LIPID CHEMISTRY

Maria Theresa Llamas - Carin MD

Department of BIOCHEMISTRY
DMSF
 Lipids…
 Organic compounds in living organisms that is
insoluble in water but soluble in nonpolar
organic solvents

 Heterogenous group of compounds

( fats, oils, steroids, waxes)
 LIPIDS
1. The ELEMENTS found in Lipids are
CARBON, HYDROGEN and OXYGEN.

2. The SMALLEST MOLECULES used to make

Lipids are: GLYCEROL plus 3 FATTY ACIDS.

3. GLYCEROL - simple molecule with just

three carbons and three OH-groups.
- colourless, gunky liquid sometimes
called 'glycerine'
 ACIDS in biological chemistry are any
molecule with the -COOH (Carboxyl)
group
 FATTY ACIDS are acids with VERY
LONG HYDROCARBON CHAINS
ATTACHED
Three fatty acids bond to the glycerol in
a TRIPLE CONDENSATION REACTION
to form a standard TRIGLYCERIDE
LIPID held together by three ESTER
BONDS
FATTY ACID: Characteristics

1. An unbranched carbon chain

2. An even number of carbon atoms in the

carbon chain

3. Double bonds, when present in the

carbon chain, in a cis configuration
 If the acyl chains are on the same side of
the bond = cis

 If on opposite sides = trans

 Example: OLEIC ACID
- L-shaped( ‘bent” 120 degrees at the
double bond)
ELAIDIC ACID – remains straight
Trans fatty acids

 Arising as by- products of the saturation

of fatty acids during hydrogenation.

 Associated with increases risk of

cardiovascular diseases and DM.
 --CH – CH2 – CH=CH-CH2-CH2

+H2

--CH- CH2 – CH2 - CH2 –CH2 –CH2

FOOD RECOMMENDATIONS:

 Fat intake limited to 30% of total daily

calories

 Combined saturated fat and trans fat

intake limited to 10% or less of daily
calories.
FATTY ACIDS

 LCFA = C12 to 26

 MCFA = C8 and C10

 SCFA = C4 and C6
BIOMEDICAL IMPORTANCE
 1.Dietary constituents
 2.Thermal insulator
 3. Electrical insulators
 4. Cellular constituents( lipoprotein)
CLASSIFICATION
 1. SIMPLE
 2. COMPLEX
 3. PRECURSOR and DERIVED lipids
CLASSIFICATION
 1.SIMPLE – esters of FA with various
alcohols

a. Fats – EFA with glycerol

b. Waxes – EFA with higher

molecular weight monohydric
alcohols
Classification
 2. COMPLEX – EFA containing groups
in addition to an alcohol and a FA
a. Phospholipids – + phosphoric acid
residue/ nitrogen-containing bases
(ex.glycerophospholipids/sphingophospholipids)

b. Glycolipids – FA +sphingosine + CHO

c. Other complex lipids – lipoproteins/
sulfolipids/ aminolipids
 COMPLEX LIPIDS
 PHOSPHOLIPIDS
- lipids + FA + alcohol +
phosphoric acid residue
- have nitrogen-containing
bases + other substances
eg.
Glycerophospholipids

Sphingophospholipids
PHOSPHOLIPIDS
 Main lipid constituents of membranes
 Derivatives of phosphatidic acid phosphate
esterified with the –OH of a suitable alcohol
A. PHOSPHATIDYLCHOLINES(lecithin)
B. PHOSPHATIDYLETHANOLAMINE
(cephalins)
C. PHOSPHATIDYLINOSITOL
D. DIPHOSPHATIDYLGLYCEROL (
cardiolipin)
PHOSPHATIDYLCHOLINES
 Most abundant phospholipids of cell
membrane
 Large proportion of the body’s store of
choline
*Choline= nervous transmission
*Dipalmitoyl lecithin = surface active
agent/ major constituent of surfactant
PHOSPHATIDYLINOSITOL
 Precursor of second messengers
 Phosphatidylinositol 4,5-biphosphate(an
important constituent of cell membrane
phospholipids

diacylglycerol inositol triphosphate

(internal signals or second messengers)

DIPHOSPHATIDYLGLYCEROL

 Major lipid of mitochondrial membranes

GLYCOLIPIDS
 Glycosphingolipids
 Nervous tissues
 Outer leaflet of plasma membranes (contribute to
cell surface carbohydrates)
 A. Galactoceramides
B. Glucosylceramides
C. Gangliosides
GLYCOLIPIDS
 GALACTOSYLCERAMIDES
-major glycolipid of brain/ nervous tissue
 GLUCOSYLCERAMIDES
-extraneural tissues
 GANGLIOSIDES
- nervous tissues
- complex glycosphingolipids derived from
glucosylceramide plus sialic acid
Classification
 3. Precursor and derived lipids
- FA, glycerol, steroids, other alcohols,
fatty aldehydes, ketone bodies,
hydrocarbons, lipid-soluble vitamins,
hormones
TYPES OF FATTY ACIDS:
 1.UNSATURATED
a. Monounsaturated = one double bond
b. Polyunsaturated= 2 or more (=)
 2.SATURATED = none
 3. EICOSANOIDS= 20-carbon polyenoic
FA ( prostanoids – prostaglandins,
prostacyclins,thromboxanes;
leukotrienes; lipoxins)
 POLYUNSATURATED FATTY
ACIDS
 ESSENTIAL PUFA’S
1. LINOLEIC ACID(18:2)ω6
2. α- LINOLENIC ACID(18:3)ω3
- Proper membrane structure
- Starting material for production of nutritionally
important longer-chain ω6 ω3 acid family
3. ARACHIDONIC ACID ( can be
formed from Linoleic acid)
The fat content of tree nuts and peanuts

 Strong protective effect against CHD

 An ounce(3-4teaspoons) 5 or more times
/week
 Antioxidant vitamins,minerals, plant fiber
protein
 Low carbohydrate
 COMMON BIOLOGICAL SATURATED
FATTY ACIDS
Symbol common name systematic structure mp(C)
name

12:0 Lauric acid dodecanoic CH3(CH2)10CO 44.2

acid OH

14:0 Myristic acid tetradecanoic CH3(CH2)12CO 52

acid OH

16:0 Palmitic acid Hexadecanoic CH3(CH2)14CO 63.1

acid OH

18:0 Stearic acid Octadecanoic CH3(CH2)16CO 69.6

acid OH

20:0 Arachidic aicd Eicosanoic acid CH3(CH2)18CO 75.4

OH
 COMMON BIOLOGICAL
UNSATURATED FATTY ACIDS
mp(C)
Symbol common name systematic name structure

16:1 Palmitoleic acid Hexadecenoic acid CH3(CH2)5CH=CH-(CH2)7COOH -0.5

18:1 Oleic acid 9-Octadecenoic acid CH3(CH2)7CH=CH-(CH2)7COOH 13.4

18:2 Linoleic acid 9,12 - CH3(CH2)4(CH=CHCH2)2(CH2)6C -9

Octadecadienoic acid OOH

18:3 Linolenic acid 9,12,15 - CH3CH2(CH=CHCH2)3(CH2)6CO -17

Octadecatrienoic acid OH
20:45,8,11,14 arachidonic acid 5,8,11,14- CH3(CH2)4(CH=CHCH2)4(CH2)2C -49

