LIPID METABOLISM (Session 1)

Rehana Omar
School of Medicine
Department of physiological sciences.
rehana@unza.zm
 Key components covered in Fatty acid
metabolism
Digestion and absorption of fatty acids.

Fatty acid synthesis.

Fatty acid oxidation.

Regulation of fatty acid metabolism.

Ketogenesis.

Changes in fatty acid metabolism in uncontrolled

diabetes and starvation.

The fate of cholesterol.

At the end of this fatty acid metabolism component, each
student should be able to;

 Explain why fatty acids are ideal for storage of energy

over a long time.

 Describe changes in fatty acid metabolism associated

with uncontrolled diabetes mellitus

 Illustrate the common origin of steroid hormones and

how subtle differences in the position of functional
groups results in functional diversity of the hormones
Breakdown of carbohydrates, lipids and proteins

Harper's Illustrated Biochemistry 26th ed

 Introduction to fatty acid catabolism
• Fatty acid catabolism i.e break down of triacylglycerides to CO₂ and
H₂0 to produce energy- process called β-oxidation

• Fatty acid oxidation can provide 80% of the energy needs of certain
tissues e.g. the heart, liver and resting skeletal muscle

• Fatty acid chains get oxidized to water and CO₂ and their electrons
pass on to the electron transport chain.

• Triacylglycerides are more highly reduced- i.e. they have many H

atoms compared to carbohydrates

• The more reduced a compound is, the more energy it produces.

• Fats produce 2x the amount of energy from glucose

 What makes lipids an ideal energy storage
macromolecule?
To answer this, we will start by comparing the structures of lipids and
sugars;

Amylose-a component of starch

A triacyglycerol
 Storage of fats
• No limit to storage of fats (in specialized fat cells called adipocytes)
• Hydrophilic therefore does NOT affect osmolarity of a cell
• Inert therefore not likely to react and harm the organism

Storage of glycogen
• Stored in small amounts in liver (provides energy for up to 24 hrs)
• Polar, therefore solvated by water (2/3 of the weight)
 Introduction to fatty acid catabolism
 Fatty substances are hydrophobic.

 Metabolic enzymes are water soluble.

 Digestion of fats requires features that help these fats be

more susceptible to enzymes.

 Other mechanisms are required to transport these fats from

the intestinal wall to cells.

 In the cells, still more mechanisms are needed to mobilize

the stored fats and transport them into the mitochondrial
matrix for β-oxidation.
 Fatty Acid transport from dietary intake to cells

Lehninger Principles of Biochemistry, Fourth Edition

 Digestion of fats

• Bile salts (amphipathic molecules) interact with

insoluble fat globules converting them into dispersed
micelles made up of the bile and fat (increasing contact
between molecules and enzymes).

• The liver makes bile from cholesterol and stores it in the

gall bladder and releases it into the small intestine after
consumption of a fatty meal. Bile acts like a detergent
and this process of breaking fats is called emulsification
 Digestion of Fats
• Water soluble intestinal lipases can now interact with the
lipid/bile micelles and convert triacylglycerols into monoglycerols,
diglycerols, glycerol and fatty acid chains

• These products diffuse from the intestine into the intestinal

epithelial cells where they are re-formed creating triacylglycerols
which are further packaged with cholesterol and specific proteins
to create aggregates called chylomicrons.

• These specific proteins called apolipoproteins bind to this

triglyceride, cholesterol complex to help transport these lipids
between organs.

• Protein component of lipoprotein in chylomicrons serve as ligands

which cell receptors recognize and aid movement of chylomicrons
from intestinal lining to the blood via lymphatic system.
 Structure of Chylomicrons
Surface of chylomicron is made
of phosphodiester head groups
of triacylglycerides.

The fatty acid chains face

inwards away from the aqueous
environment.
They make up 80% of mass of
chylomicron.

Lipoproteins B-48, C-II and C-III

serve as recognition sites for
transport and metabolism
Range from 100 to 500nm in diameter

Lehninger Principles of Biochemistry, Fourth Edition

 Digestion of Fats
• Apolipoprotein C-II activates lipoprotein lipase which hydrolyzes
(breaks down) triacylglycerides to fatty acids and glycerol.

• These are then taken to target tissues depending on energy

state of the body.

