
present in the outer mitochondrial membrane, the acyl-
CoA synthetases, which promote the general reaction

Fatty acid + CoA + ATP fatty acyl-CoA + AMP + PPi

• Fatty acyl-CoA esters formed at the cytosolic side of the
outer mitochondrial membrane can be transported into
the mitochondrion and oxidized to produce ATP, or they
can be used in the cytosol to synthesize membrane lipids.
• Fatty acids destined for mitochondrial oxidation are
transiently attached to the hydroxyl group of carnitine to
form fatty acyl-carnitine-the second reaction of the
shuttle.
• This transesterification is catalyzed by carnitine
acyltransferase.
• The fatty acyl-carnitine ester then enters the matrix by
facilitated diffusion through the acylcarnitine/
• carnitine transporter of the inner mitochondrial
membrane.
Oxidation of Fatty Acids
 Total reaction

• Palmitoyl-CoA + 7 CoA + 7 FAD + 7 NAD+ + 7H2O

8 actyl-CoA + 7 FADH2 + 7 NADH + 7 H+

Acetyl-CoA can be further 0xidized into the Citric Acid Cycle

8 Acetyl-CoA + 1602 + 80Pi + 80ADP

8CoA + 80ATP + 16CO2 + 16H2O

 Two high energy phosphate bonds are
consumed in the activation of palmitate. Thus
the complete oxidation of palmitate yields 106
ATP.
 0xidation of Unsaturated fatty Acid Requires
Two Additional Reactions
• Most of the fatty acids in the triacylglycerols and
phospholipids of animals and plants are
unsaturated, having one or more double bonds.
• These bonds are in the cis configuration and
cannot be acted upon by enoyl-CoA hydratase,
the enzyme catalyzing the addition of H2O to the
trans double bond of the delta 2-enoyl-CoA
generated during B oxidation.
• Two auxiliary enzymes are needed for Beta
oxidation of the common unsaturated fatty acids:
an isomerase and a reductase
• oxidation of oleate, an abundant 18-carbon
monounsaturated fatty acid with a cis double bond
between C-9 and C-10 (denoted Δ9).
Enoyl-CoA isomerase interconverts the 3 cis bond into 2 trans , which is then consumed in
the next ß-oxidation cycle, skipping the acyl-CoA dehydrogenase step. This brings the
12 cis bond into position 4 cis , and the next acyl CoA dehydrogenase step produces the

dienoyl CoA 2 trans, 4 cis . The enzyme 2,4 dienoyl CoA reductase converts this to the 3 cis ,
which enoyl-CoA isomerase can again convert to 2 trans.
 Oxidation of Odd numbers of Fatty acids

• Many plants and some marine organisms contains

odd numbers of fatty acids.
• They are oxidized in the same way as fatty acids
having even numbers ,except that Propionyl CoA ,
rather than two molecules of Acetyl CoA are
produced in the final round of degradation.
• The activated three carbon unit in propionyl CoA
enters the citric acid cycle after it is converted into
succinyl CoA.
 Fatty Acid 0xidation is Tightly Regulated

• Oxidation of fatty acids consumes a precious

fuel, and it is regulated so as to occur only
when the need for energy requires it.
• In the liver, fatty acyl-CoA formed in the
cytosol has two major pathways open to it:
(1) Beta oxidation by enzymes in mitochondria
or (2) conversion into triacylglycerols and
phospholipids by enzymes in the cytosol
 Ketone Bodies
• The Acetyl CoA formed in fatty acid oxidation enters the
citric acid cycle only if fat and carbohydrates are
appropriately balanced.
• As the entry of acetyl CoA into citric acid cycle depends
on the availability of Oxaloacetate.
• i.e. Fats Burn In The Flame of Carbohydrates.

• In fasting or Diabetic, Oxaloacetate is consumed to form

glucose by gluconeogenesis pathway, and hence is
unavailable for condensation with acetyl CoA.
• So acetyl CoA is diverted to the formation of Ketone
bodies.
• Ketone Bodies formed in the Liver are exported to
other organs as Fuel.
• Ketone Bodies are overproduced in diabetes and
during starvation.
• The increased blood levels of acetoacetate and -B-
hydroxybutyrate lower the blood pH, causing the
condition known as acidosis. Extreme acidosis can lead
to coma and in some cases death.
• Ketone bodies in the blood and urine of individuals
with untreated diabetes can reach extraordinary levels-
a blood concentration. This condition is called ketosis.
• Individuals on very low-calorie diets, using the fats
stored in adipose tissue as their major energy source,
also have increased levels of ketone bodies in their
blood and urine.
 Lipid Anabolism
• The formation of Malonyl CoA is the committed step
in fatty acid synthesis.
• The formation of malonyl-CoA from acetyl-CoA is an
irreversible process, catalyzed by acetyl-CoA
carboxylase.
The intermediates of
Fatty acid synthesis
are linked to an acyl
carrier protein(ACP)
• Fatty acid synthase reactions are repeated to
form Palmitate.
• Seven cycles of condensation and reduction
produce the 16-carbon saturated palmitoyl
group, still bound to ACP.
• Chain elongation by the synthase complex
generally stops at this point and free palmitate
is released from the ACP by a hydrolytic
activity (thioesterase; TE) in the
multifunctional protein.
 Stoichiometry of Fatty acid Synthesis
• The overall reaction for the synthesis of palmitate
from acetyl-CoA in two parts.
• First, the formation of seven malonyl-CoA molecules
7 Acetyl-CoA+ 7CO2+ 7ATP --- > 7 malonyl-CoA+ 7ADP+
7Pi.
then seven cycles of condensation and reduction :
Acetyl-CoA+ 7 malonyl-CoA+ 14NADPH+ 14H+ --- >
palmitate + 7CO2+ 8 CoA+ 14NADP+ + 6H2O
• The net reaction is
8 Acetyl-CoA+ 7 ATP + 14NADPH+ 14H+ --- >
palmitate+ 8 CoA+ 7ADP+ 7Pi+ 14NADP+ 6H2O
• The ATP is required to attach CO2 to acetyl-
CoA to make malonyl-CoA; the NADPH is
required to reduce the double bonds.
• In nonphotosynthetic eukaryotes there is an
additional cost to fatty acids synthesis,
because acetyl-CoA is generated in the
mitochondria and must be transported to the
cytosol.
 Fatty acids are synthesized and degraded by different ways

• Synthesis takes place in the cytosole, where

degradation occurs in mitochondrial matrix.
• Intermediates of synthesis are covalently linked to an
acyl carrier protein(ACP), whereas degradation
intermediates are bonded to coenzyme A.
• The reductant in synthesis is NADPH whereas the
oxidant in degradation are NAD+ and FAD.