Eicosatetraenoic acid OOH

20:55,8,11,14,1 EPA 5,8,11,14,17- CH3CH2(CH=CHCH2)5(CH2)2CO -54
7
Eicosapentaenoic- OH
acid

22:64,7,10,13, DHA Docosohexaenoic 22:6w3

16,19
acid
CLASSIFYING FATTY ACIDS ON THE BASIS

OF STRUCTURAL CHARACTERISTICS

1. TYPE DESIGNATION OF THE FATTY

ACID
2. Numerical shorthand designation based
on carbon chain length and degree of
saturation
3. Which ‘omega’ family belongs
4. “Delta” designation for the carbon chain
double bond locations
PHYSICAL PROPERTIES OF FATTY ACIDS

 Largely determined by the length and

degree of unsaturation of the fatty acid
carbon chain.
PHYSICAL PROPERTIES OF FATTY ACIDS

1. WATER SOLUBILITY
- SCFA have slight solubility in water
(related to the polarity of the carboxyl
group present whereas in LCFA, the
nonpolar nature of the hydrocarbon chain
completely dominates solubility)

Ex. Lauric acid(at 30*C) – 0.063g/L,

Stearic acid – 0.0034g/L
Glucose – 1100g/L
PHYSICAL PROPERTIES OF FATTY ACIDS

2. MELTING POINT
- as carbon chain length increases, melting
point increases ( greater surface area 
greater intermolecular attractions between
fatty acid molecules)

- the greater the degree of unsaturation, the

greater the reduction in melting points
 Long-chain saturated FA = solid at room
temp
 Long-chain unsaturated FA = liquid

due to the decreased molecular

attractions between carbon chains
 Triglycerides
 Triacylglycerol
 Main storage forms
of FA
 Esters of the trihydric
alcohol glycerol and
FA
 CHOLESTEROL
-Best known steroid
 Major constituent of the plasma
membrane and of plasma lipoproteins
 Precursor of large number of steroids 
bile acids, adrenocortical hormones, sex
hormones, D vitamins, cardiac
glycosides
Sources of dietary cholesterol
Richest
 egg yolk, mayonnaise and shell
fish.

Moderate
 Fat on meat, duck, goose, cold
cuts, whole milks, cream, ice
cream, cheese, butter and most
commercially made cakes, biscuits
and pastries.
Cholesterol sources
Poor
 All fish and fish canned in vegetable oil,
very lean meats, poultry without skin,
skimmed milk, low fat yoghurt and
cottage cheese.

Cholesterol free
 All vegetables, and vegetable oils, fruit
(including avocados and olives), nuts,
rice, egg white and sugar.
LIPID METABOLISM
LIPID METABOLISM

1.fatty acid activation and oxidation

2. fatty acid synthesis

 Carbohydrates, protein and other
molecules obtained from the diet in
excess of the body’s needs for
these compounds can be
converted to fatty acids, which are
stored as TRIACYLGLYCEROLS
LIPID METABOLISM

1.fatty acid synthesis

2.fatty acid activation and oxidation

 BIOSYNTHESIS OF FATTY ACIDS
 Synthesized by an extramitochondrial system
 Incorporates carbons from acetylCoA into the
growing FA chain
 Complete synthesis of PALMITATE from
ACETYL CoA
 CYTOSOL
 Liver, kidney, brain, lung, mammary gland,
adipose tissue
BIOSYNTHESIS OF FATTY ACIDS
 Co-factor requirements:
- NADPH, ATP, Mn++, Biotin, HCO2

 ACETYL CoA = immediate substrate

 FREE PALMITATE = end product
 Production of MALONYL CoA = initial
and controlling step
FA biosynthesis
 Formation of long chain FA  stored in
adipose
 ACETYL CoA
- provides all the carbon atoms
- made from pyruvate in mitochondria
- needs to enter the cytoplasm
( as CITRATE ; enz: ATP CITRATE
LYASE)
Main sources of NADPH for
lipogenesis
 1. Pentose phosphate pathway
 2. Malic enzyme
 3. Isocitrate dehydrogenase
Biosynthesis of FA

 2 enzyme systems
a. Acetyl CoA carboxylase (ACC)

b. Fatty acid synthase (FAS)

FA Synthesis - three stages
1. Transport of mitochondrial acetyl CoA to
cytosol
2. Carboxylation of acetyl CoA to malonyl
CoA (regulated step)
3. Assembly of fatty acid chain by fatty
acid synthase
1. Transport
Mitochondrial acetyl
CoA out of
mitochondria and into
cytosol via citrate
transport system (also
produces one NADPH
in the cytosol as a
result)
2. Carboxylation of
Acetyl CoA
 acetyl CoA +
HCO3- 
malonyl CoA via
acetyl CoA
carboxylase
 biotin co-factor
CARBOXYLATION OF Acetyl CoA
1.Short term regulation of AcetylCoA
carboxylase
a. the enzyme undergoes allosteric
activation by CITRATE. (but can be
inactivated by long-chain fatty acyl CoA

b. by reversible phosphorylationby counter-

regulatory hormones the enzyme is
inactivated

c. INSULIN  dephosphorylated  activated

Carboxylation…….

2.Long-term regulation of AcetylCoA

carboxylase
- prolonged intake (high-calorie/high
carbohydrate diets) causes increase in
enzyme synthesis
 3.Assembly of fatty acid chain
by fatty acid synthase
1. loading of acetyl CoA and malonyl CoA onto Acyl
Carrier Proteins (ACP)
2. Four reactions within the FAS complex:
a. condensation of acetyl ACP and malonyl ACP
b. reduction / hydrogenation
c. dehydration
d. Reduction/ hydrogenation
Fatty acid synthase
 Multienzyme complex of one polypeptide
chain with 7 separate enzyme activities
and an acyl protein carrier (ACP)

 ACP – contains phosphopantotheine

moiety carrying the intermediates of FA
synthesis
 Acetyl ACP + Malonyl ACP
1. condensation ACP + CO2

Acetoacetyl ACP
2. hydrogenation NADPH/H+
NADP+

B- Hydroxybutyryl ACP

3. Dehydration H2O

Crotonyl ACP
NADPH/H+
4. Hydrogenation
NADP+
Butyryl ACP
 Fatty acid elongation: steps
 1. a. Acetyl CoA combines with –SH
group (nz. Acetyl transcyclase)
b. Malonyl combines with –SH on
phosphopantotheine of ACP
( nz. Malonyl transcyclase)

ACETYL (ACYL)-MALONYL ENZ.

