LIPID METABOLISM

Abdul Salam M. Sofro

Faculty of Medicine YARSI University
Kasus:
Nn. G seorang mahasiswi usia 20 th curhat ke
pamannya seorang dokter berat badannya
cenderung naik terus. G mengatakan kalau
pagi tidak makan nasi, cuma makan roti 2 lapis
isi mentega, jam, telur rebus dan segelas susu
skim. Jika siang makan mi ayam dan malam
baru makan nasi atau mi goreng. Di kampus
menjelang sore suka makan French fries
(potato chips) atau beli bakso.
 Teaching aims

• To highlight utilization and storage of

energy in lipid form and
• understand the individual biochemical
pathways of lipid metabolism (general,
lipid biosynthesis and lipid catabolism)
Scope of lipid metabolism

• Biosynthesis of fatty acids

• Oxydation of fatty acids: ketogenesis
• UFA & Eicosanoids Metabolism
 Introduction

• As biomolecule, lipids are important for

structure, obtain and storage of energy
• Their characteristics are nonpolar and
hydrophobic
• Mostly contain or derived from fatty
acids
• Stored in the form of triacylglycerol 
more efficient & quantitatively more
important compared with carbohydrate
storage as glycogen
• More important functions such as:
integrity of alveoli, solubilization of
nonpolar compounds, metabolic
processes etc.
 Food

Carbohydrate Lipid Protein Others (Nucleic acids,

water, minerals,
vitamins etc.)

Lumen of GI tract Digestion of TAG to:

Mucosal cells
Lympatic system and
then blood circulation
Organs & tissues
glycerol & fatty acids
Re-esterification of TAG from :
glycerol & fatty acids
Lipid transport
Biosynthesis of fatty acids
Oxydation of fatty acids: ketogenesis
UFA & Eicosanoids Metabolism
Cholesterol synthesis, transport & excretion
Lipid transport & storage
Metabolism of acylglycerols & sphingolipids
 Food:
Carbohydrate
Protei Lipid Mucosal Body/organ
GI tract Waste
Nucleic acid cells cells
Others
water

Lymph/ Blood
Cavum oris lacteal
Oesophagus
ventriculus
Lipids are a major source of energy during
rest and exercise. Approximately half of
the lipids–stored as triglycerides–that are
used for energy come from adipose tissue
with the other half from intramuscular
stores. There are several steps in the
mitochondrial oxidation of lipids that begin
with the mobilization of the triglycerides
 Metabolism of dietary triacylglycerols
• Three primary sources of fatty acids:
– Dietary triacylglycerols
– Triacylglycerols synthesized in the liver
– Triacylglycerols stored in fat cells

Fatty acids must be delivered to cells where β-

oxydation occurs :
• Liver
• Heart
• Sceletal muscles
 Lipid Metabolism in animals
• Fats are hydrophobic
a system is needed for their absorption before
they can be metabolized

Lipase in the stomach and saliva are not

very effective
Most fat ends up in duodenum as small
globules
Bile is used at this point to aid in further
digestion
(Lipogenesis)
 Biosynthesis of fatty acids (cont.)

• Fatty acid synthesis or lipogenesis may

vary between individuals
• Highly active extramitochondrial system
is responsible for the complete synthesis
of palmitate from acetyl-CoA (in the
cytosol)
• Another system for fatty acid elongation
is also present in liver endoplasmic
reticulum
 The main pathway for de novo
lipogenesis
• Present in many tissues, including liver,
kidney, brain, lung, mammary gland, and
adipose tissue
• In most mammals, glucose is the primary
substrate for lipogenesis, but in ruminants
acetate.
• Requires cofactors, including NADPH, ATP,
Mn2+, biotin & HCO3- (as a source of CO2)
• Acetyl-CoA is the immediate substrate and
free palmitate is the end product
 Important notes in lipogenesis
• The initial & controlling step in fatty acid
synthesis is the production of Malonyl-CoA

Acetyl-CoA Malonyl-CoA
Enz = acetyl-
Enz-biotin-COO- Enz-biotin
CoA carboxylase
ADP + Pi ATP + HCO3-

