Lipid metabolism

• Lipids constitute about 15-20% of the body weight in humans

• Triacylglycerols are the most abundant lipids comprising 85-90% of body lipids
• Most of the triacylglycerols (TG; also called neutral fat) are stored in the adipose tissue and
serve as energy reserve of the body
• Triacylglycerols (TG) are highly concentrated form of energy, yielding 9 Cal/g
• The triacylglycerols are non-polar and hydrophobic in nature, hence stored in pure form
without any association with water (anhydrous form)
1. Lipolysis: hydrolysis of triacylglycerol to glycerol and free fatty acids
2. β-Oxidation: mitochondrial oxidation of fatty acids = ENERGY! ENERGY! ENERGY!
3. Ketogenesis: synthesis of ketone bodies
4. Lipogenesis: fatty acid synthesis
5. Esterification: attachment of fatty acids to glycerol to form triglycerides
6. Cholesterolgenesis: synthesis of cholesterol
7. Steroidogenesis: synthesis of steroid hormones from cholesterol
 Lipolysis
Fate of glycerol :
• It is transported to liver where it is activated
to glycerol3 –phosphate
• It may be used for the synthesis of TGs and
phospholipids
• Glycerol 3-phosphate may also enter
glycolysis by getting converted to
dihydroxyacetonephosphate (DHAP)
Fate of free fatty acids :
• The fatty acids released by lipolysis in the
adipocytes enter the circulation and are
transported
• The free fatty acids enter various tissues
and are utilized for the energy.
• About 95% of the energy obtained from fat
comes from the oxidation of fatty acids
• Certain tissues, however, cannot oxidize
fatty acids, e.g. brain, erythrocyte
Fatty acid oxidation
Fatty acid oxidation is the mitochondrial aerobic process of breaking down a fatty acid into
smaller units
TYPES OF FATTY ACID OXIDATION
1) Beta oxidation- Major mechanism, occurs in the mitochondria matrix, 2-C units are released
as acetyl CoA per cycle
2) Alpha oxidation- Predominantly takes place in liver, one carbon is lost in the form of CO2 per
cycle and sometimes in brain to produce cerebronic acid which synthesizes cerebroside
3) Omega oxidation- Minor mechanism, but becomes important in conditions of impaired beta
oxidation
4) Peroxisomal oxidation- Mainly for the trimming of very long chain fatty acids
Beta-oxidation
• Is a significant source of metabolic energy during interprandial periods and high energy
demand states, such as exercise, fasting, starvation, hibernation
• This metabolic pathway provides a large portion of the energy requirement of skeletal
muscle, heart muscle, and kidneys when glycogen and glucose become scarce
• Thus, fatty acid oxidation provides an alternative mode of high-efficiency energy
production while simultaneously sparing muscles and proteins from catabolic breakdown
• The fatty acyl chain is shortened by two carbon atoms as a result of these reactions FADH2,
NADH, and acetyl Co A are generated
• Because oxidation is on the β carbon and the chain is broken between the α (2nd ) and β
(3rd ) carbon atoms hence the name β oxidation
Stages in β oxidation of Fatty acids
1. Activation of Fatty acids
2. Transport of Fatty acid in to mitochondrial matrix
3. Steps of β oxidation
Transport

Activation Catabolism:
Proper B-
oxidation

β oxidation proper
1. Activation of Fatty acids
Fatty acids must first be converted to an active intermediate before they can be catabolized
This is the only step in the complete degradation of a fatty acid that requires energy from
ATP the activation of a fatty acid is accomplished in two steps
Transport of Fatty acid
The inner mitochondrial membrane is impermeable to fatty acids. A specialized
carnitine carrier system (carnitine shuttle) operates to transport activated fatty acids
from cytosol to the mitochondria
β oxidation at mitochondrial matrix
Occurs in a sequence of four reaction
1. Oxidation : Acyl CoA undergoes dehydrogenation
by an FAD-dependent acyl CoA dehydrogenase
A double bond is formed between α and β carbons
2. Hydration : Enoyl CoA hydratase brings
about the hydration of the double bond to form
β hydroxyacyl CoA
3. Oxidation : β Hydroxyacyl CoA dehydrogenase
catalyses the second oxidation and generates
NADH
4. Cleavage : The final reaction is the liberation of
acetyl CoA from acyl CoA
This occurs by a thiolytic cleavage catalysed by
thiolase
 Fatty acid β oxidation Energetics
ATP yield by β oxidation of C16 Fatty Acid (Palmitate)

Products ATP equivalent Total

FADH2 1.5
NADH 2.5
Acetyl CoA
Gross total
Energy used for activation of FA
Net yield
Odd number Fatty Acid β oxidation

L
Ketogenesis

• With a high rate of fatty acid oxidation

the liver produces considerable quantities
of acetoacetate and β-hydroxybutyrate
• Acetoacetate continually undergoes
spontaneous decarboxylation to yield
acetone
• These three substances are collectively
• known as the ketone bodies (also called
acetone bodies)
• Provide an alternative form of energy for
the body
Ketone bodies utilization

• The ketone bodies, being water-soluble,

are easily transported from the liver to
various tissues
• the ketone bodies are used as fuels in all
tissues except the liver
• The ketone bodies can meet 50-70% of the
brain’s energy needs
• The production of ketone bodies and their
utilization become more significant when
glucose is in short supply to the tissues, as
observed in starvation, and diabetes
mellitus
• Ketone bodies are the major fuel source for the brain and other parts of
the central nervous system during prolonged starvation
• Diabetes mellitus is associated with insulin deficiency impaired
Carbohydrate metabolism thus increased lipid catabolism hence more
ketone bodies
 Ketonemia, Ketonuria, and Ketosis:
• When the rate of synthesis of ketone bodies Summary of ketone body synthesis,
utilization and excretion
exceeds the rate of utilization, their
concentration in blood increases, this is
known as ketonemia
• The term ketonuria represents the
excretion of ketone bodies in urine
• The overall picture of ketonemia and
ketonuria is commonly referred to as
ketosis
• Smell of acetone in breath is a common
feature in ketosis
Ketoacidosis:
• When ketosis combined with acidosis, is called ketoacidosis.
• Both acetoacetate and β-hydroxybutyrate are strong acids. Increase in their concentration
in blood would cause acidosis (pKa around 4)
• If not treated, Diabetic ketoacidosis is dangerous: may result in coma, and even death
Fatty acid biosynthesis
The dietary carbohydrates and amino acids, when consumed in excess, can be converted to
fatty acids and stored as TGs
Synthesis of fatty acids occurs predominantly in liver, kidney, adipose tissue and lactating
mammary glands
The enzyme machinery is located in the cytosol
Acetyl CoA is the source of carbon atoms and heavily depends on availability of NADPH
The fatty acid synthesis is in 3 stages
1. Recycle of acetyl CoA in cytosol
2. Conversion of acetyl CoA to malonyl CoA
3. Reactions of fatty acid synthase complex
Fatty acid synthase multienzyme complex:
The complex is a dimer of two identical polypeptide monomers, each consisting of seven
enzyme activities and the acyl carrier protein (ACP)
Thus, two acyl chains are produced simultaneously
Fatty acid synthesis pathway
 Priming
1. Condensation
2. Reduction
3. Dehydration
4. Reduction