Fatty acid elongation: steps
 2. Acetyl group attacks the methylene
group of the malonyl residue

CO2

3- ketoacyl enzyme
Fatty acid elongation: steps
 3. 3-Ketoacyl group=
reduced,dehydrated, reduced again

corresponding acyl –S- enzymes

Fatty acid elongation: steps
 4. sequence repeated 6X

16-carbon acyl radical assembled

Thioesterase

FREE PALMITATE
Fatty acid elongation: steps
 Fates of free palmitate
1. esterification into acylglycerol
2. chain elongation / desaturation
3. esterification to cholesteryl esters
BIOSYNTHESIS OF FATTY ACIDS

CO2
Acetyl CoA Malonyl CoA

PALMITATE
 Overall synthesis of palmitate
from acetyl and malonyl CoA

AcetylCoA + 7 malonylCoA + 14 NADPH +

14 H+
 Palmitic + 7CO2 + 6H2O + 8Coenz A +
14NADP
Regulation of LIPOGENESIS
 1. Nutritional state = main factor
- excess CHO, pyruvate,lactate, acetyl
CoA stored as fat
- rate is high in well-fed state;
depressed in DM
Regulation of LIPOGENESIS
 2. ACETYL CoA CARBOXYLASE
- most important enzyme
- activated from an inactive dimer to
an active polymeric form by
CITRATE
- regulated by glucagon, epinephrine,
insulin
INSULIN
 Stimulates lipogenesis
a. Increases transport of glucose into
the cell ( eg. ADIPOSE)
b. Increasing the availability of both
pyruvate for FA synthesis and
glycerol 3-phosphate for esterification of the
newly formed FA
c. Converts the inactive form of pyruvate
dehydrogenase to the active form in adipose
tissue
INSULIN
 Ability to depress the level of intracellular
cAMP  inhibits LIPOLYSIS in
adipose  reduces the concentration of
plasma FFA and long chain acylCoA
INSULIN
 Depress cAMP  inhibits lipolysis

plasma FFA
LIPID METABOLISM

fatty acid synthesis

2.fatty acid activation and oxidation

FATTY ACID OXIDATION NOT THE
SIMPLE REVERSE OF FATTY ACID
SYNTHESIS
Fatty acid oxidation
 Involves Acyl CoA derivatives catalyzed
by separate enzymes
 NAD+ and FAD+
 Generates ATP
 Aerobic process
 mitochondria
FATTY ACID OXIDATION: process

 1. The FA must be activated by bonding to

CoA

 2. The FA must be transported into the

mitochondrial matrix by a shuttle mechanism

 3. The FA must be repeatedly oxidized,

cycling through a series of four reactions to
produce Acetyl CoA, FADH2, NADH
Fatty acid oxidation
 FFA – unesterified state
- 1. converted to active intermediate
( Acyl-CoA synthetase or Thiokinase)
- 2. Long chain acyl –CoA enters
mitochondria by Carnitine Palmitoyl
Transferase I  ACYLCARNITINE
Enzyme systems
 FA converted to active FA (acyl-CoA) by
acyl CoA synthetase ( ATP and CoA)
 Carnitine palmitoyltransferase 1 (outer
mitochondrial membrane)
 Carnitine-acylcarnitine translocase
 Carnitine palmitoyl transferase 11
Fatty acid oxidation
 FFA-
3. Acylcarnitine enters inner
membrane  BETA OXIDATION
Beta-oxidation pathway

 Is a repetitive series of four biochemical

reactions that degrades acyl CoA to
acetyl CoA by removing 2 carbons at a
time, with FADH2 and NADH also being
produced.
 Beta Oxidation STEPS:

1.OXIDATION (dehydrogenation)

- hydrogen atoms are removed from the α

and β carbons creating a double bond
- FAD is the oxidizing agent
- FADH2 is a product
Beta-oxidation: STEPS

2. HYDRATION

- a molecule of water added across the

trans double bond  secondary alcohol
Beta – oxidation: STEPS

3. OXIDATION (dehydrogenation)

- β-hydroxy group is oxidized to a ketone

functional group
- NAD+ as oxidizing agent
- NADH2 as product
Beta-oxidation: STEPS

4. CHAIN CLEAVAGE

- FA chain is broken between α and β

carbons by a reaction with a CoA
molecule Acetyl CoA + new acyl
molecule that is shorter by 2 carbon
atoms
Beta
oxidation
of fatty
acids
FATES of Acetyl CoA formed by
beta Oxidation
1. From glycolysis  oxidized to CO2 and
H2O via citric acid cycle
2. Precursor for synthesis of cholesterol
and other steroids
3. In the liver, it forms ketone bodies
( acetone, acetoacetate,
3-hydroxybutyrate)
Oxidation of FA with ODD #
Carbon
 Acetyl CoA + Propionyl CoA

Succinyl CoA
(constituent of citric acid cycle)
*Propionyl residue is the only part of a FA that is
glucogenic
Oxidation of FA produces a
large quantity of ATP
 A.Transport in the respiratory chain of
electrons from FADH2 and NADH 
yields 4 high energy phosphates for
each of the first 7 acetyl CoA formed by
Beta oxidation of PALMITATE
( 7 x 4 = 28)
Oxidation of FA produces a
large quantity of ATP
 2. A total of 8 mol of acetyl CoA formed
and each give rise to 10 mol of ATP on
oxidation in the citric acid cycle
( 8 X 10 = 80)
Oxidation of FA produces a
large quantity of ATP

 3. 2 must be subtracted for the initial

activation of FA
net gain = 106 mol of ATP/mole of
palmitate
Comparison of Fatty Acid b-
Oxidation and Synthesis
KETOGENESIS
 Occurs in liver when acetyl CoA
production exceeds the limits of its
oxidation in the citric acid cycle
(starvation or uncontrolled diabetes.)
 Increased FA oxidation (starvation/DM)
 ketone body formation (KETOSIS)

 Mitochondrial enzymes
Conditions Favoring
Ketoacidosis:
 KETOGENESIS
 Increased fatty acid oxidation
 DM and starvation
 Liver
 KETONE BODIES extrahepatic tissue fuels
1. Acetoacetate  decarboxylated 
ACETONE
2. B-hydroxybutyrate
KETOGENESIS
A. 2 acetyl CoA molecules formed in Beta
oxidation condense  acetoacetyl CoA by a
reversal of Thiolase reaction

 Acetoacetyl CoA
– the starting material
- may arise directly from terminal 4
carbons of a FA during B-oxidation
Ketogenesis
B. Condensation of acetoacetyl CoA with
another molecule of Acetyl CoA by
3-hydroxy-3 methylglutaryl CoA synthase

HMG-CoA
Ketogenesis
c. Acetyl CoA split off from HMG-CoA
leaving free acetoacetate
(nz. HMG-CoA Lyase)

hydroxybutyrate dehydrogenase
3-hydroxybutyrate
EXTRAHEPATIC KETOGENESIS
1.Acetoacetate activated to acetoacetyl CoA by
succinyl-CoA acetoacetate CoA transferase

