Dr.

LOO HIAN DAO

E
M
S
I
L

O
B
A
T
E
M
D
I
P
I
L
1
1
0
2

INTRODUCTION of LIPIDS
common property of lipid:
relatively insoluble in water and
soluble in nonpolar solvents such as ether and chloroform.
high energy value

fat-soluble vitamins (A,D,E,K)

thermal insulator in the subcutaneous tissues and around certain
organs.
electrical insulators, allowing rapid propagation of depolarization
waves along myelinated nerves.
transporting lipids (lipid + protein lipoprotein

CLASSIFIED
Simple lipids: Esters of fatty acids with various alcohols.
a. Fats: Esters of fatty acids with glycerol. Oils are fats in the liquid state.
b. Waxes: Esters of fatty acids with higher molecular weight monohydric alcohols.

Complex lipids: Esters of fatty acids containing groups in addition to an

alcohol and a fatty acid.

a. Phospholipids: Lipids containing, in addition to fatty acids and an alcohol, a

phosphoric acid residue. They frequently have nitrogen containing bases and other
substituents, eg, in glycerophospholipids the alcohol is glycerol and in
sphingophospholipids the alcohol is sphingosine.
b. Glycolipids (glycosphingolipids): Lipids containing a fatty acid, sphingosine, and
carbohydrate.
c. Other complex lipids: Lipids such as sulfolipids and aminolipids. Lipoproteins
may also be placed in this category.

Precursor and derived lipids: These include fatty acids, glycerol,

steroids, other alcohols, fatty aldehydes, ketone bodies, hydrocarbons, lipidsoluble vitamins, and hormones.

gestion and absorption of triacylglycerols

LIPOGENESIS

Elongation of Fatty A cid C hains

This

pathway (the microsomal system)

elongates saturated and unsaturated fatty acylCoAs (from C10 upward) by two carbons, using
malonyl-CoA as acetyl donor and NADPH as
reductant, and is catalyzed by the microsomal
fatty acid elongase system of enzymes

R EG U LATES LIP O G EN ESIS

Lipogenesis converts surplus glucose and intermediates such as

pyruvate, lactate, and acetyl-CoA to fat, assisting the anabolic
phase of this feeding cycle.

Lipogenesis is depressed under conditions of restricted caloric

intake, on a fat diet, or when there is a deficiency of insulin, as in
diabetes mellitus.

These latter conditions are associated with increased

concentrations of plasma free fatty acids, and an inverse
relationship has been demonstrated between hepatic lipogenesis
and the concentration of serum-free fatty acids.

Lipogenesis is increased when succrose is fed instead of glucose

because fructose bypasses the phosphofructokinase control
point in glycolysis and floods the lipogenic pathway.

R egulation of Lipogenesis

Acetyl-CoA carboxylase is an allosteric enzyme and is activated by

citrate, which increases in concentration in the well-fed state
and is an indicator of a plentiful supply of acetyl-CoA, and long-chain
acyl-CoA inhibits its activity.

Acyl-CoA may also inhibit the mitochondrial tricarboxylate

transporter, thus preventing activation of the enzyme by
egress of citrate from the mitochondria into the cytosol.

Acyl-CoA causes an inhibition of pyruvate dehydrogenase by

inhibiting the ATP-ADP exchange transporter of the inner
mitochondrial
membrane,
which
leads
to
increased
intramitochondrial [ATP]/[ADP] ratios and therefore to conversion of
active to inactive pyruvate dehydrogenase.

Insulin activates acetyl-CoA carboxylase whereas glucagon and

epinephrine have opposite actions.

 Fatty acids with an odd number of carbon atoms

are oxidized by the pathway of -oxidation,

producing acetyl-CoA, until a three-carbon
(propionyl-CoA) residue remains.
This compound is converted to succinyl-CoA, a

constituent of the citric acid cycle.

Hence, the propionyl residue from an odd-chain

fatty acid is the only part of a fatty acid that is

glucogenic.
Peroxisomes Oxidize Very Long Chain Fatty

Acids and leads to the formation of acetyl-CoA

and H2O2 (from the flavoprotein-linked
dehydrogenase step), which is broken down by
catalase.
These enzymes are induced by high-fat diets and

in some species by hypolipidemic drugs such as

clofibrate.