• Fatty acid synthase complex is a multienzyme

polypeptide complex with acyl carrier protein
(ACP) as its part containing seven enzyme
activities
• Bicarbonate as a source of CO2 is
required in the initial reaction for
carboxylation of acetyl-CoA to
malonyl-CoA in the presence of ATP
& Acetyl-CoA carboxylase that
requires vitamin Biotin.
Important notes in lipogenesis (cont.)
• The main source of NADPH for
lipogenesis is the Pentose Phosphate
Pathway (PPP)
• Acetyl-CoA is the principal building block
of fatty acids
• Elongation of fatty acid chains occurs in
the endoplasmic reticulum
• Chain elongation also occurs in
mitochondria but less active and uses
acetyl-CoA as acetyl donor (its function is
speculative)
 Important notes in lipogenesis (cont.)
• Nutritional state regulates lipogenesis 
the rate is higher in the well-fed animal
whose diet contains a high proportion of
carbohydrate (Nutritional state of organism
is the main factor regulating the rate of
lipogenesis)
• There is inverse relationship between
hepatic lipogenesis & concentration of
serum FFA => decreased lipogenesis in
increased serum FFA (which is associated
with restricted caloric intake, on a high-fat
diet or insulin deficiency as in DM)
Important notes in lipogenesis (cont.)

• High fat in the diet causes depression of

lipogenesis, or when there is more than
10% of fat in the diet, there is little
conversion of dietary carbohydrate to fat
• Insulin stimulate lipogenesis by several
mechanism  increases glucose transp.
into the cell (e.g. in adipose tissue)
• Insulin inhibits lipolysis (lipid degradation)
in adipose tissue
• Fatty acid synthase complex & acetyl-
CoA carboxylase are adaptive enzymes
 Short term & long term mechanisms
regulate lipogenesis
• Short term by allosteric & covalent
modification of enzymes
• Long term by changes in gene
expression governing rates of
enzymes synthesis (FA Synthase
Complex & Acetyl-CoA Carboxylase
are adaptive enzymes)
 Oxidation of Fatty Acids:
(& Ketogenesis)

Fatty acid.
• Oxidized to Acetyl-CoA and synthesized from
Acetyl-CoA
• Starting material of one process is identical to
the product of the other and the chemical
stages involved are comparable, the fatty acid
(FA) oxidation is not the simple reverse of FA
biosynthesis. It is entirely different process
taking place in a separate cell compartment =>
oxidation in mitochondria, synthesis in cytosol.
Oxidation of Fatty Acids: Ketogenesis
Biomedical importance:
• Increased in starvation & DM leading to
ketone body production by the liver (ketosis)
 when produced in excess over long
periods, as in DM, cause ketoacidosis
(ultimately fatal)
• Gluconeogenesis is dependent upon fatty
acid (FA) oxidation  any impairment in this
FA oxidation leads to hypoglycemia. This
occurs in various states of carnitine
deficiency or deficiency of essential enzymes
in FA oxidation
 Oxidation of fatty acids

• Occurs in mitochondria
• Origin of FA : blood & cells, transported
in blood as “free fatty acids” (FFA =
unesterified state)
• In plasma FFA of longer chain FA are
combined with albumin and in the cell
they are attached to a FA binding
protein (protein Z).
 Oxidation of fatty acids (cont.)
• Shorter-chain FA are more water soluble
and exist as the un-ionized acid or as a
FA anion
• FA are activated before being
catabolized  in the presence of ATP &
CoA, acyl-CoA synthetase (thiokinase)
catalyzes the conversion of FFA to
“active fatty acid” or acyl-CoA:

FA + ATP + CoA  Acyl-CoA + PPi + AMP

• Long chain FA penetrate the inner
mitochondrial membrane as carnitine
derivatives

Acetyl-CoA Carnitine acetyl Acetylcarnitine

+ carnitine transferase
+ CoA
.

• Activation of lower FA & their oxidation

within mitochondria may occur
independently of carnitine
 Long-chain FA (Acyl-
CoA cannot pass
through the inner
mitochondrial
membrane, but its
metabolic product,
acylcarnitine, can

Role of carnitine in the transport of long-chain FA through the inner mitochondrial membrane
Transport of fatty acids from the cytoplasm to the inner mitochondrial space for oxidation. Following
activation to a fatty-CoA, the CoA is exchanged for carnitine by carnitine-palmitoyltransferase I. The
fatty-carnitine is then transported to the inside of the mitochondrion where a reversal exchange takes
place through the action of carnitine-palmitoyltransferase II. Once inside the mitochondrion the fatty-CoA
is a substrate for the b-oxidation machinery.
 Types of FA oxidation

• Alfa Oxidation : the removal of one carbon

at a time from the carboxyl end of
themolecule (have been detected in brain
tissue => it does not require CoA
intermediate and does not generate high
energy-P
• Beta Oxidation : two carbon atoms are
cleaved at a time from acyl-CoA
molecules, starting at the carboxyl end to
produce acetyl-CoA => produce a large
quantity of ATP. It is the main FA oxidation
 Types of FA oxidation (cont.)