2.CoA transferred from succinyl CoA forming

Acetoacetyl CoA

3. Acetoacetyl is split to acetylCoA by Thiolase

and oxidized in citric acid cycle
 Ketonemia is due to the increased
production of ketone bodies by the
liver rather than to a deficiency in their
utilization by extrahepatic tissues
REGULATION OF
KETOGENESIS:CRUCIAL STEPS
1. Control of FFA mobilization from adipose
tissue
2. The activity of carnitine palmitoyl-transferase I
in the liver, which determines the proportion
of the FA flux that is oxidized rather than
esterified
3. Partition of acetyl-CoA between the pathway of
ketogenesis and the citric acid cycle.
Role of INSULIN
CLINICAL ASPECTS
 Ketosis
- Ketonuria
- Ketonemia
* Starvation/ high fat diet

 Ketoacidosis
- DM
 diabetic ketoacidosis (DKA)
 increase in fatty acid oxidation (due to a
concomitant increase in circulating
glucagon).

 increased production of acetyl-CoA

ketone body production. acidification
 impairs the ability of hemoglobin to bind
oxygen.
Clinical aspects
 Carnitine deficiency
-inability to transport fatty acids into
the mitochondria for oxidation.
- preterm infants
- hemodialysis
- CMx: mild occasional muscle
cramping to severe weakness
 UNSATURATED FATTY
ACIDS AND EICOSANOIDS
Review:
 FATTY ACIDS :
- esters in natural fats and oils
- unesterified form as free fatty acids
- straight-chain derivatives in natural fats
( even number of carbon atoms)
* SATURATED – no double bonds
( Ex. Palmitic ; stearic acids)
* UNSATURATED – one or more double
bonds
 refer to the number of hydrogens
attached to the hydrocarbon tails of the
fatty acids as compared to the number of
double bonds between carbon atoms in
the tail
SATURATED FATS
 The hydrocarbon chains in these fatty
acids are, thus, fairly straight and can
pack closely together, making these fats
solid at room temperature

 ANIMAL SOURCES
UNSATURATED FATS
 some double bonds between the
carbons in the hydrocarbon tail, causing
bends or “kinks” in the shape of the
molecules.
 not bonded to as many hydrogens
 can’t pack as closely together
 liquid at room temperature.
FATTY ACIDS: Systematic
Nomenclature
@ Saturated acids end in –anoic
(Ex. octanoic acid)

@ unsaturated acids end in –enoic

( Ex. octadecenoic acid)
FATTY ACIDS
 Carbon atoms are numbered from the
carboxyl carbon (C1)
 α,β,γ (C2,3,4)
Adjacent to C1 =
 Terminal methyl carbon =ω or n-carbon
SATURATED FATTY ACIDS
 Acetic acid as first member of the series
( CH3 - COOH)
 - CH2 – progressively added between
terminal CH3 – and - COOH
 SATURATED ACIDS
Common name # of C atoms

1. ACETIC 2 Major End product of carbohydrate

fermentation
2. PROPIONIC 3 - Same -

3. BUTYRIC 4 - Same - ;

4. VALERIC 5 - Same -

5. CAPROIC 6 - Same -

6. LAURIC 12 Coconut oils

7. MYRISTIC 14 Coconut oils

8.PALMITIC 16 Common in plant and animal fats

9. STEARIC 18 - same-
UNSATURATED FATTY ACIDS
 1. MONOUNSATURATED
- Monoenoic; one double bond
 2. POLYUNSATURATED
- polyenoic ; 2 or more double bonds
 3. EICOSANOIDS
- derived from –eicosa (20-carbon) polyenoic
FA
- Prostanoids ( prostaglandins,
prostacyclins,thromboxanes ), leukotrienes,
lipoxins,
 Unsaturated FA of Physiologic and
Nutritional significance
A. MONOENOIC/MONOUNSATURATED
#of C COMMON Systematic name Occurrence
atoms : NAME
Positio
n of ∆
16:1;9 Palmitoleic 9-Hexadecenoic all fats

18:1;9 Oleic 9-Octadecenoic Most

common FA
in natural fats
B. DIENOIC ACIDS
18: 2;9,12 LINOLEIC 9,12- Corn,
Octadecadie peanut,
noic soybean,
many plant
oils
 C. TRIENOIC ACIDS
18:3;6,9,12 ‫ץ‬- Linolenic 6,9,12 – Some
Octadeca plants
-trienioc

18:3;9,12,15 α- Linolenic 9,12,15- Linseed

Octadeca oil
-trienoic
Linoleic and α- Linolenic Acids
 Essential FA
 Required for prostaglandin,
thromboxane, leukotriene, lipoxin
formation
 Found in structural lipids of cell
 Structural integrity of mitochondrial
membrane
D. TETRAENOIC ACIDS
20:4; Arachidonic 5,8,11,14 – Animal
5,8,11,14 Eicosa - fats;
tetranoic peanut oil;
important
component
of
phospho-
lipids
ARACHIDONIC ACIDS
 Present in membranes
 5-15% of FA in phospholipids
 E. PENTANOIC ACIDS
20:5; Timnodonic 5,8,11,14,17- -fish oils,
5,8,11,14,17 Eicosapenta- ( cod liver,
noic mackerel,
salmon)
F. HEXANOIC ACIDS
22;6; CERVONIC 4,7,10,13, -FISH
4,7,10,13, 16,19, - OILS;
16, 19 DOCOSA- Phospho-
HEXANOIC lipids in
brain
DHA
 High concentrations in RETINA,
CEREBRAL CORTEX, TESTIS, SPERM
 Low levels in Retinitis Pigmentosa
POLYUNSATURATED FATTY
ACIDS
 ESSENTIAL PUFA’S
1. LINOLEIC ACID
2. α- LINOLENIC ACID
3. ARACHIDONIC ACID ( can be
formed from Linoleic acid)
UNSATURATED FATTY ACIDS:
IMPORTANCE
1.In phospholipids of cell membrane – maintain membrane
fluidity; structural integrity of mitochondrial membrane

2.EFA  eicosanoids
Prostaglandins = mediate inflammation;
pain; sleep; blood
coagulation;reproduction
Leukotrienes = muscle contraction;
chemotaxis; allergic and
inflammatory reactions
EICOSANOIDS
 Formed from C20 PUFA’s
 1. prostaglandins
2. thromboxanes
3. leukotrienes
4. lipoxins
 Act as local hormones functioning
through G-protein linked receptors
Metabolism of eicosanoids
 Arachidonic acid = substrate for
synthesis
 Cyclooxygenase pathway – responsible
for Prostanoid synthesis
 Lipooxygenase pathway – Leukotriene
and Lipoxin
 ALL MAMMALIAN CELLS EXCEPT
ERYTHROCYTES SYNTHESIZE
EICOSANOIDS
Arachidonic Acid Biosynthesis:
SUMMARY

 precursor of arachidonic acid is the essential

fatty acid, linoleic acid (18: 2 D9, 12)
 arachidonic acid (all-cis-D5, D8, D11,
D14)used as precursors for other molecules
 arachidonic acid is formed in liver
 most enzymes are in endoplasmic reticulum
 5 enzyme catalyzed reactions from linoleic to
arachidonic acids
Pathway from linoleic acid to
arachidonic acid.
arachidonic acid
 (all-cis-D5, D8, D11, D14) used as precursors
for other molecules
• stored at position 2 of phospholipids
• released upon hormone signaling to phospholipase A2
which cleaves arachidonic acid off phospholipid
• Prostaglandin endoperoxide synthase converts
arachidonic acid to prostaglandin G2 (PGG2 which is
then converted to PGH2) but PG synthesis is inhibited
by aspirin (acetylsalicylic acid) by acetylation of
cyclooxygenase portion of the PG synthase complex
 PROSTANOID SYNTHESIS
 Cyclooxygenase pathway
 PROSTAGLANDIN H SYNTHASE (PGHS)
1. Cyclooxegenase
2. Peroxidase