KETOGENESIS

Im paired O xidation of Fatty A cids G ives R ise to D iseases

O ften
A ssociated w ith H ypoglycem ia
C arn itin e d ef i
cien cy
in the new born and especially in preterm infants
Hypoglycemia, impaired fatty acid oxidation and lipid

accumulation
muscular weakness

Treatment is by oral supplementation with carnitine

CPT-I deficiency: only the liver
CPT-II deficiency affects primarily skeletal
muscle and, when severe, the liver

Im paired O xidation of Fatty A cids G ives R ise to D iseases

O ften
A ssociated w ith H ypoglycem ia

Jam aican vom itin g sickn ess

caused by eating the unripe fruit of the akee tree , which

contains the toxin hypoglycin.

inactivates medium- and short-chain acyl-CoA
dehydrogenase, inhibiting -oxidation and
causing hypoglycemia.

KETOACIDOSIS
Higher than normal quantities of ketone bodies present in the

blood or urine constitute ketonemia (hyperketonemia) or

ketonuria, respectively. The overall condition is called ketosis.
Acetoacetic and 3-hydroxybutyric acids are both moderately
strong acids and are buffered when present in blood or other
tissues.
However, their continual excretion in quantity progressively
depletes the alkali reserve, causing ketoacidosis. This may be
fatal in uncontrolled diabetes mellitus.

METABOLISM OF UNSATURATED FATTY ACID

Linoleic and -linolenic acids are known
as the nutritionally essential fatty acids.
Arachidonic acid can be formed from
linoleic acid.
Double bonds can be introduced
introduced at the 4, 5, 6, and 9
positions in most animals, but never
beyond the 9 position.
In contrast, plants are able to synthesize
the nutritionally essential fatty acids by
introducing double bonds at the 12 and
15 positions.

METABOLISM OF UNSATURATED FATTY ACID

Several tissues including the liver are
considered to be responsible for the
formation
of
nonessential
monounsaturated
fatty
acids
from
saturated fatty acids.
MONOUNSATURATED FATTY ACIDS
ARE
SYNTHESIZED
BY 9
DESATURASE SYSTEM in the endo
plasmic reticulum will catalyze the
conversion of palmitoyl-CoA or stearoylCoA to palmitoleoyl-CoA or oleoyl-CoA
SYNTHESIS OF POLYUNSATU RATED
FATTY
ACIDS
INVOLVES
DESATURASE
&
ELONGASE
ENZYME SYSTEMS

EICOSANOIDS
Thromboxanes are synthesized in platelets and upon release cause

vasoconstriction and platelet aggregation.

Their synthesis is specifically inhibited by low-dose aspirin.
Prostacyclins (PGI2) are produced by blood vessel walls and are potent
inhibitors of platelet aggregation.
Slow-reacting substance of anaphylaxis (SRS-A) is a mixture of leukotrienes C4,
D4, and E4. This mixture of leukotrienes is a potent constrictor of the bronchial
airway musculature.
These leukotrienes together with leukotriene B4 also cause vascular permeability
and attraction and activation of leukocytes and are important regulators in many
diseases involving inflammatory or immediate hypersensitivity reactions, such as
asthma.

ESTERIFICATION

TYPE of PHOSPHOLIPID +
SPHYNGOLIPID
Gliserolipid

Triasilgliser
ol
Simpanan
adiposa
Lipoprotein
darah

Gliserofosfolipi
d

Fosfatidilkolin (lesitin)
Fosfatidiletanolamin
(sefalin)
Fosfatidilserin
Fosfatidil inositol bisfosfat
Fosfatidilgliserol
Kardiolipin

Fosfolipid

Eter gliserolipid

Plasmalogen
PAF

Sphingolipid

Sphingofosfoli
pid

Sfingomielin

Glikolipid

Serebrosida
Sulfatida
Globosida
Gangliosida

Phospholipids
Some phospholipids have specialized functions;

eg, dipalmitoyl lecithin is a major component of

lung surfactant, which is lacking in
respiratory distress syndrome of the newborn.
Inositol phospholipids in the cell membrane act
as precursors of hormone second
messengers, and platelet-activating factor
is an alkylphospholipid.

