METABOLISM OF LIPIDS

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 METABOLISM OF LIPIDS
INTRODUCTION
• Triglycerides are the major dietary lipids but also the major
form of lipids stored in the human body in the adipose tissue
• When dietary carbohydrates are not sufficient, triglycerides
are broken down to fatty acids which can then be catabolized
to produce energy
• Oxidation of fats yields more than twice the metabolic energy
yielded from 1g glucose.

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 METABOLISM OF LIPIDS
LIPID CATABOLISM
• In order to produce energy, lipids are catabolized in a multi
step process
• Hormones such as epinephrine and glucagon trigger lipolysis in
adipose tissue during fasting and starvation
• Insulin inhibits lipolysis but promotes lipid biosynthesis during
the fed state
• Triglycerides in the adipose cellsare hydrolyzed by lipases,
releasing one fatty acid at a time to produce diglycerides,
monoglycerides and eventually glycerol
• The adipose cells then release the fatty acids and glycerol into
the blood where they are carried in complexes with serum
albumin to sites of utilization e.g. in muscle
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 METABOLISM OF LIPIDS
LIPID CATABOLISM
• Glycerol formed from lipolysis is absorbed by the liver
• In the liver, glycerol is converted to dihydroxyacetone
phosphate,
• Dihydroxyacetonephosphate, can be used in glycolysis or
gluconeogenesis depending on the needs of the cells

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 METABOLISM OF LIPIDS
FATTY ACID CATABOLISM
• Fatty acids from triglyceride breakdown are metabolized in
three stages before they can be used to produce energy
1. Activation- takes place on the outer mitochondrial
membrane
2. Transport into the mitochondria
3. Degradation to two-carbon fragments (acetyl CoA) in the
mitochondrial matrix (β-oxidation pathway)

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 METABOLISM OF LIPIDS
FATTY ACID CATABOLISM –
1. Activation of fatty acids
• Fatty acids are activated by acyl CoA synthetase which is
located on the outer mitochondrial membrane.
• The activation occurs in two steps.
• First the fatty acid reacts with ATP to form an acyl-
adenylate and pyrophosphate.
• The sulfhydryl group of CoA then attacks the acyl-
adenylate intermediate to form acyl-CoA and AMP

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 METABOLISM OF LIPIDS
FATTY ACID CATABOLISM –
1. Activation of fatty acids
• Fatty acids are activated in an ATP-dependent acylation
reaction to form fatty acyl-CoA
• Activation is catalyzedby acyl CoA synthetase (Thiokinase)
which is located on the outer mitochondrial membrane.

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 METABOLISM OF LIPIDS
FATTY ACID CATABOLISM-
2. Transportation into mitochondria matrix
• Fatty acids activated on the outer mitochondrial membrane need to
be transported into the matrix where they are oxidized
• The activated fatty acids are transported by the carnitine shuttle
system
• The acyl group of activated fatty acid is transferred from CoA to
carnitine to form acyl-carnitine
• This is calalyzed by the enzyme carnitine acyltransferase I which is
bound to the outer mitochondrial membrane.
• The acyl-carnitine is then transported cross the inner mitochondrial
membrane by a specific translocase
• Inside the matrix, acyl carnitine transfers the acyl group back to CoA,
a process catalyzed by enzyme carnitine acyltransferase II 8
 METABOLISM OF LIPIDS
FATTY ACID CATABOLISM-
2. Transportation into mitochondria matrix

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 METABOLISM OF LIPIDS
FATTY ACID CATABOLISM-
3. β-oxidation
• Saturated fatty acyl-CoAs are catabolizedd in the matrix by a
reoccurring sequence of four reactions in a process called β-
oxidation.
• The β-oxidation pathway degrades fatty acids two carbons at a
time to form acetyl-CoA




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 METABOLISM OF LIPIDS
FATTY ACID CATABOLISM-
3. β-oxidation –
• Involves the oxidation of fatty acid moiety of fatty acyl-CoA
• Is catalyzed by acyl-CoA dehydrogenase to produce a trans-
α,β double bond between carbon atoms 2 and 3.
• FAD is the prosthetic group that
accepts electrons in this reaction

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 METABOLISM OF LIPIDS
FATTY ACID CATABOLISM-
3. β-oxidation –
• Involves hydration of the trans double bond produced in
reaction 1
• Is catalyzed by enoyl-CoA hydratase yielding 3-L-hydroxyacyl-
CoA

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 METABOLISM OF LIPIDS
FATTY ACID CATABOLISM-
3. β-oxidation –
• Involves oxidation of the hydroxyl group in the β position
(C3) to a ketone
• Is catalyzed by hydroxyacyl-CoA dehydrogenase
• NAD+ is the electron acceptor.