 PGHS = has isoenzymes

a. PGHS -1( COX 1)
b. PGHS -2 (COX2)
COX ACTIVITY
 1. COX 1(PGHS1)
– gastric mucosa, kidneys, platelets,
vascular endothelial cells

 2. COX 2 (PGHS2)
- macrophages, monocytes
- primary triggers: platelet activating factor
Interleukin 1
THROMBOXANE
 produced in platelets by thromboxane
synthetase, which is produced from
the endoperoxides by the
cyclooxygenase
 a vasoconstrictor and a potent
hypertensive agent, and it facilitates
the clumping of platelets (role in clot
formation (thrombosis).
PROSTANOID SYNTHESIS
 Inhibitors
1. ASPIRIN – acetylation of both PGHS-
1 and 2
2. Indomethacin/ Ibuprofen – compete
with arachidonate
3. Corticosteroids – inhibit transcription
of PGHS-2
LEUKOTRIENE and LIPOXIN
SYNTHESIS

 Lipoxygenase pathway
Synthesis of the clinically relevant
leukotrienes from arachidonic acid.
Leukotrienes (Lts)

 synthesized by 5-lipoxygenase

 selectively distributed in pulmonary tissue,

platelets and WBCs (neutrophils, monocytes,
macrophages & mast cells)

 active 30 mins to several hrs after initial insult

 Normal Physiological effects of
Leukotrienes

 extremely potent smooth muscle contractors

 LTB4 promotes WBC adherence, chemotaxis

& degranulation
Normal Physiological effects of
Leukotrienes
 LTC4, LTD4 & LTE4
- promote increased vascular
permeability, plasma exudation &
mucus secretion
• also promote bronchoconstriction and
vasoconstriction
• decreased myocardial contractility & coronary
blood flow
LEUKOTRIENES and LIPOXINS
 Slow-Reacting Substance of Anaphylaxis
(SRS-A)
- mixture of LTC4, D4, E4
- potent bronchoconstrictor
• SRS-A plus LTB4
- leukocyte attraction and activation
- cause vascular permeability
- regulators of inflammatory and immediate
hypersensitive reactions
 Therapeutic areas of Eicosanoid
Intervention
PROSTAGLANDINS LEUKOTRIENES
- Platelet aggregation
- Uterine motility - Allergic response
- Cardiac arterial insufficiency (anaphylaxis)
- Vasoconstriction
- Bronchodilation/ - clinical trials of leukotriene
inhibitors to prevent anaphylaxis
bronchoconstriction
- Renal tubule stimulation
- Inflammation
- Gastric ulcers
- Myocardial infarction
prophylaxis
METABOLISM OF
ACYLGLYCEROLS
 ACYLGLYCEROLS

TRIACYLGLYCEROL
- major lipids in fat depots and
food
CATABOLISM of
TRIACYLGLYCEROLS: STEPS

1. Hydrolysis by lipase
2. Release of FFA into plasma
3. Binding with serum albumin
4. FFA uptake into tissues
5. Oxidation and esterification
BIOSYNTHESIS OF
TRIACYLGLYCEROL
 Acylglycerol Biosynthesis

* substances formed from

GLYCEROL 3-PHOSPHATE
1. TRIACYLGLYCEROL
2. PHOSPHATIDYLCHOLINE
3. PHOSPHATIDYLETHANOLAMINE
4. PHOSPHATIDYLINOSITOL
5. CARDIOLIPIN
 Overview of ACYLGLYCEROL
Biosynthesis

Glycerol 3 phosphate _____ DHAP

Phosphatidate Plasmalogens PAF

Diacylglycerol cardiolipin phosphatidylinositol

phosphatidylcholine TAG Phosphatidylinositol

phosphatidylethanolamine 4,5 bi PO4
LIPID TRANSPORT AND
STORAGE
 Lipid transport:
 Problem:LIPIDS INSOLUBLE IN WATER

1. Solubilization by bile acids

2.Access to pancreatic lipase ( lipase
and PLA2)  FFA + mono/diacylglycerides
3. Dietary TG and cholesterol solubilized in
LIPOPROTEINS
LIPIDS ARE TRANSPORTED IN
THE PLASMA AS LIPOPROTEINS
PLASMA LIPIDS:
 1. TRIACYLGLYCEROLS (TAG)= 16%
 2. PHOSPHOLIPIDS =30%
 3. CHOLESTEROL = 14%
 4. CHOLESTERYL ESTERS = 36%
 5. Unesterified LCFA(FFA) = 4%
- the most active
- arise in the plasma from lipolysis of TAG
or as a result of lipoprotein lipase action
during uptake of plasma TAG into tissues
LIPOPROTEINS

 Spherical macromolecular complexes of

lipids and specific proteins
 Differ in lipid and protein composition,
size , density and site of origin
4 major groups of plasma
lipoproteins
1. CHYLOMICRONS
2. VLDL
3. LDL
4. HDL
CHYLOMICRONS
 Found in chyle
 Predominantly TAG
 Derived from intestinal absorption of
TAG and other lipids
 Responsible for transport of all dietary
lipids into the circulation
VLDL
 Pre-B-lipoproteins
 Derived from the liver for the export of
TAG to the extrahepatic tissues
 Hepatic origin
 Predominantly TAG
LDL
 B- lipoproteins
 Final stage in the catabolism of VLDL
 Predominantly cholesterol
HDL
 α – lipoproteins
 Involved in VLDL and chylomicron
metabolism
 Involved in cholesterol transport
 Predominantly phospholipids
 Density
Complex Source %Protein %TGa %PLb %CEc %Cd %FFAe
(g/ml)

Chylomic
Intestine <0.95 1-2 85-88 8 3 1 0
ron
VLDL Liver 0.95-1.006 7-10 50-55 18-20 12-15 8-10 1
IDL VLDL 1.006-1.019 10-12 25-30 25-27 32-35 8-10 1
LDL VLDL 1.019-1.063 20-22 10-15 20-28 37-48 8-10 1

Intestine,
liver
*HDL2 1.063-1.125 33-35 5-15 32-43 20-30 5-10 0
(chylomicron
s and VLDLs)

Intestine,
liver
*HDL3 1.125-1.21 55-57 3-13 26-46 15-30 2-6 6
(chylomicron
s and VLDLs)