G lycosphingolipids
Glycosphingolipids, containing sphingosine and

sugar residues as well as fatty acid and found in

the outer leaflet of the plasma membrane with
their oligosaccharide chains facing outward,
form part of the glycocalyx of the cell surface
and are important
(1) in cell adhesion and cell recognition;
(2) as receptors for bacterial toxins (eg, the toxin that

causes cholera); and

(3) as ABO blood group substances.

LIPID TRANSPORT
Four major groups of lipoproteins have been

identified that are important physiologically

and in clinical diagnosis. These are
(1) chylomicrons, derived from intestinal

absorption of triacylglycerol and other lipids;

(2) very low density lipoproteins (VLDL, or
pre--lipoproteins), derived from the liver for
the export of triacylglycerol;
(3) low-density lipoproteins (LDL, or lipoproteins), representing a final stage in the
catabolism of VLDL; and
(4) high-density lipoproteins (HDL, or lipoproteins), involved in VLDL and chylomicron
metabolism and also in cholesterol transport.

LIPID TRANSPORT

Apolipoproteins
Apolipoproteins carry out several roles:
(1) they can form part of the structure of the

lipoprotein, eg, apo B;

(2) they are enzyme cofactors, eg, C-II for
lipoprotein lipase, A-I for lecithin:cholesterol
acyltransferase, or enzyme inhibitors, eg, apo
A-II and apo C-III for lipoprotein lipase, apo C-I
for cholesteryl ester transfer protein;
and (3) they act as ligands for interaction with
lipoprotein

20+ years of studies:

Patients with smaller LDL size have greater CHD risk
at any given level of LDL-C.
Lower risk

Higher risk

130 mg/dL

Large LDL
(Pattern A)

130 mg/dL

LDL
Cholesterol
Balance

Small LDL
(Pattern B)
But they also
have more
particles!

FATTY LIVER
Fatty livers fall into two main categories.
The first type is associated with raised levels of plasma free fatty acids

resulting from mobilization of fat from adipose tissue or from the hydrolysis
of lipoprotein triacylglycerol by lipoprotein lipase in extrahepatic tissues.
The production of VLDL does not keep pace with the increasing influx and
esterification of free fatty acids, allowing triacylglycerol to accumulate, causing
a fatty liver.
This occurs during starvation and the feeding of high-fat diets.
The ability to secrete VLDL may also be impaired (eg, in starvation). In
uncontrolled diabetes mellitus, twin lamb disease, and ketosis in cattle, fatty
infiltration is sufficiently severe to cause visible pallor (fatty appearance) and
enlargement of the liver with possible liver dysfunction.

FATTY LIVER
The second type of fatty liver is usually due to a metabolic

block in the production of plasma lipoproteins, thus allowing

triacylglycerol to accumulate.
Theoretically, the lesion may be due to
(1) a block in apolipoprotein synthesis,
(2) a block in the synthesis of the lipoprotein from lipid and

apolipoprotein,
(3) a failure in provision of phospholipids that are found in
lipoproteins, or
(4) a failure in the secretory mechanism itself.

Nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease

(NAFLD) is the most common liver

disorder worldwide.
When accumulation of lipid in the liver
becomes chronic, inflammatory and
fibrotic changes may develop leading
to nonalcoholic steatohepatitis
(NASH), which can progress to liver
diseases including cirrhosis,
hepatocarcinoma, and liver failure.

alcoholic fatty liver disease

Alcoholic fatty liver is the first stage in alcoholic liver

disease (ALD) which is caused by alcoholism and

ultimately leads to cirrhosis.
Changes in the [NADH]/[NAD+ ]
Oxidation of ethanol by alcohol dehydrogenase leads to
excess production of NADH.

The increased [NADH]/[NAD+ ] ratio also causes

increased [lactate]/[pyruvate], resulting in
hyperlacticacidemia, which decreases excretion of uric
acid, aggravating gout.

 Some metabolism of ethanol takes place via a

cytochrome P450-dependent microsomal ethanol

oxidizing system (MEOS) involving NADPH and O2
.
This system increases in activity in chronic
alcoholism.
Ethanol also inhibits the metabolism of some
drugs, eg, barbiturates, by competing for
cytochrome P450-dependent enzymes.

