Lipid Metabolism
Lipid Metabolism
Lipid Metabolism
Lipids
Metabolism
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Lecture 6+7 Clinical Biochemistry Dr. Ali Fahim & Prof. Dr. Talat T.K & Dr. Dalya Shakir
Lipids are a family of biomolecules that have the common property of being soluble in
organic solvents, like ether or chloroform, but not in water. They serve multiple purposes in
the body, such as storing energy, protecting and insulating internal organs, and acting as
chemical messengers. Because they are not soluble in water, lipids are also important
components of cellular membranes that function to separate the internal contents of cells from
the external environment.
Unlike the polysaccharides, proteins and nucleic acids, lipids are not polymers. Further, lipids
are mostly small molecules.
Classification of lipids
Lipids are broadly classified into simple, complex, derived and miscellaneous lipids.
1. Simple lipids : Esters of fatty acids with alcohols. These are mainly of two types
(a) Fats and oils (triacylglycerols) : These are esters of fatty acids with glycerol.
The difference between fat and oil is only physical. Thus, oil is a liquid while fat is a solid at
room temperature.
(b) Waxes : Esters of fatty acids (usually long chain) with alcohols other than glycerol. Waxes
are used in the preparation of candles, lubricants, cosmotics, ointments, polishes etc.
2. Complex (or compound) lipids : These are esters of fatty acids with alcohols
containing additional groups such as phosphate,
nitrogenous base, carbohydrate, protein etc.
They are further divided as follows
(a) Phospholipids : They contain phosphoric
acid and frequently a nitrogenous base. This is
in addition to alcohol and fatty acids.
(i) Glycerophospholipids: These phospho-
lipids contain glycerol as the alcohol e.g.,
lecithin, cephalin (figure A).
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Lecture 6+7 Clinical Biochemistry Dr. Ali Fahim & Prof. Dr. Talat T.K & Dr. Dalya Shakir
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Lecture 6+7 Clinical Biochemistry Dr. Ali Fahim & Prof. Dr. Talat T.K & Dr. Dalya Shakir
Metabolism of lipids
In both animals and plants, the excessive fat is stored in various parts of the body in large
quantities in the form of neutralized and insoluble triglycerides (fat). It decomposes and
quickly destroys to provide energy necessary for the cell.
Fat has an important role in nutrition, because it has a high energy value (9.3 kilocalories per
gram)
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Lecture 6+7 Clinical Biochemistry Dr. Ali Fahim & Prof. Dr. Talat T.K & Dr. Dalya Shakir
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Lecture 6+7 Clinical Biochemistry Dr. Ali Fahim & Prof. Dr. Talat T.K & Dr. Dalya Shakir
[(figure 1) carnitine shuttle for transport of activated fatty acid (acyl CoA) into mitochondria]
III. β-Oxidation proper in the mitochondrial matrix.
Each cycle of β-oxidation, liberating a two carbon unit-acetyl CoA, occurs in a sequence of
four reactions (Fig.2).
1. Oxidation : Acyl CoA undergoes dehydrogenation by an FAD-dependent
flavoenzyme, acyl CoA dehydrogenase. A double bond is formed between β and α
carbons (i.e., 2 and 3 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. The product formed is β-ketoacyl CoA.
4. Cleavage : The final reaction in β-oxidation is the liberation of a 2 carbon fragment, acetyl
CoA from acyl CoA. This occurs by a thiolytic cleavage catalysed by β-ketoacyl CoA
thiolase (or simply thiolase).
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Lecture 6+7 Clinical Biochemistry Dr. Ali Fahim & Prof. Dr. Talat T.K & Dr. Dalya Shakir
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Lecture 6+7 Clinical Biochemistry Dr. Ali Fahim & Prof. Dr. Talat T.K & Dr. Dalya Shakir
Figure (3) Summary of the energy yield from the oxidation of palmitoyl CoA (16 carbons). CC = acetyl CoA.
*Activation of palmitate to palmitoyl CoA requires the equivalent of 2 ATP.
Energy calculation:
Number of round = number of carbon atom of fatty acid / 2 = 16/2= 8 round
8 rounds give 7 FADH2 = 7 *2 = 14 ATP
8 rounds give 7 NADH = 7 *3 = 21 ATP
8 rounds give 8 acetyl CoA (8 TCA cycle)= 8 * 12= 96 ATP
Activation step of fatty acid consumed two ATP = - 2 ATP
Overall net energy = 14 + 21+ 96 – 2 = 129 ATP
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Lecture 6+7 Clinical Biochemistry Dr. Ali Fahim & Prof. Dr. Talat T.K & Dr. Dalya Shakir
Ketone bodies are formed in the mitochondrial matrix in the liver and are released from the
liver to the blood, generating what is called ketosis, then they are transported through the
blood to the surrounding tissues such as the brain, heart, kidney and muscles, where they are
oxidized by TCA. ketone bodies reach the highest levels in the event of extreme hunger or
eating large quantities of fat or diabetes.