Albumin- Adipose
>1.281 99 0 0 0 0 100
FFA tissue

aTriacylglycerols, bPhospholipids, cCholesteryl

esters, dFree cholesterol, eFree fatty acids
*HDL2 and HDL3 derived from nascent HDL as a result of the acquisition of cholesteryl
esters
APOLIPOPROTEINS
 Apo α - HDL
 Apo β - LDL(β-100), also in VLDL,
chylomicrons (β-48)
Apo E – VLDL, HDL, Chylomicron, CR
APOLIPOPROTEINS: ROLES
 1. Form part of lipoprotein structure
eg. Apo B
 2. Enzyme cofactors
- C-II for lipoprotein lipase
- A-I for LCAT
 3.Enzyme inhibitors
- Apo –II /Apo C-III for lipoprotein lipase
- Apo C –I for cholesteryl ester transfer protein
 4. Act as ligands for interaction with lipoprotein receptors
in tissues
- Apo B-100/Apo E for LDL receptor
- Apo A-I for HDL receptor
 Apoprotein Classifications

Function and
Apoprotein - MW (Da) Lipoprotein Association
Comments

major protein of HDL,

activates
apoA-I - 29,016 Chylomicrons, HDL
lecithin:cholesterol
acyltransferase, LCAT

primarily in HDL,
apoA-II - 17,400 Chylomicrons, HDL enhances hepatic
lipase activity
present in
apoA-IV - 46,000 Chylomicrons and HDL triacylglycerol rich
lipoproteins
 exclusively found in
chylomicrons, derived from apoB-
apoB-48 - 100 gene by RNA editing in
Chylomicrons
241,000 intestinal epithelium; lacks the
LDL receptor-binding domain of
apoB-100

major protein of LDL, binds to

apoB-100 -
VLDL, IDL and LDL LDL receptor; one of the longest
513,000
known proteins in humans

Chylomicrons, VLDL,
apoC-I - 7,600 may also activate LCAT
IDL and HDL
Chylomicrons, VLDL,
apoC-II - 8, 916 activates lipoprotein lipase
IDL and HDL
 Chylomicrons, VLDL,
apoC-III - 8,750 inhibits lipoprotein lipase
IDL and HDL

apoD, 33,000 HDL closely associated with LCAT

cholesterol ester transfer protein, exclusively associated with HDL,

HDL
CETP cholesteryl ester transfer

apoE - 34,000 (at least 3 alleles [E2, Chylomicron binds to LDL receptor, apoE-4 allele
E3, E4] each of which have multiple remnants, VLDL, IDL amplification associated with late-
isoforms) and HDL onset Alzheimer's disease

apoH - 50,000 (also known as -2-

Chylomicrons triacylglycerol metabolism
glycoprotein I)

disulfide bonded to apoB-100, forms a

complex with LDL identified as
apo(a) - at least 19 different alleles; lipoprotein(a), Lp(a); strongly
protein ranges in size from 300,000 - LDL resembles plasminogen; may deliver
800,000 cholesterol to sites of vascular injury,
high risk association with premature
coronary artery disease and stroke
LIPOPROTEIN METABOLISM
 HDL: Important functions

1. Reservoir of apolipoproteins
- Apo C-II/ Apo E
2. Uptake of unesterified cholesterol
3. Esterification of cholesterol
- PCAT( phosphatidylcholine:cholesterol
acyltransferase)
4. Reverse cholesterol transport
- bile acids synthesis/disposal via the bile
- hormone synthesis
 Lipoprotein Metabolism and
Transport Pathways: summary
Exogenous Pathway

 dietary fats - chylomicrons in intestine

 chylomicrons - Triglycerides and chylomicron remnants by action
of lipoprotein lipase (LPL) in adipose tissue and muscle and
endothelial cells
 chylomicron remnants are removed by liver and cleaved, releasing
free cholesterol
- cholesterol can be:
 stored in hepatocytes as esters
 released in bile
 used to form membranes or lipoproteins
 Lipoprotein Metabolism and Transport
Pathways: summary
 ENDOGENOUS PATHWAY
- VLDL synthesized in liver
1. FFA from VLDL is deposited in adipose tissue
and muscle after lipolysis of TG by
Lipoprotein lipase
2. the resulting IDL and LDL are taken up by
hepatocytes involving high affinity receptor-
mediated endocytosis by the LDL receptor

 LDL constitutes 60-70% of plasma cholesterol levels

 Lipoprotein Metabolism and
Transport Pathways: summary
ENDOGENOUS PATHWAY
 in lysosomes the esterified cholesterol is hydrolysed and
released as free cholesterol for synthesis of cell membranes

 HDL is involved in the transport of cholesterol from

peripheral cells back to the liver

 when plasma lipoprotein concentrations are high,

macrophages and other scavenger cells degrade lipoprotein
 cholesterol deposits in macrophages or arterial walls
(atheroma) and of tendons and skin (xanthomas)
Role of liver in lipid transport
and metabolism
 1. Facilitates digestion and absorption of lipids
by the production of bile
 2. Has active enzyme systems for synthesizing
and oxidizing FA
 3. Has enzyme systems for synthesizing TAG
and phospholipids
 4. Converts FA to ketone bodies
 5. Synthesis and metabolism of plasma
lipoproteins
Hepatic VLDL secretion
 Stimulus: Hepatic TAG synthesis
 Sources:
1. From acetyl-CoA from CHO
- well –fed ( FA synthesis is high)
2. FFA uptake from the circulation
- starvation; high fat diets; DM
( hepatic lipogenesis inhibited)
Factors enhancing hepatic TAG
synthesis and VLDL secretion
1. Fed state rather than the starved state
2. Feeding of diets high in CHO
3. High levels of circulating FFA
4. Ingestion of ethanol
5. Presence of high concentrations of
insulin and low glucagon enhance FA
synthesis and esterification/ inhibit
oxidation
 CLINICAL IMPLICATIONS
 FATTY LIVER
2 CATEGORIES:
1. Raised levels of plasma FFA/ TAG
accumulation

Production of VLDL

fat mobilization from adipose/

lipoprotein lipase action on TAG
Fatty liver
2. Metabolic block in the production of plasma
lipoproteins

TAG accumulation
Lesion:
a. apolipoprotein synthesis
b. synthesis of lipoprotein from lipid
and apolipoprotein
c. failure in provision of phospholipids
d. failure in the secretory mechanism itself
ALCOHOLISM
 ALCOHOLISM
NADH
-competes with reducing
equivalents from other
substrates for the
respiratory chain 
inhibited FA oxidation 
increased FA esterification
 FATTY LIVER
ALCOHOLISM
 ETHANOL:
1. Increased lipogenesis
2. Cholesterol synthesis from acetyl-CoA
3. Lipid peroxidation
HORMONES REGULATING FAT
MOBILIZATION
1. INSULIN
a. inhibits FFA release from adipose
b. enhances lipogenesis and the
synthesis of acylglycerol
c. increases the oxidation of glucose to
CO2 via the PPP.
Hormones
 INSULIN increases activity of pyruvate
dehydrogensae, acetyl CoA carboxylase,
glycerol phosphate acyltransferase

increased glucose uptake 

enhance FA and acylglycerol synthesis
HORMONES
 INSULIN on adipose

inhibit lipase release of FFA

and glycerol
Hormones promoting LIPOLYSIS
1. Epinephrine
2. Norepinephrine
3. Glucagon
4. ACTH
5. MSH
6. TSH
7. GH
8. Vasopressin
 hyperlipoproteinemias
Disorder Defect Comments
slow chylomicron clearance,
Type I (familial LPL
(a) deficiency of LPL; reduced LDL and HDL levels;
deficiency, familial
(b) production of abnormal LPL; treated by low fat/complex
hyperchylomicronemi
(c) apoC-II deficiency carbohydrate diet; no increased ri
a)
of coronary artery disease
reduced LDL clearance leads to
Type II (familial
hypercholesterolemia, resulting in
hypercholesterolemia, 4 classes of LDL receptor defect
athersclerosis and coronary artery
FH)
disease