• Omega Oxidation : normally a very minor

pathway and is brought about by hydroxylase
enzymes involving cytochrome P450 in
endoplasmic reticulum  – CH3 group is
converted to a H2OH group that subsequently
is oxidized to -COOH thus forming dicarboxylic
acid. This is usually -oxidized to adipic (C6)
and suberic (C8) acids which are excreted in
the urine
• Oxidation of unsaturated FA occurs by a
modified -oxidation pathway
 108
16
24

146

146 x 51.6* = 7533.6 kJ

Comparison of FA oxidation & FA biosynthesis
(lipogenesis)
• Oxidation:
* location • Lipogenesis:
mitochondria * location cytosol
* uses NAD+ & FAD * uses NADP+ as
as coenzymes coenzymes &
* generates ATP requires ATP +
* involving acyl-CoA bicarbonate ion
derivatives * involving acyl
derivatives bound to
the multienzyme
complex
 Ketogenesis

• Ketogenesis is the generation of ketone

bodies (acetoacetate, D(-)-3-
hydroxybutyrate = -OH-butyrate &
acetone)
• Occurs when there is a high rate of FA
oxidation in the liver
• The enzyme system is in mitochondria,
with FFA precursor in the liver
 Ketogenesis (cont.)

• Two molecules of acetyl-CoA

condence to form acetoacetyl-CoA,
and with the addition of another
acetyl-CoA produce 3-OH-3-methyl-
glutaryl-CoA (HMG-CoA) catalyzed by
HMG-CoA synthase
• HMG-CoA is an intermediate in the
pathway of ketogenesis -> in the
presence of HMG-CoA lyase is split
into acetyl-CoA and acetoacetate
 Ketogenesis (cont.)
• Acetoacetate is in equilibrium with D(-)-
3-OH-butyrate (predominant keton body
present in the blood and urine in ketosis)
catalyzed by D(-)-3-OH butyrate DH &
NADH, or spontaneously converted into
acetone releasing CO2
• Liver is the only organ in non-ruminants
to add significant quantities of ketone
bodies to the blood
 Ketogenesis (cont.)
• Ketone bodies serve as a fuel for
extrahepatic tissues  while acetoacetate
& D(-)-3-OH butyrate are readily oxidized
by extrahepatic tissues, acetone is
difficult to oxidize in vivo and volatilized in
the lungs
• Prolonged ketosis leads to ketoacidosis
(such as in DM). In starvation  simple
ketosis
• Measurement of ketonemia is preferred
than that of ketonuria
 Clinical aspects of impaired oxidation
of FA
• Carnitine deficiency
• Carnitine palmitoyltransferase-I deficiency
• Carnitine palmitoyltransferase-II deficiency
• Acute fatty liver of pregnancy
• HMG-CoA lyase deficiency
• Jamaican vomiting sickness
• Dicarboxylic aciduria
• Refsum’s disease
• Zellweger’s (cerebrohepatorenal) syndrome
 Metabolism of Unsaturated FA
• Compared with plants, animal tissues have
limited ability in desaturating FA  need
PUFA (polyunsaturated FA) from a plant
source which are essential FA to give rise
to eicosanoic (C20) FA, from which are
derived families of compounds known as
eicosanoids.
• Eicosanoids are physiologicaly &
pharmacologically active compounds
known as prostaglandins (PG),
tromboxanes (TX), leukotrienes (LT) &
lipoxins (LX)
Metabolism of Unsaturated FA (cont.)

