Metabolism of lipids: tryacylglycerols,

fatty acids, cholesterol and

phospholipids metabolism. Ketogenesis
and ketolysis. Regulation and pathology
of lipid metabolism. Atherosclerosis.

 Lipids are water-insoluble organic

biomolecules that can be extracted
from cells and tissues by nonpolar
solvents, e.g., chloroform, ether, or
benzene.

Classification of lipids, based on their

backbone structures:

Simple lipids:
Acylglycerols, steroids, waxes.
Complex lipids:
phospholipids
glycerophospholipids, sphingophospholipids.
glycolipids
glycosylglycerols, glycosphingolipids.

Triacylglycerols (Triglycerides)
Fatty acid esters of the alcohol
glycerol are called acylglycerols
or glycerides; they are sometimes
referred to as "neutral fats," a
term that has become archaic.
When all three hydroxyl groups
of glycerol are esterified with
fatty acids, the structure is called
a triacylglycerol:

Triacylglycerols are the most

abundant family of lipids and the
major components of depot or
storage lipids in plant and animal
cells. Triacylglycerols that are
solid at room temperature are
often referred to as "fats" and
those which are liquid as "oils."

Storage and Mobilization of

Fatty Acids
TGs are delivered to adipose tissue in the
form of chylomicrones and VLDL, hydrolyzed
by lipoprotein lipase into fatty acids and
glycerol, which are taken up by adipocytes.
Then fatty acids are reesterified to TGs.
TGs are stored in adipocytes.
To supply energy demands fatty acids and
glycerol are released mobilisation of TGs.

At low carbohydrate and insulin concentrations (during

fasting), TG hydrolysis is stimulated by epinephrine,
norepinephrine, glucagon, and adrenocorticotropic
hormone.

TG hydro-lysis is inhibited by insulin in fed state

 Lipolysis - hydrolysis of
triacylglycerols by
lipases.
A hormone-sensitive
lipase converts TGs to
free fatty acids and
monoacylglycerol
Monoacylglycerol is
hydrolyzed to fatty acid
and glycerol or by a
hormone-sensitive
lipase or by more
specific and more active
monoacylglycerol lipase

Oxidation of Glycerol
Glycerol is absorbed by the liver.
Steps: phosphorylation, oxidation and isomerisation.
Glyceraldehyde 3-phosphate is an intermediate in:
glycolytic pathway
gluconeogenic pathways

Isomerase

ATP Generation from Glycerol Oxidation

glycerol glycerol 3-phosphate
glycerol 3-phosphate - dihydroxyaceton
2.5ATP (1 NADH)

- 1 ATP

glyceraldehyde 3-phosphate pyruvate

4,5 ATP (1NADH + 2 ATP)

pyruvate acetyl CoA

2.5 ATP (1 NADH)

acetyl CoA in Krebs cycle

10 ATP (3NADH + 1 FADH2 + 1GTP)
Total

19,5-1 = 18,5 ATP

phosphate

Reaction
sequence in
the boxidation

Connections to Electron Transport and

ATP.
One turn of the fatty acid spiral produces ATP from the
interaction of the coenzymes FAD (step 1) and NAD+ (step 3) with
the electron transport chain.

Total ATP per turn of the fatty acid spiral is

Step 1 - FAD into e.t.c. = 2 ATP
Step 3 - NAD+ into e.t.c. = 3 ATP
Total ATP per turn of spiral = 5 ATP

Example with Palmitic Acid = 16 carbons = 8 acetyl

groups
Number of turns of fatty acid spiral = 8-1 = 7 turns
ATP from fatty acid spiral = 7 turns and 5 per turn = 35 ATP.

NET ATP from Fatty Acid Spiral = 35 - 1 = 34

ATP

Fatty Acid Synthesis

Occurs mainly in liver and adipocytes, in
mammary glands during lactation
Occurs in cytoplasm
FA synthesis and degradation occur by
two completely separate pathways

 Three stages of fatty acid synthesis:

A. Transport of acetyl CoA into cytosol
Acetyl CoA from catabolism of carbohydrates and
amino acids is exported from mitochondria via
the citrate transport system
Cytosolic NADH also converted to NADPH
Two molecules of ATP are expended for each
round of this cyclic pathway

B. Carboxylation of acetyl CoA

C. Assembly of fatty acid chain

Sources of NADPH for Fatty Acid Synthesis

1. One molecule of NADPH is generated for each molecule
of acetyl CoA that is transferred from mitochondria to the
cytosol (malic enzyme).
2. NADPH molecules come from the pentose phosphate
pathway.

B. Carboxylation of Acetyl CoA

Enzyme: acetyl CoA carboxylase
Prosthetic group - biotin

A carboxybiotin intermediate is formed.

ATP is hydrolyzed.
The CO2 group in carboxybiotin is transferred to acetyl CoA to
form malonyl CoA.
Acetyl CoA carboxylase is the regulatory enzyme.