Type III (familial

dysbetalipoproteinem hepatic remnant clearance impaired causes xanthomas,
ia, remnant removal due to apoE abnormality; patients hypercholesterolemia and
disease, broad beta only express the apoE2 isoform that athersclerosis in peripheral and
disease, interacts poorly with the apoE coronary arteries due to elevated
apolipoprotein E receptor levels of chylomicrons and VLDL
deficiency)
 frequently associated with type-II
Type IV
non-insulin dependent diabetes
(familial elevated production of VLDL
mellitus, obesity, alcoholism or
hypertriacyl associated with glucose intolerance
administration of progestational
glycerolemia and hyperinsulinemia
hormones; elevated cholesterol as
)
a result of increased VLDLs

frequently associated with type-II

Type IV
non-insulin dependent diabetes
(familial elevated production of VLDL
mellitus, obesity, alcoholism or
hypertriacyl associated with glucose intolerance
administration of progestational
glycerolemia and hyperinsulinemia
hormones; elevated cholesterol as
)
a result of increased VLDLs

hypertriacylglycerolemia and
Type V elevated chylomicrons and VLDLs
hypercholesterolemia with
familial due to unknown cause
decreased LDLs and HDLs
 Familial a rare condition that
hyperalphalipoprot increased level of HDLs is beneficial for
einemia health and longevity

Type II increased LDL production strongly associated

Familial and delayed clearance of with increased risk
hyperbetalipoprotei triacylglycerols and fatty of coronary artery
nemia acids disease
dramatic increase in
LDL levels; no affect
2 different mutations: Gln on HDL, VLDL or
for Arg (amino acid 3500) plasma triglyceride
Familial ligand- or Cys for Arg (amino acid levels; significant
defective apoB 3531); both lead to reduced cause of
affinity of LDL for LDL hypercholesterolemia
receptor and premature
 decreased levels of
plasma cholesteryl
absence of LCAT leads to
Familial esters and lysolecithin;
inability of HDLs to take up
LCAT abnormal LDLs (Lp-X)
cholesterol
deficiency and VLDLs; symptoms
(reverse cholesterol transport)
also found associated
with cholestasis
Wolman's reduced LDL clearance
disease leads to
defect in lysosomal cholesteryl
(cholesteryl hypercholesterolemia,
ester hydrolase; affects
ester resulting in
metabolism of LDLs
storage athersclerosis and
disease) coronary artery disease
heparin-
releasable deficiency of the lipase leads to
hepatic accumulation of triacylglycerol- causes xanthomas and
triglyceride rich HDLs and VLDL remnants coronary artery disease
lipase (IDLs)
 Hypolipoproteinemias
Disorder Defect Comments

rare defect; intestine and liver

Abetalipoproteinemia accumulate, malabsorption of
no chylomicrons, VLDLs or
(acanthocytosis, fat, retinitis pigmentosa, ataxic
LDLs due to defect in apoB
Bassen-Kornzweig neuropathic disease,
expression
syndrome) erythrocytes have thorny
appearance
at least 20 different apoB
Familial gene mutations identified,
mild or no pathological
hypobetalipoproteinem LDL concentrations 10-
changes
ia 20% of normal, VLDL
slightly lower, HDL normal

Familial alpha- all of these related tendency to

lipoprotein deficiency syndromes have reduced hypertriacylglycerolemia;
(Tangier disease, Fish- HDL concentrations, no some elevation in VLDLs;
eye disease, apoA-I effect on chylomicron or Fish-eye disease characterized
and -C-III deficiencies) VLDL production by severe corneal opacity
CHOLESTEROL
METABOLISM
 CHOLESTEROL
-Best known steroid
 Major constituent of the plasma
membrane and of plasma lipoproteins
 Precursor of large number of steroids 
bile acids, adrenocortical hormones, sex
hormones, D vitamins, cardiac
glycosides
CHOLESTEROL

Structure:
- very hydrophobic compound
- four fused hydrocarbon rings (A,B,C,D
“steroid nucleus”)
- eight-carbon, branched hydrocarbon
chain attached to C17 of D ring
- Ring A with OH at C-3
- Ring B With double bond (C-5 and C6)
 CHOLESTEROL

- Directly associated with

ATHEROSCLEROSIS
- >50% derived from biosynthesis de novo
( 10% each from intestine and liver)
 CHOLESTEROL:
BIOSYNTHESIS

- CYTOPLASM and endoplasmic

reticulum
- Two acetate group of acetyl CoA
 CHOLESTEROL:
Biosynthesis

5 steps:
1. Acetyl CoA converted to 3-HMG-CoA
2. HMG CoA converted to mevalonate
3. Mevalonate converted to the isoprene based molecule.
Isopentenyl pyrophosphate(IPP), with concomitant loss
of CO2
4. IPP converted to squalene
5. Squalene give rise to lanosterol  CHOLESTEROL
 CHOLESTEROL:
Biosynthesis

- all tissues in humans

- liver, intestine, adrenal cortex,
reproductive tissues (ovaries, testes,
placenta)
*CYTOPLASM(cytosolic and ER)
*Endergonic
 CHOLESTEROL:
Biosynthesis

- Acetyl CoA  Mevalonate  IPP

- (C2) (C6) (C5)

-  Squalene  Lanosterol 
- (Acyclic C30) ( Multiring C30)

CHOLESTEROL
( Multiring C27)
 CHOLESTEROL:
Biosynthesis

5 steps:
1. Acetyl CoA converted to 3-HMG-CoA
2. HMG CoA converted to mevalonate
3. Mevalonate converted to the isoprene based molecule.
Isopentenyl pyrophosphate(IPP), with concomitant loss
of CO2
4. IPP converted to squalene
5. Squalene give rise to lanosterol  CHOLESTEROL
 CHOLESTEROL:
Biosynthesis

Rate limiting step:

3-hydroxy -3-methylglutaryl CoA
reductase catalyzed step
- cytosol
- uses 2 molecules NADPH
- releases CoA
 CHOLESTEROL:
Biosynthesis

- IPP formation:
- requires 3 ATP
- after decarboxylation of mevalonate
 CHOLESTEROL:
Biosynthesis

- condensation of 6 IPP polyisoprenoid squalene

* requires a total of 18 ATPs
 CHOLESTEROL:
Biosynthesis

Squalene  Lanosterol
* utilizes molecular oxygen and NADPH
* the hydroxylation of squalene triggers the
cyclization of the structure of lanosterol
 CHOLESTEROL:
Biosynthesis

