chapter III

LIPID METABOLISM
Steps of Lipid Digestion and Absorption
• Minor digestion of
triacylglycerols in mouth and
stomach by lingual (acid-stable)
lipase
• Major digestion of all lipids in
the lumen of the
duodenum/jejunum by
pancreatic lipolytic enzymes
• Bile acid facilitated formation of
mixed micelles that present the
lipolytic products to the mucosal
surface, followed later by
enterohepatic bile acid recycling
Steps of Lipid Digestion and Absorption
• Passive absorption of the
lipolytic products from the
mixed micelle into the intestinal
epithelial cell
• Reesterification of 2-
monoacylglycerol, lysolecithin,
and cholesterol with free fatty
acids inside the intestinal
enterocyte
• Assembly and export from
intestinal cells to the lymphatics
of chylomicrons coated with
Apo B48 and containing
triacylglycerols, cholesterol
esters and phospholipids
Steps of Lipid Digestion and Absorption
Lipid Digestion and Absorption
• highly efficient: average adult intakes 60 – 160 g
fat/day (90% as TGs); only 5% returns to the
environment as “fecal fat”

• To digest and absorb dietary fat must overcome 2

problems:
a. lipids are not very soluble in aqueous
solution;
b. lipid hydrolysis products aggregate and
form large complexes that make poor
contact with the cell surface.
Lipid Digestion and Absorption
• Solutions:
a. increase surface area of lipid droplets by
emulsification
• aided by detergent properties of bile salts
+ mechanical mixing due to peristalsis
b. solubilization of the hydrolysis products with
detergents
Fatty Acid Metabolism
• consists of catabolic processes which generate
energy and primary metabolites from fatty acids
(lipolysis), and anabolic processes which create
biologically important molecules from fatty acids
and other dietary carbon sources (lipogenesis)

• Major contributions:
– lipolysis: production of energy
– lipogenesis: structural cellular component,
precursor of regulatory substances
 Degradation of Fatty Acids
Overview
CAPILLARY
MITOCHONDRION
lipoproteins
L FABP
[2]
P FA acetyl-CoA TCA
L cycle[7]
[3] A -oxidation
[4] C
FA FA S [6]
albumin FA FA acyl-CoA acyl-CoA
FA FABP FABP [5]
carnitine
[1] CYTOPLASM transporter

from
fat
cell cell membrane FA = fatty acid
LPL = lipoprotein lipase
FABP = fatty acid binding protein
ACS = acyl CoA synthetase
Degradation of Fatty Acids
A. Release from adipose tissue: free fatty acids are
released into the bloodstream and circulate
throughout the body
1. hormones induce lipolysis (epinephrine,
norepinephrine, glucagon, adrenocorticotropic
hormone); attachment to and activation of
7TM receptors, which triggers adenylate
cyclase; increased production of cAMP, which
activates protein kinase A, which subsequently
activate lipases found in adipose tissue
2. triglycerides undergo lipolysis (hydrolysis by
lipases) and are broken down into glycerol and
fatty acids
Degradation of Fatty Acids
Degradation of Fatty Acids
3. release into the blood; the free fatty acids bind
to serum albumin for transport to tissues that
require energy
4. glycerol backbone is absorbed by the liver and
eventually converted into glyceraldehyde 3-
phosphate (G3P), which is an intermediate in
both glycolysis and gluconeogenesis
Degradation of Fatty Acids
B. Transport into Mitochondria
1. fatty acid + ATP ↔ acyl adenylate + PPi
2. acyl adenylate + HS-CoA ↔ acyl CoA + AMP
3. acyl CoA is conjugated to carnitine by
carnitine palmitoyltransferase I
4. acyl carnitine is shuttled inside by carnitine
acyltranslocase
5. acyl carnitine is converted to acyl CoA by
carnitine palmitoyltransferase II
Degradation of Fatty Acids
Degradation of Fatty Acids
Degradation of Fatty Acids
C. β-Oxidation
1. Oxidation by FAD
- the oxidation of the fatty acid by FAD; the
following reaction is catalyzed by acyl CoA
dehydrogenase (catalyzes the formation of a
double bond between the C-2 and C-3; the
end product is trans-Δ2-enoyl-CoA)
Degradation of Fatty Acids
2. Hydration
- hydration of the bond between C-2 and C-3;
catalyzed by enoyl CoA hydratase; the
reaction is stereospecific, forming only the L
isomer; the end product is L-3-hydroxyacyl
CoA
Degradation of Fatty Acids
3. Oxidation by NAD+
- the oxidation of L-3-hydroxyacyl CoA by
NAD+, catalyzed by L-3-hydroxyacyl CoA
dehydrogenase (converts the hydroxyl group
into a keto group); the end product is 3-
ketoacyl CoA
Degradation of Fatty Acids
4. Thiolysis
- the cleavage of 3-ketoacyl CoA by the thiol
group of another molecule of CoA; catalyzed
by Β-ketothiolase (the thiol is inserted
between C-2 and C-3, which yields an acetyl
CoA molecule and an acyl CoA molecule,
which is two carbons shorter)