In muscle: oxidized to release energy– e.g. when starving or doing

demanding physical work

In adipose tissue: stored as fat reserves (reconstituted as

triacylglycerols)- e.g. in fully fed state (sufficient blood glucose
levels)

(Also stored in cells that synthesise steroid hormones like the

ovaries, testes and adrenal cortex).

.
 Mobilization of stored fatty acid droplets

Lehninger Principles of Biochemistry, Fifth Edition

 Mobilization of fatty acids
• Lipid droplet is coated with perilipins- protect the lipid droplet
from untimely lipid mobilization.
• Hormones signal release of fatty acids for use by metabolically
active tissue e.g. skeletal muscle, heart and kidney
• Epinephrine and glucagon (response to low sugar levels).
• These hormones trigger formation of cyclic AMP by enzyme
adenylyl cyclase (in the plasma membrane of adipocyte).
• In response to cAMP, perilipins (protein on stored fatty acid
droplets get phosphorylated by cAMP dependent protein kinase
A (PKA).
• Phosphorylated perilipins are now able to interact with hormone
sensitive lipase within cytosol leading to hydrolysis of
triglycerides to free fatty acids
 Mobilization of fatty acids
• Action of lipase releases free fatty acids (FFAs) from
the adipocyte into blood
• As many as 10 FFAs bind to serum albumin in the
blood and thus get transported to heart, skeletal
muscle and renal cortex.
• They are released from albumin and enter the cells of
these organs via plasma membrane transporters
• This is a way of transporting an insoluble molecule
within an aqueous medium (blood).
 Transportation of fatty acids into the mitochondrial
matrix

• This shuttle is an important rate-limiting/regulatory

shuttle of β- oxidation.
Lehninger Principles of Biochemistry, Fourth Edition
 Transportation of fatty acids into mitochondria
• Enzymes of β-oxidation are found in the mitochondrial
matrix.

• FFA with <14C enter mitochondria via protein porin

channels

• FFA of 14 or more carbons (majority of fatty acids)

require special transporters help to pass into
mitochondria.

• Occurs in 3 enzymatic steps of the carnitine shuttle;

 Transportation of fatty acids into mitochondria
Reaction 1
Adding CoA to fatty acid catalysed by acyl CoA synthetases :

Reaction 2
The fatty acyl carnitine passes from the intermembrane space into
the mitochondrial matrix via acyl carnitine/carnitine transporter in
the membrane.

Reaction 3
In mitochondrial matrix, carnitine acyl transferase ll transfers the
fatty acyl group back to Coenzyme A recreating the fatty acyl CoA
molecule
 Disorders associated with the acyl
carnitine/carnitine shuttle

Carnitine palmitoyl transferase l deficiency

• Hypoketotic hypoglycemia
• Liver dysfunction resulting in liver failure

Carnitine acyl carnitine translocase deficiency

• Cardiomyopathy
• Hypoglycemia
• hyperammonemia
• Sudden death
 The 3 steps of Beta Oxidation- STEP 1
2 carbons are successively removed in form
of acetyl CoA.
 This starts from COOH end.

 First enzyme has 3 isozymes that act on 4-

8, 4-14 & 12-18C

 E.g. a 16 carbon fatty acid will yield 8

acetyl CoA molecules (i.e. passes through
this process 7 times).

 NADH and FADH₂ are produced during

each cycle.
Lehninger Principles of Biochemistry, Fourth Edition
 Beta oxidation
• Two types of enzymes catalyze the last 3 reactions. The
exact enzyme depends on the fatty acid chain length.
• 12+ carbons- by multi enzyme complex (TFP-
Trifunctional Protein)-made of 8 chains (4 alpha and 4
beta).
Alpha chains have β-enoyl-CoA hydratase and β-
hydroxyacyl CoA dehydrogenase active sites.
Beta chains have thiolase active sites.
• Fatty acid chains 12 carbons or shorter are acted on by
single enzymes that are dissolved in the matrix.
Mutations in the genes encoding these enzymes are
inherited in an autosomal recessive manner

Short chain acyl CoA dehydrogenase deficiency

• Poor feeding and seizures or asymptomatic

Medium chain acyl CoA dehydrogenase deficiency

• Most common, 20% mortality rate
• Vomiting, dehydration, hypoketotic hypoglycemia,
liver dysfunction, hyperammonemia, brain edema,
death

Very long chain acyl CoA dehydrogenase deficiency

• Severe cardiomyopathy and death

Long chain 3-hydroxyacyl CoA dehydrogenase and

Trifunction Protein deficiency
• Rapid onset cardiomyopathy, myopathy, peripheral
neuropathy, liver necrosis
Nutritional management of fatty acid oxidation disorders
 Beta oxidation- STEP 2

Acetyl CoA units produced go

through the citric acid cycle yielding
more NADH and FADH₂.