Ketone bodies are important sources of energy for the peripheral tissues because:
1) they are soluble in aqueous solution and, therefore, do not need to be
incorporated into lipoproteins or carried by albumin as do the other lipids.
2) serve as important sources of energy for the peripheral tissues such as skeletal muscle,
cardiac muscle, renal cortex etc. Also during prolonged starvation, ketone bodies are the
major fuel source for the brain and other parts of central nervous system.
3) The production of ketone bodies and their utilization become more benefit when glucose is
in short supply to the tissues, as observed in starvation, and diabetes mellitus.
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Lecture 6+7 Clinical Biochemistry Dr. Ali Fahim & Prof. Dr. Talat T.K & Dr. Dalya Shakir
Metabolism of cholesterol
Cholesterol is found exclusively in animals; hence it is often called as animal sterol. The total
body content of cholesterol in an adult man weighing 70 kg is about 140 g i.e., around 2 g/kg
body weight. Cholesterol is amphipathic in nature, since it possesses both hydrophilic and
hydrophobic regions in the structure.
Functions of cholesterol
Cholesterol is essential to life, as it performs a number of important functions
1. It is a structural component of cell membrane.
2. Cholesterol is the precursor for the synthesis of all other steroids in the body. These
include steroid hormones, vitamin D and bile acids.
3. It is an essential ingredient in the structure of lipoproteins in which form the lipids in
the body are transported.
4. Fatty acids are transported to liver as cholesteryl esters for oxidation.
Cholesterol biosynthesis
About 1 g of cholesterol is synthesized per day in adults. Almost all the tissues of the body
participate in cholesterol biosynthesis. The largest contribution is made by liver (50%),
intestine (15%), skin, adrenal cortex, reproductive tissue etc.
The enzymes involved in cholesterol synthesis are found in the cytosol and microsomal
fractions of the cell. Acetate of acetyl CoA provides all the carbon atoms in cholesterol.
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Lecture 6+7 Clinical Biochemistry Dr. Ali Fahim & Prof. Dr. Talat T.K & Dr. Dalya Shakir
The reducing equivalents are supplied by NADPH while energy are provided by ATP. For
the production of one mole of cholesterol, 18 moles of acetyl CoA, 36 moles of ATP and 16
moles of NADPH are required.
The synthesis of cholesterol may be learnt in 5 stages
1. Synthesis of HMG CoA
2. Formation of mevalonate (6C)
3. Production of isoprenoid units (5C)
4. Synthesis of squalene (30C)
5. Conversion of squalene to cholesterol (27C).
The detailed reactions of cholesterol biosynthesis are given in figure (5) as follow:
1. Synthesis of β-hydroxy β-methylglutaryl CoA (HMG CoA) :
Two moles of acetyl CoA condense to form acetoacetyl CoA. Another molecule of acetyl
CoA is then added to produce HMG CoA.
2. Formation of mevalonate :
HMG CoA reductase is the rate limiting enzyme incholesterol biosynthesis. This enzyme is
present in endoplasmic reticulum and catalyses the reduction of HMG CoA to mevalonate.
The reducing equivalents are supplied by NADPH.
3. Production of isoprenoid units :
In a threestep reaction catalysed by kinases, mevalonate is converted to 3-phospho 5-
pyrophosphomevalonate which on decarboxylation forms isopentenyl pyrophosphate (IPP).
The latter isomerizes to dimethylallyl pyrophosphate (DPP). Both IPP and DPP are 5-carbon
isoprenoid units.
4. Synthesis of squalene:
IPP and DPP condense to produce a 10-carbon geranyl pyrophosphate (GPP). Another
molecule of IPP condenses with GPP to form a 15-carbon farnesyl pyrophosphate (FPP). Two
units of farnesyl pyrophosphate unite and get reduced to produce a 30-carbon squalene.
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Lecture 6+7 Clinical Biochemistry Dr. Ali Fahim & Prof. Dr. Talat T.K & Dr. Dalya Shakir
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Lecture 6+7 Clinical Biochemistry Dr. Ali Fahim & Prof. Dr. Talat T.K & Dr. Dalya Shakir
Degradation of cholesterol
The steroid nucleus (ring structure) of the cholesterol cannot be metabolized in humans.