C. The Reactions of Fatty Acid Synthesis

n Five separate stages:

(1) Loading of precursors via thioester
derivatives
(2) Condensation of the precursors
(3) Reduction
(4) Dehydration
(5) Reduction

 The elongation phase of fatty acid synthesis starts with

the formation of acetyl ACP and malonyl ACP.
Acetyl transacylase and malonyl transacylase
catalyze these reactions.
Acetyl CoA + ACP acetyl ACP + CoA
Malonyl CoA + ACP malonyl ACP + CoA

 Condensation
reaction.
Acetyl ACP and
malonyl ACP react to
form acetoacetyl ACP.
Enzyme acyl-malonyl ACP
condensing enzyme.

 Reduction.
Acetoacetyl ACP is
reduced to D-3hydroxybutyryl ACP.
NADPH is the
reducing agent
Enzyme: -ketoacyl
ACP reductase

 Dehydration.
D-3-hydroxybutyryl
ACP is dehydrated to
form crotonyl ACP

Enzyme:
3-hydroxyacyl ACP
dehydratase

 Reduction.
The final step in the
cycle reduces crotonyl
ACP to butyryl ACP.
NADPH is reductant.
Enzyme - enoyl ACP
reductase.
This is the end of first
elongation cycle (first
round).

 In the second round

butyryl ACP condenses
with malonyl ACP to
form a C6--ketoacyl
ACP.
Reduction, dehydration,
and a second reduction
convert the C6-ketoacyl ACP into a C6acyl ACP, which is
ready for a third round
of elongation.

Final reaction of FA synthesis

Rounds of synthesis continue until a
C16 palmitoyl group is formed
Palmitoyl-ACP is hydrolyzed by a thioesterase

The overall equation for palmitic

acid biosynthesis starting from
acetyl-S-CoA:
8 AcetylSCoA + 14NADPH + 14H+ + 7ATP
+ H2O palmitic acid + 8CoA + 14NADP+ +
7ADP + 7P.

Ketogenesis
The ketone
bodies are
acetoacetate
bhydroxybutyrate
acetone

Ketogenesis is the process by which ketone bodies are

produced as a result of fatty acid breakdown

The ways of formation of active form of glycerol.

There are two ways of formation of active form
of glycerol.
1. Phosphorilation of glycerol through the action
of glycerol kinase:
ATP + glycerol glycerol 3-phosphate + ADP
2. Reduction of dihydroxyacetone phosphate
which is the product of the aldolase reaction of
glycolysis. Dihydroxyacetone phosphate is
reduced to glycerol 3-phosphate by the NADlinked glycerol-3-phosphate dehydrogenase of
the cytosol:
Dihydroxyacetone phosphate + NADH + H+
glycerol 3-phosphate + NAD

Biosynthesis of triacylglycerols
The first stage in
triacyglycerol formation
is the acylation of the
free hydroxyl groups of
glycerol phosphate by
two molecules of fatty
acyl-CoA to yield first a
lysophosphotidic acid
and then a phosphatidic
acid:

H2C OH
HC

R1 - COSKoA

OH

H2C O

KoA - SH

O
H2C O C R1
HC

OH

H2C O

Lysophosphotidic acid
Phosphatidic acid

O
H2C O C R1
HC

OH

H2C O

O
R2 - COSKoA

KoA - SH

H2C O C R1
O
HC O C R2
H2C O

 The activity of acetyl-CoA

carboxylase depends on its
phosphorylation status .
In its inactive form acetyl-CoA
carboxylase is phosphorylated in
serine, whereas the active form is
not phosphorylated.

The phosporylation of acetyl CoA carboxylase is catalyzed

by an AMP-dependent protein kinase (AMPK).
High AMP levels induce the phosphorylation and
inactivation of acetyl-CoA carboxylase.

Pathway of cholesterol biosynthesis

Bile acids perform such functions:

1. eliminating cholesterol from the body;

driving the flow of bile to eliminate
catabolites from the liver;
2. emulsifying lipids and fat soluble
vitamins in the intestine;
3. and aiding in the reduction of the
bacteria flora found in the small
intestine and biliary tract.

Obesity is a major risk factor for coronary

heart disease, which can lead to heart attack.

Atherosclerosis

Atherosclerosis - the process in which deposits

of fatty substances, cholesterol, cellular waste
products, calcium and other substances build up
in the inner lining of an artery. It usually affects
large and medium-sized arteries.
Plaques can grow large enough to significantly
reduce the blood's flow through an artery. But
most of the damage occurs when they become
fragile and rupture. Plaques that rupture
cause blood clots to form that can block blood
flow or break off and travel to another part of the
body. If either happens and blocks a blood vessel
that feeds the heart, it causes a heart attack. If it
blocks a blood vessel that feeds the brain, it
causes a stroke. And if blood supply to the arms
or legs is reduced, it can cause difficulty walking
and eventually lead to gangrene.