Lehninger Principles of Biochemistry, Fourth Edition

 Beta oxidation- STEP 3
FADH₂ and NADH produced from the first two stages
pass through the electron transport chain in the
mitochondrial matrix, creating ATP.

Lehninger Principles of Biochemistry, Fourth Edition

 Beta oxidation and energy yield
• Each FADH₂ donates 1 electron pair to the ETC- yields
1.5 ATP molecules.
• 2.5 ATP yielded per NADH electron pair transfer.
• So total of 4 ATP per 1 cycle of fatty acid oxidation
where 2carbon units are removed.
• The overall reaction for Palmitate would be;

• Remember NADH + H⁺ + ⅟2 O₂ NAD⁺ + H₂O

• Now lets consider the energy yield per molecule of
acetyl CoA;
• Acetyl CoA enters the citric acid cycle.

Lehninger Principles of Biochemistry, Fourth Edition

 Energy production from Acetyl CoA produced from β-
oxidation
• Each Palmitoyl CoA yields the following (just an example);

Double check this

2CO₂ X8 = 16 CO₂ from the products
1 FADH₂ (1.5 ATP) x 8 = 12 ATP of the citric acid
cycle on the
3NADH (2.5 ATP X 3) x 8 = 60 ATP previous page
1GTP (1 ATP) x 8 = 8 ATP

• (1 FADH₂ + 3NADH + H⁺ + 2O₂) X 8 i.e. 16O₂ that are

reduced to 16H₂O.
 KETONE BODIES
• Fatty acid metabolism is triggered in part by response to
low glucose levels.

• Some acetyl CoA produced goes to TCA cycle to produce

energy and some intermediates of TCA are channeled
into gluconeogenesis.

• Coenzyme A is required for continued B-oxidation, but it

is in limited amounts

• Cells free up CoA from acetyl CoA by oxidizing it to

ketone bodies-this way B-oxidation can continue
 KETONE BODIES
• Ketone bodies are formed in the liver (brain can use this
as alternative fuel source when glucose is low).

• All organs except liver ( which lacks enzymes to convert

them to acetyl CoA) use this as fuel.

• Ketone bodies: acetoacetate, acetone and β-

hydroxybutyrate.

• Acetone is volatile and can be detected in the breathe-

(sometimes used to diagnose diabetes).
 Formation of ketone bodies from acetyl CoA

Ketone bodies are acidic

Lehninger Principles of Biochemistry, Fourth Edition

Formation of acetyl CoA from ketone bodies in extra hepatic tissues

Lehninger Principles of Biochemistry, Fourth Edition

Ketone body overproduction diabetes and low carb diets
When a person is starving, all their carbohydrate stores get depleted and the body relies on
gluconeogenesis (i.e. citric acid cycle intermediates are channeled into the production of
sugar).

Important to remember that organs such as the brain require glucose as the primary source
of energy.

To free up more Coenzyme A, acetylCoA is converted to ketone bodies

In untreated diabetes mellitus, low insulin or insulin insensitivity means glucose entering the
body after a meal cannot be adequately absorbed and stored for fuel.

Once again the citric acid cycle intermediates get channeled towards gluconeogenesis but at
the same time more fatty acids enter the mitochondria (the enzyme carnitine acyl
transferase 1 is very active during starvation or low energy state). Βeta oxidation proceeds
but the acetyl CoA being produced has nowhere to go since the citric acid cycle
intermediates are being used up to make glucose so the brain can function.

To relieve the build up of acetyl CoA and free up Co-A, acetyl CoA is converted to ketone
bodies. Since ketone bodies are acidic, blood pH reduces (causing acidosis which can lead to
comatose state and eventual death).