Cholesterol (50%) is converted to bile acids, excreted in feces, serves as a precursor for the
synthesis of steroid hormones, vitamin D, coprostanol and cholestanol. The latter two are the
fecal sterols, besides cholesterol.
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Lecture 6+7 Clinical Biochemistry Dr. Ali Fahim & Prof. Dr. Talat T.K & Dr. Dalya Shakir
Figure (6) Outline of bile acid synthesis (*–Primary bile acids, **–Secondary bile acids).
Enterohepatic circulation : The conjugated bile salts synthesized in the liver accumulate in
gall bladder. From there they are secreted into the small intestine where they serve as
emulsifying agents for the digestion and absorption of fats and fat soluble vitamins. A large
portion of the bile salts (primary and secondary) are reabsorbed and returned to the liver through
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Lecture 6+7 Clinical Biochemistry Dr. Ali Fahim & Prof. Dr. Talat T.K & Dr. Dalya Shakir
portal vein. Thus the bile salts are recycled and reused several times in a day. This is known as
enterohepatic circulation. About 15-30 g of bile salts are secreted into the intestine each day
and reabsorbed. However, a small portion of about 0.5 g/day is lost in the feces. An equal
amount (0.5 g/day) is synthesized in liver to replace the lost bile salts. The fecal excretion of
bile salts is the only route for the removal of cholesterol from the body.
Cholelithiasis: Bile salts and phospholipids are responsible for keeping the cholesterol in bile
in a soluble state. Due to their deficiency (particularly bile salts), cholesterol crystals
precipitate in the gall bladder often resulting in cholelithiasis—cholesterol gall stone disease
figure (7). Cholelithiasis may be due to defective absorption of bile salts from the intestine,
impairment in liver function, obstruction of biliary tract etc.
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Lecture 6+7 Clinical Biochemistry Dr. Ali Fahim & Prof. Dr. Talat T.K & Dr. Dalya Shakir
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Lecture 6+7 Clinical Biochemistry Dr. Ali Fahim & Prof. Dr. Talat T.K & Dr. Dalya Shakir
Fi.gure (8) Simplified scheme of steroid biosynthesis. The enzymes involved are (1) the cholesterol side
chain cleavage enzyme, (2) steroid C17 hydroxylase, (3) steroid C17, C20 lyase, (4) steroid C21 hydroxylase, (5)
steroid 11β-hydroxylase, (6) steroid C18 hydroxylase, (7) 18-hydroxysteroid oxidase, and (8) aromatase
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Lecture 6+7 Clinical Biochemistry Dr. Ali Fahim & Prof. Dr. Talat T.K & Dr. Dalya Shakir
heat
Lipoproteins
Lipoproteins are molecular complexes that consist of lipids and proteins (conjugated
proteins). They function as transport vehicles for lipids in blood plasma. Lipoproteins deliver
the lipid components (cholesterol, triacylglycerol etc.) to various tissues for utilization.
Classification of lipoproteins
Five major classes of lipoproteins are identified in human plasma.
1. Chylomicrons : They are synthesized in the intestine and transport exogenous (dietary)
triacylglycerol to various tissues. They consist of highest (99%) quantity of lipid and lowest
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Lecture 6+7 Clinical Biochemistry Dr. Ali Fahim & Prof. Dr. Talat T.K & Dr. Dalya Shakir
(1%) concentration of protein. The chylomicrons are the least in density and the largest in size,
among the lipoproteins.
2. Very low density lipoproteins (VLDL) :
They are produced in liver and intestine and are responsible for the transport of endogenously
synthesized triacylglycerols.
3. Low density lipoproteins (LDL) : They are formed from VLDL in the blood circulation.
They transport cholesterol from liver to other tissues.
4. High density lipoproteins (HDL) : They are mostly synthesized in liver. HDL particles
transport cholesterol from peripheral tissues to liver (reverse cholesterol transport).
5. Free fatty acids—albumin : Free fatty acids in the circulation are in a bound form to
albumin. Each molecule of albumin can hold about 20-30 molecules of free fatty acids.
Metabolism of lipoproteins
Lipoprotein metabolism divided into two class
1. Transport of exogenous
(dietary)lipids (chylomicron
processing)
2. Transport of endogenous lipids
Apo B-100 lipoprotein guided
system Apo A1 governed lipoprotein
system
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Lecture 6+7 Clinical Biochemistry Dr. Ali Fahim & Prof. Dr. Talat T.K & Dr. Dalya Shakir
cholesterol. Circulating HDL donates apo C II and apo E to convert nascent VLDL to VLDL.
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Lecture 6+7 Clinical Biochemistry Dr. Ali Fahim & Prof. Dr. Talat T.K & Dr. Dalya Shakir
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