Impairment of Other Metabolic

Processes
MALATE-ASPARTATE
SHUTTLE

NADH/NAD+

GLYCEROL 3-P

RESPIRATORY
CHAIN
INHIBITED of
GLUCONEOGENESIS

LACTATE/PYRUVATE

INHIBITED of
TCA CYCLE

ACETYL-CoA

HYPOGLYCEMIA
LIPOGENESIS

LACTIC ACIDOCIS
FFA
EXCRETION of
URIC ACID

TRIACYLGLYCEROL
HYPERLIPIDEMIA

HYPERURICEMIA

KETOGENESIS

KETOSIS

CHOLESTERO
GENESIS

FATTY LIVER
HYPERCHOLESTEROL

Adipose tissue secretes hormones such as adiponectin, which modulates glucose and lipid
metabolism in muscle and liver, and leptin, which regulates energy homeostasis.

BROWN ADIPOSE TISSUE

Brown adipose tissue is the
site of nonshivering
thermogenesis. It is found in
hibernating and newborn
animals and is present in small
quantity in humans.
Thermogenesis results from
the presence of an uncoupling
protein, thermogenin, in the
inner mitochondrial membrane.

Cholesterol
Cholesterol is present in tissues and in plasma either as free

cholesterol or as a storage form, combined with a long-chain

fatty acid as cholesteryl ester.
Cholesterol is an amphipathic lipid and as such is an essential
structural component of membranes and of the outer layer of
plasma lipoproteins.
It is synthesized in many tissues from acetyl-CoA and is the
precursor of all other steroids in the body such as
corticosteroids, sex hormones, bile acids, and vitamin D.
As a typical product of animal metabolism, cholesterol occurs in
foods of animal origin such as egg yolk, meat, liver, and brain.

Stage 1
Acetyl CoA (C2)
HMG-CoA
NADPH
HMG-CoA
Reductase
NADP+
Mevalonate (C6)
Stage 2
Mevalonate
3ATP
3ADP

CO2
Active Isoprenoids (C5)
Several
NADPH
Condensation Steps
NADP+
Squalene (C30)

Biosynthesis of
cholesterol
rate-determining step
cholesterol is feedback inhibitor
mevalonate is feedback inhibitor
target site for statin drugs
Stage 3
Squalene (C30)
Cyclization
O2
NADPH
Squalene
epoxidase/
+
NADP
cyclase
Lanosterol (C30)
(4-ring structure)

Stage 4
Lanosterol (C30)
O2
NADPH

(19 steps)

3 CH3
NADP+
Cholesterol (C27)

The ER is the primary site of cholesterol synthesis

HMG-CoA reductase, the key

rate-limiting enzyme in the
cholesterol biosynthetic
pathway.

XANTHELASMA

TH ERAPY ofH YPERCH O LESTERO LEM IA

Significant reductions of plasma cholesterol can be

effected medically by the use of cholestyramine resin

or surgically by the ileal exclusion operations.
Both procedures block the reabsorption of bile acids,
causing increased bile acid synthesis in the liver.
This increases cholesterol excretion and up-regulates LDL
receptors, lowering plasma cholesterol.
Sitosterol is a hypocholesterolemic agent that acts by
blocking the absorption of cholesterol from the
gastrointestinal tract.

TH ERAPY ofH YPERCH O LESTERO LEM IA

The formation of cholesterol

at various stages in the

biosynthetic pathway.
The statins inhibit HMGCoA reductase, thus upregulating LDL receptors.
Statins currently in use
include atorvastatin,
simvastatin, and
pravastatin.

TH ERAPY ofH YPERCH O LESTERO LEM IA

Fibrates such as clofibrate and gemfibrozil act mainly to

lower plasma triacylglycerols by decreasing the secretion of

triacylglycerol and cholesterol-containing VLDL by the liver.
In addition, they stimulate hydrolysis of VLDL triacylglycerols by
lipoprotein lipase.
Probucol appears to increase LDL catabolism via
receptorindependent pathways, but its antioxidant properties
may be more important in preventing accumulation of oxidized
LDL, which has enhanced atherogenic properties, in arterial
walls.
Nicotinic acid reduces the flux of FFA by inhibiting adipose
tissue lipolysis, thereby inhibiting VLDL production by the liver.

Lipoprotein (a)
Type of LDL bound to ApoB and Apo(a)
Prothrombotic
Binding domain similar to plasminogen, may

compete, favoring thrombosis

Proatherogenic
preferentially binds oxidized phospholipids

and taken up into atheromatous plaques

Lipoprotein (a)