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 METABOLISM OF LIPIDS
FATTY ACID CATABOLISM-
3. β-oxidation –
• The final reaction cleaves the 2-carbon unit releasing acetyl
CoA
• The enzyme involved is thiolase
• The reaction type is thiolysis, the attack of a molecule by
coenzyme A on the β-carbon
• In addition to the acetyl CoA, a
fatty acyl CoA, two carbons
shorter than the beginning fatty
acid is also produced

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 METABOLISM OF LIPIDS
FATTY ACID CATABOLISM-
3. β-oxidation –
• The β -oxidation pathway is cyclic.
• The fatty acyl CoA (2 carbons shorter) produced in the 4th
reaction, is the input to another round of the pathway.
• A fatty acid containing an even number of C atoms yields
butyryl-CoA in the final reaction cycle.
• The butyryl-CoA is converted to 2 copies of acetyl-CoA.
• However, oxidation of odd-chain fatty acids produces
propionyl-CoA which is converted to succinyl-CoA for entry
into TCA cycle

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 METABOLISM OF LIPIDS
FATTY ACID CATABOLISM-
3. β-oxidation –
Each round of β-oxidation generates one molecule each of:
• FADH2
• NADH
• Acetyl CoA
• Fatty acyl CoA (2 carbons shorter each round)

Fates of the products of β-oxidation:

• NADH and FADH2 - are used in ETC
• Acetyl CoA - enters the citric acid cycle
• Fatty acyl CoA – undergoes the next cycle of oxidation16
 METABOLISM OF LIPIDS
FATTY ACID CATABOLISM- β-Oxidation of Odd Numbered Fatty
Acids
• Odd-chain fatty acids occur in
some bacteria
• Final product of β-oxidation of
odd numbered fatty acids is
propionyl CoA
• Three enzymes convert
propionyl CoA to succinyl CoA
• Succinyl CoA can then be used
in the TCA cycle

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 METABOLISM OF LIPIDS
Ketone bodies
 During fasting, carbohydrate starvation or diabetes,
oxaloacetate is depleted in liver because it is used for
gluconeogenesis.
 This impedes entry of acetyl-CoA (from fatty acid oxidation)
into Krebs cycle.
 Acetyl-CoA is then converted to ketone bodies, acetoacetate,
β–hydroxybutyrate and acetone by the process of ketogenesis.
 Ketogenesis occurs in liver mitochondria
 The major ketone body produced is β-hydroxybutyrate.
 Acetone is not metabolized, but is exhaled.
 Ketosis is a condition in which levels of ketone bodies in the
blood are elevated.
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 METABOLISM OF LIPIDS
Biosynthesis of ketone bodies

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 METABOLISM OF LIPIDS
Ketone bodies
• Ketone bodies are water soluble and can be used by all
other tissues as a source of energy
• β-hydroxybutyrate, passes
into the blood and thus to
other tissues, where it is
converted in three steps to
acetyl-CoA.
• The acetyl-CoA thus formed
is used for energy
production.
• Ketones that build up in the
body for a long time lead to
serious illness and coma.
(diabetic ketoacidosis) 20
 METABOLISM OF LIPIDS
FATTY ACID BIOSYNTHESIS (ANABOLISM)
• Occurs mainly in liver and adipocytes, and in mammary glands
during lactation
• Occurs in cytoplasm
• Pathway for synthesis of fatty acids is different from pathway
for oxidation
• When glucose is in plenty, high amounts of acetyl CoA are
produced by glycolysis and can be used for fatty acid synthesis
• Fatty acids are synthesized by a multienzyme complex known
as fatty acid synthetases
• NADPH is the reducing agent in fatty acid biosynthesis

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 METABOLISM OF LIPIDS
FATTY ACID BIOSYNTHESIS (ANABOLISM)
• There are three steps involved in fatty acid biosynthesis
1. Transport of acetyl CoA from mitochondria to cytoplasm
2. Carboxylation of acetyl CoA to form malonyl CoA
3. Assembly/ Elongation of fatty acid chain

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 METABOLISM OF LIPIDS
FATTY ACID BIOSYNTHESIS (ANABOLISM)
1. Transport of acetyl CoA from mitochondria to cytoplasm
• Acetyl CoA from catabolism of carbohydrates
and amino
acids is exported from mitochondria via the citrate
transport system

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 METABOLISM OF LIPIDS
FATTY ACID BIOSYNTHESIS (ANABOLISM)
2. Carboxylation of acetyl CoA to malonyl CoA
• Formation of malonyl–CoA is the committed step in fatty acid
synthesis

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 METABOLISM OF LIPIDS
FATTY ACID BIOSYNTHESIS (ANABOLISM)
3. Assembly/ Elongation of fatty acid chain
• To start an elongation cycle, Acetyl–CoA and Malonyl–CoA
are each transferred to an acyl carrier protein

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 METABOLISM OF LIPIDS
FATTY ACID BIOSYNTHESIS (ANABOLISM)
3. Assembly/ Elongation of fatty acid chain
 Begins by synthesis of butyryl
ACP from Acetyl ACP and
malonyl ACP through four
reactions:
 Condensation – Acetoacetyl
ACP
 Reduction – β-Hydroxybutyryl
ACP
 Dehydration – Crotonyl ACP
 Reduction – Butyryl ACP

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 METABOLISM OF LIPIDS
FATTY ACID BIOSYNTHESIS (ANABOLISM)
3. Assembly/ Elongation of fatty acid chain
 The elongation cycle is repeated six more times, using malonyl–CoA
each time, to produce palmityl–ACP
 Palmityl–ACP is then hydrolyzed by a thioesterase, forming free
palmitate
Thioesterase
Palmitoyl-ACP + H2O palmitate + ACP-SH

 Palmitate can then undergo separate elongation and/or

unsaturation to yield other fatty acid molecules
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 METABOLISM OF LIPIDS
REGULATION OF FATTY ACID METABOLISM
Catabolism/Oxidation
• Regulation mainly through hormones glucagon and
epinephrine
• These hormones which activate hormone sensitive lipase
and other lipases that catalyze hydrolysis of triglycerides
in that adipose tissue
Biosynthesis/ Anabolism
• Stimulated by hormone insulin which activates acetyl CoA
carboxylase which converts acetyl coA to malonyl CoA

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