LIPID METABOLISM
Lipid Metabolism
Fats are high metabolic energy molecules…yield 9.3 kcal of energy (carbohydrates
and proteins yield 4.1 kcal)
They are the best heat producers when compared to the other macromolecules i.e.
carbohydrates and proteins
The significant difference is due to the long hydrocarbon chain
When our calorie intake is greater than energy expenditure, the excess calorie is
stored as fats
Due to their hydrophobic and inert properties, fats can be stored for very long
periods
Lipid Metabolism
Fats can also be stored in large amounts
N.B. Carbohydrates can be stored (glycogen) to a limited extent – and is
broken down first to release energy. Proteins cannot be stored
Fats are stored as triaclyglycerols in the fat cells (adipose tissue)
These molecules coalesce to form large globules that are able to occupy most of
the cell volume
The liver and adipose tissue are the sites for metabolic activity of fats
Lipid Metabolism
Triacylglycerols are hydrophobic in nature and unreactive. They can therefore be
stored extracellularly
They will not react with other cellular components because they are insoluble in
water…
Triacylglycerols must be emulsified to fatty acids and glycerol because the
enzymes necessary for digestion are water soluble
The emulsified form can then be digested and absorbed in the intestines
Free fatty acids can move through the cell membrane of the adipocytes into the
plasma
Fatty Acid Synthesis
A large proportion of fatty acids used
by the body is from dietary source
Carbohydrates and proteins obtained
from the diet can also be converted to
fatty acids. The synthesis occurs in the
liver and lactating mammary glands
Acetyl CoA formed in the
mitochondria is transported across
the membrane into the cytosol
…acetyl CoA must first be converted
to citrate and then once in the cytosol,
the citrate is converted to acetyl CoA
Fatty Acid Synthesis
The acetyl CoA then acts as substrate for palmitate
Palmitate acts as precursor for other long chain fatty acids
Separate enzymatic processes in the endoplasmic reticulum and mitochondria
facilitates the elongation of palmitate by the addition of two carbon units
The brain also has an additional capability, allowing it to produce the very long
chain fatty acids (up to 24 carbons) that are required for synthesis of brain lipids
There are enzymes present in the ER that are responsible for desaturating fatty
acids (i.e. adding cis double bonds)
Humans have carbon 4, 5, 6 and 9 desaturases, but lack the ability to introduce
double bonds from carbon 10 to the ω end of the chain
Examples of some fatty acids derived from palmitate (C 16) include stearate (C18)
and oleate (C18)
β-Oxidation of Fatty Acids
Proteins (albumin) help to transport the fatty acids and glycerols in the
blood
In order for fatty acids to be used as fuel, they must undergo β-oxidation
The reaction occurs in the mitochondrial matrix
Erythrocytes which have no mitochondria cannot use fatty acids as fuel
The brain also does not use fatty acid as fuel due to an impermeable
blood brain barrier
β-Oxidation of Fatty Acids
This is a catabolic reaction for fatty acids
It involves the complete combustion of fatty acids to CO2 and H2O and
ultimately the generation of ATP
The reaction involves 2 key steps
1. The sequential oxidation of all the carbons in the fatty acid to acetyl
CoA
2. The acetyl CoA is channeled into the TCA cycle where it is oxidized
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β-Oxidation of Fatty Acids
Both reactions produce molecules that can generate ATP via oxidative
phosphorylation
The formation of acetyl CoA via β-oxidation serves mainly as a precursor
for biosynthetic reactions…(secondary fuel source)
Acetyl CoA may also be converted to ketone bodies
These ketone bodies are water soluble and are able to cross the blood
brain barrier
They can serve as fuel for the brain and other tissues when
glucose becomes unavailable
β-Oxidation of Fatty Acids
Fatty acids undergo an activation step before beta oxidation takes place
Fatty Acid Activation
Long chain fatty acids are transported into the cell where they are converted into a
fatty acyl derivative e.g. The fatty acid palmitic acid is converted to palmitoyl-CoA.