- Lanosterol  cholesterol
* shortening of carbon chain (C30 to C27)
* removal of 2 methyl groups at C4
* migration of the double bond from C8 to C5
* reduction of the double bond between C24
and C25
 CHOLESTEROL:
Biosynthesis

- CHOLESTEROL: fates
* biosynthetic pathways are available to convert it to
each of the 5 major classes of steroid hormones
1. Progestins 4. Androgens
2. Glucocorticoids 5. Estrogens
3. Mineralocorticoids
* bile acids and Vitamin D
CHOLESTEROL SYNTHESIS:
REGULATION
 Average dietary consumption- 0.3g/day
 1.5 to 2.0 grams of cholesterol synthesized de novo
 Constant level = 150-200mg/dl

 Diet: a decrease of 100mg dietary cholesterol= decrease

approx. 0.13mmol/L of serum

 Controlled by regulation of HMG-CoA reductase

a. feedback inhibition
b. hormones ( Insulin/TH increases;
glucagon/glucocorticoids decreases
The UTILIZATION of CHOLESTEROL
 CHOLESTEROL is transported in the
plasma as cholesteryl esters associated
with lipoproteins
 Dietary cholesterol  chylomicrons
 EXCESS CHOLESTEROL IS
EXCRETED FROM THE LIVER IN THE
BILE AS CHOLESTEROL OR BILE
SALTS
Bile acid synthesis and
utilization
 Primary Bile acids:
a. Cholic acid
b. Chenodeoxycholic acid

* The 7α-hydroxylation of cholesterol is the first and

principal regulatory step in the biosynthesis
• ( cholesterol 7α-hydroxylase)
* enter the bile as glycine and taurine conjugates (bile
salts)
Bile acid synthesis and utilization

 Secondary bile acids:

 1. deoxycholic acid
 2. lithocholic acid

 * undergo changes secondary to

deconjugation and 7α - dehydroxylation of
intestinal bacteria
Bile acid synthesis and
utilization
 The ultimate fate of bile acids is secretion into the
intestine,  emulsification of dietary lipids.

 In the gut the glycine and taurine residues are removed

and the bile acids are either excreted (only a small
percentage) or reabsorbed by the gut and returned to the
liver.

 This process of secretion from the liver to the gallbladder,

to the intestines and finally re-absorbtion is termed the
enterohepatic circulation.
Enterohepatic circulation
Clinical Significance of Bile Acid
Synthesis

Physiologically significant functions:

1. their synthesis and subsequent excretion in the feces
represent the only significant mechanism for the
elimination of excess cholesterol.
2. bile acids and phospholipids solubilize cholesterol in the
bile, thereby preventing the precipitation of cholesterol in
the gallbladder.
3. they facilitate the digestion of dietary triacylglycerols by
acting as emulsifying agents that render fats accessible to
pancreatic lipases.
4. they facilitate the intestinal absorption of fat-soluble
vitamins.
CLINICAL SIGNIFICANCE:
 Atherosclerosis and coronary heart
disease
Atherosclerosis
 Deposition of cholesterol and cholesteryl
esters from the plasma lipoproteins into
the artery wall
Pharmacologic Intervention

Drug treatment to lower plasma lipoproteins and/or

cholesterol is primarily aimed at reducing the risk of
athersclerosis and subsequent coronary artery
disease that exists in patients with elevated circulating
lipids.
Drug therapy usually is considered as an option only if
non-pharmacologic interventions (altered diet and
exercise) have failed to lower plasma lipids
Mevinolin, Mevastatin,
Lovastatin
 HMG-CoA reductase inhibitors.

 increased cellular uptake of LDLs,

(intracellular synthesis of cholesterol is
inhibited and cells are therefore
dependent on extracellular sources of
cholesterol).
Clofibrate, Gemfibrozil,
Fenofibrate:
 promote rapid VLDL turnover by
activating lipoprotein lipase.
 induce the diversion of hepatic free fatty
acids from esterification reactions to
those of oxidation, thereby decreasing
the liver's secretion of triacylglycerol-
and cholesterol-rich VLDLs.
Cholestyramine or colestipol
(resins):
 nonabsorbable resins that bind bile acids
which are then not reabsorbed by the liver but
excreted.
 The drop in hepatic reabsorption of bile acids
releases a feedback inhibitory mechanism that
had been inhibiting bile acid synthesis.
 As a result, a greater amount of cholesterol is
converted to bile acids to maintain a steady
level in circulation..
Nicotinic acid:
 reduces the plasma levels of both VLDLs
and LDLs by inhibiting hepatic VLDL
secretion, as well as suppressing the flux
of FFA release from adipose tissue by
inhibiting lipolysis.
 used to treat Type II, III, IV and V
hyperlipoproteinemias
Thank you for learning
with me!!
 Normal Physiological effects of
Prostaglandins
and Thromboxanes
 A. Effects on Smooth Muscle:
1. Vascular Effects:
* PGE's & PGI2 -----> smooth muscle
dilatation -----> vasodilation

* PGF2a & TXA2 -----> vasoconstriction

Normal Physiological effects of
Prostaglandins and Thromboxanes
A. Effects on Smooth Muscle

2.. Effects on Lungs:

 TXA2 is a vasoconstrictor &

bronchoconstrictor

 PGF's contract & PGE's relax respiratory

smooth muscle
Normal Physiological effects of
Prostaglandins
and Thromboxanes
A. Effects on Smooth Muscle

3. Effects on GI tract:
 PGI2, PGF2 & PGI2 -----> smooth m.
contraction -----> cramps

 (PGE -----> decreased gastric acid

secretion & ulceration)
Normal Physiological effects of
Prostaglandins
and Thromboxanes

B. Effects on Platelets:
 PGE1 & PGI2 -----> decreased platelet
aggregation

 TXA2 -----> increased platelet

aggregation
Normal Physiological effects of
Prostaglandins
and Thromboxanes

C. Effects on Reproductive Organs:

 PGE2 & PGF2a -----> abortion: soften

cervix -----> uterine contractions
• initiate & stimulate labor
• menstrual pain
Normal Physiological effects of
Prostaglandins
and Thromboxanes

D. Kidney Effects:
 PGE regulates arteriolar tone
• compensatory vasodilatation

 maintains normal blood flow

• increased glomerular filtration rate (GFR)
 Normal Physiological effects of
Prostaglandins
and Thromboxanes

E. Pro-inflammatory Effects:
 1. Fever: PGE's act on thermoregulatory center
in brain
• increased body temperature
 2. Pain: PG -----> sensitise pain receptors to
stimulation
• increased pain
 3. PGs promote vasodilation & increased
vascular permeability
THANK YOU
FOR YOUR
KIND
ATTENTION!
SUMMARY
 Lipid metabolism concerned mainly with
FA and cholesterol
 Source of LCFA: dietary or de novo
synthesis from acetyl CoA
 FA may be oxidized to acetyl CoA or
esterified with glycerol TAG
 Acetyl CoA is the principal building block
of FA