This process continues until the entire chain is

cleaved into acetyl CoA units. For every cycle, one
molecule of FADH2, NADH and acetyl CoA are
formed.
Degradation of Fatty Acids
β-oxidation of odd-numbered chains
Chains with an odd-number of carbons are
oxidized in the same manner as even-numbered
chains, but the final products are propionyl CoA
and acetyl CoA. Propionyl CoA is converted into
succinyl CoA (which is an intermediate in the citric
acid cycle) in a reaction that involves Vitamin
B12. Succinyl CoA can then enter the citric acid
cycle. Because it cannot be completely
metabolized in the citric acid cycle, the products
of its partial reaction must be removed in a
process called cataplerosis. This allows
regeneration of the citric acid cycle intermediates,
possibly an important process in certain metabolic
diseases.
 Palmitoylcarnitine
inner
mitochondrial Carnitine
respiratory chain
membrane translocase

Palmitoylcarnitin
matrix side e 2 ATP
3 ATP
Palmitoyl-CoA
FAD
oxidation
FADH2
hydration H2O

recycle NAD+
oxidation
6 times
NADH
cleavage CoA

CH3-(CH)12-C-S-CoA + Acetyl CoA

Citric
O acid
cycle 2 CO2
Degradation of Fatty Acids
Degradation of Fatty Acids
Lipolysis vs. Lipogenesis
Fatty Acid Synthesis
• Lipogenesis is a collective name for the complex
process of producing lipids (fatty acids) from
smaller precursor molecules.
• The main ingredient in the production of fatty
acids is glucose.
• Glucose is what most of the carbohydrates are
turned into before entering the blood stream, so
in a way, lipogenesis is the conversion of
carbohydrates into fat.
• 55% of carbs are involved in fat synthesis.
• Fat metabolism is in a constant state of dynamic
equilibrium, where some fats are constantly
oxidized to meet energy requirements, and some
fats are synthesised and stored.
Fatty Acid Synthesis
• In rats, a single lipid molecule lasts for between 2
and 10 days, this is likely to be the same in
humans.
• Lipogenesis starts with an acetyl CoA which
builds with the addition of two carbon units.
• It takes place in the cytoplasm, unlike oxidation
which happens in the mitochondria.
• Many enzymes involved are in a multienzyme
complex called fatty acid synthetase.
• Important points to remember are that
lipogenesis requires ATP and that the reactions
involved are reductions (the addition of H+ and
the use of NADPH), which is the opposite to fatty
acid spiral oxidations.
Fatty Acid Synthesis
A. Condensation
• The first step is condensation of acetyl ACP and
malonyl ACP, catalyzed by acyl-malonyl ACP
condensing enzyme. This results in the formation
of acetoacetyl ACP.
• Although this reaction is thermodynamically
unfavourable, the evolution of CO2 drives the
reaction forward.
Fatty Acid Synthesis
B. Reduction of acetoacetyl ACP
• In this step, acetoacetyl ACP is reduced by
NADPH into D-3-Hydroxybutyryl ACP. This
reaction is catalyzed by β-Ketoacyl ACP
reductase. The double bond is reduced to a
hydroxyl group. Only the D isomer is formed.
Fatty Acid Synthesis
C. Dehydration
• In this reaction, D-3-Hydroxybutyryl ACP is
dehydrated to crotonyl ACP. This reaction is
catalyzed by 3-Hydroxyacyl ACP dehydrase.
Fatty Acid Synthesis
D. Reduction of crotonyl ACP
• During this final step, crotonyl ACP is reduced by
NADPH into butyryl ACP. This reaction is
catalyzed by enoyl ACP reductase.
 C A
E C ACP = acyl carrier protein
P CE = condensing enzyme
acetyl CoA
SH SH malonyl CoA
Malonyl CoA
CoA

2CoA 2NADP+ [5]

CO2 2NADPH
C A A A A
A C C
E C C C C C
C E E
P C E P P
COO- E P
[2] P [3] [4]
S S S SH S S
SH S
SH S
C=O C=O COO- C=O C=O C=O C=O
C=O
CH3 CH2 CH2 CH2 CH2
CH2
C=OC=O CH2
COO- CH2 CH2 CH2 COO-
CH3 CH C=O
3
CH3 CH3 CH3
CH3
General mechanism for FAS. Steps 1 - 4 represent the first cycle that generates
a 4-carbon intermediate. Step 5 prepares for further chain growth
 A
C C
E P
S S
C=OC=O
CH2 CH2
[6] CH2 COO-
A A [7] A
C C [8] C C C C CH3
[9] E P E P E P
S SH SH S CO2
SH S 2NADP+
2NADPH
Palmitate C=O C=O C=O
CH2 CH2 CH2
CH2 CH2 C=O
CH2 CH2 CH2
CH2 CH2 CH2
CH3 CH3 CH3

General mechanism for FAS. Addition of 2 carbons continues until palmitate is

formed and then released for activation
Fatty Acid Synthesis
Synthesis of Triglycerides
•Fatty acids are stored for future use as triacylglycerols in all
cells, but primarily in adipocytes of adipose tissue.
Triacylglycerols constitute molecules of glycerol to which
three fatty acids have been esterified. The fatty acids
present in triacylglycerols are predominantly saturated. The
major building block for the synthesis of triacylglycerols, in
tissues other than adipose tissue, is glycerol.
•Adipocytes lack glycerol kinase, therefore,
dihydroxyacetone phosphate (DHAP), produced during
glycolysis, is the precursor for triacylglycerol synthesis in
adipose tissue. This means that adipoctes must have
glucose to oxidize in order to store fatty acids in the form of
triacylglycerols. DHAP can also serve as a backbone
precursor for triacylglycerol synthesis in tissues other than
adipose, but does so to a much lesser extent than glycerol.
Synthesis of Triglycerides
thank you.