This step requires ATP
The Co-A derivatives must then transported across the inner mitochondrial
membrane
However the mitochondrial membrane is impermeable to Co-A derivatives
therefore specialized carriers called carnitine transport the molecule from the
cytosol into the mitochondrial matrix
β-Oxidation of Fatty Acids
The β-oxidation of fatty acids result in a consecutive shortening of the
chain by 2 carbon atoms
These 2 carbon atoms are used to form acetyl CoA
The long chain fatty acids will be broken down to produce many acetyl
CoA molecules
NADH and FADH2 are other products of the reaction
β-Oxidation of Fatty Acids
The acetyl CoA formed can be channeled into the TCA cycle and be
incorporated in gluconeogenesis
The acetyl CoA formation therefore links fatty acid metabolism with
glucose metabolism
The complete oxidation of one acetyl CoA molecule yields 12 molecules
of ATP (taking into consideration NADH and FADH2 produced)
β-Oxidation of Fatty Acids
Example, palmitic acid contains 16 carbon atoms
Each step in the β-oxidation of the fatty acid yields acetyl CoA and
1 molecule each of FaDH2 and NADH
The last step in the breakdown produces 2 acetyl CoA molecules
β-Oxidation of Fatty Acids
C16 → C14 + C2 + FADH2 + NADH
C14 → C12 + C2 + FADH2 + NADH
C12 → C10 + C2 + FADH2 + NADH
C 10 → C8 + C2 + FADH2 + NADH
C8 → C6 + C2 + FADH2 + NADH
C6 → C4 + C2 + FADH2 + NADH
C4 → C2 + C2 + FADH2 + NADH
Therefore if 8 molecules of Acetyl CoA and 7 molecules each of FADH2
and NADH are formed
β-Oxidation of Fatty Acids
Therefore the number of ATP molecules produced are as follows
8 molecules of acetyl Co A = 96 ATP
7 molecules of FADH2 = 14 ATP
7 molecules of NADH = 21 ATP
131 ATP
2 ATP was used in the process, therefore the total amount of ATP = 129
Carnitine
Carnitine can be obtained from the diet (meat products)
It can also be synthesized from the amino acids lysine and methionine
by a reaction pathway that occurs in the liver and kidney
The heart and skeletal muscle depends on carnitine that is
endogenously made or acquired in the diet and transported in the
blood
Skeletal muscle contains 97% of all carnitine in the body
Carnitine
A deficiency in carnitine results in an inability of long chain fatty acids
to be used as fuels
This may occur in persons with
Liver disease (unable to make carnitine)
Malnourished (protein deficiency)
Strict vegetarian (meat is a good source of carnitine)
Undergoing haemodialysis (removes carnitine from blood)
An increased demand for carnitine e.g. Burn victims, severe infection
etc.
Ketogenesis
This is the formation of ketone bodies from acetyl coA
Ketone bodies include 3 substances
1. acetoacetate
2. D-3-hydroxybutyrate (predominant ketone body)
3. acetone
Ketogenesis
Ketone bodies are formed when fat breakdown predominates i.e. there is a
decrease in carbohydrate breakdown
In such a situation the acetyl CoA is not fed into the TCA cycle , this is because
the concentration of oxaloacetate is lowered
The acetyl CoA undergoes a different fate, i.e. to form ketone bodies
A reduction in oxaloacetate concentration occurs during fasting and in
diabetes
…Remember that oxaloacetate is an intermediate used in gluconeogenesis
Ketogenesis
Ketogenesis occurs in the mitochondria of the liver and kidneys
The acetoacetate and D-3-hydroxybutyrate that are formed, diffuse from the
liver mitochondria into the blood where it is transported to peripheral
tissues. They are then reconverted to acetyl CoA which can be oxidized by
the TCA cycle. Therefore they act as a source of energy
Acetone is a ketone body that cannot be further metabolized
Ketolysis
The process by which ketone bodies are reconverted to produce energy for
peripheral tissues is called ketolysis.
The brain is able to use ketone bodies as an energy source
Ketone bodies are soluble in polar solvents and as such do not need proteins
to aid in transportation as the lipids
They are used based on there concentration in the blood by the skeletal and
cardiac muscles and the renal cortex. As a result glucose is preserved
When the concentration of ketone bodies is greater than the rate of usage,
then this increased concentration becomes evident in the blood (ketonemia)
and urine (ketonuria)
In addition the smell of acetone is detected on the breath of these individual
Ketolysis
The normal concentration of ketone bodies in the blood is <3 mg/100 mL and
in the urine is ≤ 125 mg/24 h
For untreated diabetics the concentration of ketone bodies
can increase to 90 mg/ 100mL in the blood and
5000 mg/ 24 h in urine
