BMS204

Lipid Metabolism

Dr. Reem Arafa

Prof. of Biomedical Sciences
 Key Concepts in Lipid Metabolism

• Stored lipids is the primary source of energy in most organisms.

• The three sources of triacylglycerols in animals are:

– dietary lipids,
– stored triacylglycerols in adipose tissue, and
– fatty acids synthesized in the liver.

 -oxidation is the mitochondrial process by which fatty acids are

oxidized to yield NADH, FADH2, and acetyl-CoA.
Overview of Lipid Transport in Animals
Fat is stored in fat cells
(adipocytes). Obesity, especially
childhood obesity, can be due to
both more fat storage per cell, and
to a larger number of adipocytes.
 Review of lipid structures:
Fatty acids are stored as triacylglycerols

Glycerol
Fatty acid #2
Fatty acid #1

Fatty acid #3

Glycerol esterification of fatty acids

protects cell membranes from the
amphipathic nature of fatty acids. Soap
is made out of fatty acids and works well
to remove oils from hands and clothes by
forming micelles that trap the lipids in a
water soluble particle.
Lipid Metabolism
Lipid Metabolism
 Pathway Questions

1. What purpose does fatty acid metabolism serve in animals?

– Fatty acid oxidation in mitochondria is responsible for providing

energy to cells when glucose levels are low. Triacylglycerols
stored in adipose tissue of most humans can supply energy to
the body for ~3 months during starvation.

– Fatty acid synthesis reactions in the cytosol of liver and adipose

cells convert excess acetyl CoA that builds up in the
mitochondrial matrix when glucose levels are high into fatty
acids that can be stored or exported as triacylglycerols.
 Pathway Questions

2. What are the net reactions of fatty acid degradation and

synthesis for the C16 fatty acid palmitate?

Fatty acid oxidation:

Palmitate + 7 NAD+ + 7 FAD + 8 CoA + 7 H2O + ATP →
8 acetyl CoA + 7 NADH + 7 FADH2 + AMP + 2 Pi + 7 H+

Fatty acid synthesis:

8 Acetyl CoA + 7 ATP + 14 NADPH + 14 H+ →
Palmitate + 8 CoA + 7 ADP + 7 Pi + 14 NADP+ + 6 H2O
 Pathway Questions
3. What are the key enzymes in fatty acid metabolism?
Catabolism

Fatty acyl CoA synthetase – enzyme catalyzing the "priming" reaction in

fatty acid metabolism which converts free fatty acids in the cytosol into
fatty acyl-CoA using the energy available from ATP and PPi hydrolysis.

Carnitine acyltransferase I - catalyzes the commitment step in fatty acid

oxidation which links fatty acyl-CoA molecules to the hydroxyl group of
carnitine. The activity of carnitine acyltransferase I is inhibited by malonyl-
CoA, the product of the acetyl-CoA carboxylase reaction, which signals
that glucose levels are high and fatty acid synthesis is favored.
 Pathway Questions

4. What are examples of fatty acid metabolism in real life?

A variety of foods are prominently advertised as "non-fat," even though

they can contain a high calorie count coming from carbohydrates. Eating too
much of these high calorie non-fat foods (e.g., non-fat bagels) activates the
fatty acid synthesis pathway resulting in the conversion of acetyl-CoA to
fatty acids, which are stored as triacylglycerols.
Transport and storage of fatty acids and
triacylglycerols
Transport and storage of fatty acids and
triacylglycerols
The fatty acid  oxidation pathway in
mitochondria
-oxidation yields large
amounts of ATP

The energy conversion Palmitate

(C16)
process of fatty acid --> ATP
involves oxidation of fatty
acids by sequential
degradation of C2 units
leading to the generation
FADH2, NADH, and acetyl
CoA.

The subsequent oxidation of

these reaction products by the
citrate cycle and oxidative
phosphorylation generates
lots of ATP.

106 ATP - WOW!

-oxidation reactions
OXIDATION

The -oxidation pathway

occurs at the  carbon of
the fatty acid, thereby
releasing the C-1 carboxyl HYDRATION

carbon and  carbon as

the acetate component of
acetyl CoA. OXIDATION

THIOLYSIS
 (1) Activation of Fatty Acids
• Fatty acids are converted to CoA thioesters by acyl-CoA
synthetase (ATP dependent)
• The PPi released is hydrolyzed by a pyrophosphatase
to 2 Pi
• Two phosphoanhydride bonds (two ATP equivalents) are
consumed to activate one fatty acid to a thioester
(2) Transport of Fatty Acyl CoA into Mitochondria

• The carnitine shuttle system.

• Fatty acyl CoA is first converted to acylcarnitine (enzyme carnitine
acyltransferase I (bound to the outer mitochondrial membrane).
• Acylcarnitine enters the mitochondria by a translocase.
• The acyl group is transferred back to CoA (enzyme - carnitine
acyltransferase II).
• Carnitine
shuttle
system
• Path of
acyl group
in red
 (3) The Reactions of β oxidation
• The β-oxidation pathway (β-carbon atom (C3) is
oxidized) degrades fatty acids two carbons at a time



1. Oxidation of acyl CoA by
acyl CoA dehydrogenase to
give an enoyl CoA

Coenzyme - FAD
2. Hydration of the double
bond between C-2 and C-3
by enoyl CoA hydratase
with the 3-hydroxyacyl CoA
(β-hydroxyacyl CoA)
formation
3. Oxidation of
3-hydroxyacyl CoA
to 3-ketoacyl CoA by
3-hydroxyacyl CoA
dehydrogenase

Coenzyme – NAD+
4. Cleavage of 3-ketoacyl
CoA by the thiol group of
a second molecule of CoA
with the formation of
acetyl CoA and an acyl
CoA shortened by two
carbon atoms.

Enzyme – β ketothiolase.
The shortened acyl CoA
then undergoes another
cycle of oxidation

The number of cycles: n/2 - 1,

where n – the number of
carbon atoms
 Fatty acyl CoA
-Oxidation of saturated
fatty acids
• One round of β oxidation: 4 enzyme steps produce acetyl
CoA from fatty acyl CoA
• Each round 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
- acyl CoA – undergoes the next cycle of oxidation
 ATP Generation from Fatty Acid Oxidation
Net yield of ATP per one oxidized palmitate
Palmitate (C15H31COOH) - 7 cycles – n/2 - 1
• The balanced equation for oxidizing one palmitoyl CoA by
seven cycles of b oxidation
Palmitoyl CoA + 7 HS-CoA + 7 FAD+ + 7 NAD+ + 7 H2O
8 Acetyl CoA + 7FADH2 + 7 NADH + 7 H+
ATP generated
8 acetyl CoA 10x8=80
7 FADH2 7x1.5=10.5
7 NADH 7x2.5=17.5
108 ATP
ATP expended to activate palmitate -2
Net yield: 106 ATP
per Acetyl-CoA
-oxidation is a chemical source of water for desert animals
Besides the payout of ATP that comes from fatty acid oxidation,
another benefit is the generation of H2O that occurs when O2 is
reduced by the final reaction in the electron transport system, as well
as, the formation of H2O in oxidative phosphorylation.

2 NADH + 2 H+ + O2 --> 2 H2O

2 FADH2 + O2 --> 2 H2O
ADP + PO42- --> ATP + H2O