• Some PUFA cannot be synthesized by

mammals and are therefore nutritionally
essential
• Other C20, C22 & C24 polyenoic FA may
be detected in the tissues  may be
derived from oleic, linoleic, & -linoleic
acids by chain elongation. The double
bond present in naturally occuring
unsaturated FA of mammals are the cis
configuration
Metabolism of Unsaturated FA (cont.)
• Trans-UFA may compete with cis-UFA
• Up to 15% of tissue UFA have been found
to be in trans configuration
 metabolized more like saturated than like
cis-UFA
tend to raise LDL levels & lower HDL levels
and thus contraindicated with respect to the
prevention of atherosclerosis & coronary
heart disease
 do not possess essent. FA activity and may
antagonize the metabolism of essent. FA &
exacerbate essent. FA deficiency
Metabolism of Unsaturated FA (cont.)
• Monounsaturated FA are synthesized by a
9 desaturase system and synthesis of
PUFA involves desaturase and elongase
enzyme systems
• Eicosanoids are formed from C20 PUFA
(arachidonate and some other C20 FA)
• Deficiency of essential PUFA (linoleic,
linolenic & arachidonic acid) leads to a
deficiency syndrome in experiment rats
include scaly skin, necrosis of the tail, and
lesion in the urinary system
Metabolism of Unsaturated FA (cont.)

• Essential PUFA functions are various,

apart from prostaglandin & leukotriene
formation. They are found in the
structural lipids of the cell & are
concerned with the structural integrity of
the mitochondrial membrane
 Metabolism of Unsaturated FA (cont.)
Example : arachidonic acid is present in
membrane, accounts for 5-15% of FA in
phospholipids; docosahexanoic acid
(DHA 3,2:6) synthesized from -
linolenic acid or obtained directly from
fish oils is present in high concentrations
in retina, cerebral cortex, testis & sperm.
DHA is particularly needed for
development of the brain & retina and is
supplied via the placenta & milk
Pathway from linoleic acid to arachidonic acid. Numbers in parentheses refer
to the fatty acid length and the number and positions of unsaturations.
Biosynthetic pathways of Eicosanoids

• Two pathways from arachidonate:

* Cyclooxygenase pathway forms
Prostanoids (PG2 & TX2 series : PGD2,
PGE2, PGF2, PGI2, TXA2)
* Lypoxygenase pathway forms
Leucotrienes (LTA4, LTB4, LTC4, LTD4,
LTE4) & Lipoxins (LXA4, LXB4, LXC4,
LXD4, LXE4)
 PGE2

TXA2

LTA4

The eicosanoids consist of the prostaglandins (PGs), thromboxanes (TXs)

and leukotrienes (LTs). The PGs and TXs are collectively identified as
prostanoids.
Biosynthetic pathways of Eicosanoids
(cont.)

• Prostanoids are potent biologically active

substances:
* thromboxanes are synthesized in
platelets and upon release cause
vasoconstriction & platelet aggregation
* prostacyclins (PGI2) are produced by
blood vessel walls and are potent
inhibitors of platelet aggregation
Biosynthetic pathways of Eicosanoids
(cont.)

* Leucotrienes & lipoxins are potent

regulators of many disease processes 
a mixture of leucotrienes C4, D4 & E4 is a
slow reacting reacting substance of
anaphylaxis (SRA-A) which is 100-1000
times more potent than histamine or
prostaglandins as a constrictor of the
bronchial airway musculature
Synthesis of the clinically relevant prostaglandins and thromboxanes from arachidonic acid.
Numerous stimuli (e.g. epinephrine, thrombin and bradykinin) activate phospholipase A2
which hydrolyzes arachidonic acid from membrane phospholipids. The prostaglandins are
identified as PG and the thromboxanes as TX. Prostaglandin PGI2 is also known as
prostacyclin. The subscript 2 in each molecule refers to the number of -C=C- present.
Synthesis of the clinically relevant leukotrienes from arachidonic acid. Numerous stimuli (e.g. epinephrine,
thrombin and bradykinin) activate phospholipase A2 which hydrolyzes arachidonic acid from membrane
phospholipids. The leukotrienes are identified as LT. The leukotrienes, LTC4, LTD4, LTE4 and LTF4 are
known as the peptidoleukotrienes because of the presence of amino acids. The peptidoleukotrienes,
LTC4, LTD4 and LTE4 are components of slow-reacting substance of anaphylaxis The subscript 4 in
each molecule refers to the number of -C=C- present.
Biosynthetic pathways of Eicosanoids
(cont.)

 together with LT B4 also cause

vascular permeability, attraction &
activation of leukocytes  seems to
be important regulators in many
diseases involving inflammatory or
immediate hypersensitivity
reactions, such as asthma
 Various stuimuli, e.g.
Membrane phospholipid Angiotensin II,
bradykinin.,
Epinephrine
thrombin

PHOSPHOLIPASE
A2

Arachidonate

LIPOXYGENASE CYCLOOXYGENASE

Leukotrienes Prostaglandins
Lipoxins Thromboxanes