LIPID METABOLISM

By:
Asst. Professor

Dr. Salar A. Ahmed

PhD. Aristotle University of Thessaloniki – Greece

Tel: 0750 4101917

Email: salar.adnan@med.hmu.edu.krd
1- Introduction:

Lipids are a heterogeneous group of water-insoluble,

bio-organic molecules. Because of their insolubility in
aqueous solutions, body lipids are generally
compartmentalized, as can be seen with:
Membrane associated lipids

Droplets of triglyceride

Lipid transport in plasma in association with protein

The functions of lipids

1. A Storage form of energy (1gr. =9.1 calories)

2. Structural components of cell membranes
3. Serve as a thermal insulator in the subcutaneous
tissues and around certain organs.
4. Metabolic regulations
5. Acting as electrical insulators in neurons.
6. Helping in the absorption of fat-soluble Vitamins.
7. A Lipid supply that’s so called “essential fatty acids”.
Biomedical importance

Not surprisingly, a deficiency or imbalance of

lipid metabolism can lead to some of the
major clinical problems encountered by
physicians such as
•Atherosclerosis and cardiovascular disease
•Obesity and truncal obesity
•ketosis
 2. Classification of lipids
2-1- Simple lipids (esters of fatty acids and
an alcohol):
 Neutral Fats: Fatty acid + glycerol (TGs)
 Waxes: Fatty acid +High molecular
weight alcohols other than glycerol

Wax
2-2 Complex lipids (Compound lipids): Fatty acids esterified with alcohol but, in addition,
they contain other groups, like:
Ex. Phospholipids:
 Phosphatidyl cephalin
 Phosphatidyl serines
 Phosphatidyl choline (lecithin)
 Phosphatidyl inositol

O H2C O C R2

R1 C O CH O CH3
+
H2C O P O CH2 CH2 N CH3

O CH3

phosphatidylcholine
• Non-phosphorylated lipids like sulpholipids or glycosphingolipids
• lipids forming complexes with other compounds, like in lipoproteins.

2.3. Precursor & Derived lipids:

Substance derived from the above groups by hydrolysis like fatty acids, steroids, prostaglandins and ketone bodies.
 4- The Digestion & Absorption of Dietary
Lipids

An adult ingests about 60-150g of lipid, more

than 90% of which is normal TGs, with the
remains consisting primarily of cholesterol,
cholesterol esters, phospholipids and
unesterified FFAs
A- the processing of dietary lipids in the
stomach:
The digestion of lipids begins in the stomach,
catalyzed by lingual lipase (that originates
from glands at the back of the tongue)

Lingual & gastric lipase

TG 2-monoacyl glycerol + 2FA
<12 Carbon-long chains
B- Emulsification of dietary lipids in the small
intestine:
Emulsification increases the surface area of
the hydrophobic lipids droplets so that the
digestive enzymes, which work at the
interface of the droplet and the surrounding
aqueous solution, can act effectively.
c- Degradation of dietary lipids by pancreatic enzymes
lipase
TG 2-mono acyl glycerol + FFAs

pancreatic cholesterol ester hydrolase

Cholesterol ester Cholesterol + FFA
(Eseterase)

PhLipase A2 (Remove one FA from C2 of Ph lipid)

Phospholipids Lysophospholipids + FA

lysophospholipase (Remove FA from C1)

lysophospholipids Glycerylphosphoryl Base + FA
4- Absorption of lipids by intestinal mucosal cells
(enterocytes):
These molecules are later then transported across the
plasma membrane of intestinal wall cells where they
are reconverted to the TG. Enterocytes combine TG,
Cholesterol, newly synthesized phospholipids and
proteins to form chylomicrons.
 Control of lipid digestion:

Pancreatic secretion of hydrolytic enzymes in the

small intestine is hormonally controlled.
Cholecystokinin (pancreozymin) is a peptide hormone
of the GI system which plays a key role in facilitating
digestion within the small intestine. It acts on the:

•Gallbladder: it causes the gallbladder to constrict

and release bile
•Exocrine cells of the pancreas, causing them to
release digestive enzymes.
•It also decreases gastric motility, resulting in a
slower release of gastric contents into the small
intestine
 Transportation of plasma lipids

5. Plasma lipids and lipoproteins

5.1. Plasma lipids

There is a small amount of lipids in body
plasma, which is called plasma lipids.
The proportion of plasma lipids is
extremely small in comparison with the
lipids in other part of the body. However,
they can reflect the metabolic state of the
body lipids.
 Constituents and amounts of plasma lipids

Total lipids 500mg/dl (400-700)

TAG (TG) 100mg/dl (10-160)
PL 200mg/dl (150-250)
Total Ch 200mg/dl (150-250)
ChE 145mg/dl (90-200)
Ch 55mg/dl (40-70)
NEFA* 5-20mg/dl

*(non-esterified fatty acids)

5.2. - Plasma lipoproteins
Plasma lipoproteins are the primary form of lipids
in plasma.
Lipids in general are hydrophobic materials; how
are they transported in an aqueous environment
(blood)? They are transported by being conjugated
with proteins to form lipoproteins. Lipoproteins can
be said to be the “transportation form” of lipids.
 Structure of lipoproteins 5-2-3

The issue of lipids being hydrophobic and plasma lipid

transport is solved by combining the insoluble lipids
with proteins to form hydrophilic lipoprotein complexes.

A lipoprotein has a lipid core of non-polar TAG and

Cholesterol esters surrounded by the more polar
phospholipids, cholesterol and proteins. The protein
moieties are named apolipoproteins or apoproteins
(Apo).
General Structure of Lipoproteins
• 5-2-4 Classification of plasma lipoproteins

Lipoproteins can be divided into 4 types by

electrophoresis and ultracentrifugation:

Ultracentrifugation:

Chylomicrons, CM
Very low density lipoproteins, VLDL
Low density lipoproteins, LDL
High density lipoproteins, HDL
 Chemical composition of different plasma lipoproteins
Lipoprotein Total total lipids
Classes Protein %
%
CM/Chy. 2 98
VLDL 7 93
LDL 23 77
HDL 44 56

Note: TAGs are the predominant lipids in the particles of CM/Chy. and VLDL.
ChEs and PLs are the predominant lipids in the particles of LDL and HDL
 Functions of Apoproteins (Apo)

•Structural: Stabilize & maintain the molecular

structure of the lipoprotein

•Regulatory: Cofactors for enzymes involved

in lipoprotein metabolism

•Mediation: Serve as a ligands for lipoprotein

interactions with receptors
Types Association Functions

B48 Chylomicron Binds LDL receptor

B100 VLDL, IDL, LDL Binds LDL receptor

C-II Chy, VLDL, IDL, HDL Activates LPL

C-III Chy, VLDL, IDL, HDL Inhibits LPL

E Chy, VLDL, IDL, HDL Binds LDL receptor

A-1 HDL/Chylomicron LCAT activator

(lecithin: cholesterol
acyltransferase)
5.3. Lipoproteins metabolism

Chylomicrons
VLDLs Very Low Density Lipoprotein
IDLs Intermediate Density Lipoprotein
LDLs Low Density Lipoprotein
HDLs High Density Lipoprotein
 5.3.1. Chylomicrons
Origin: Mucosal cells of intestine.

Major lipid: TG (Note: remember that most of our dietary lipid

intake is composed of TG)

Apolipoproteins: Shown in the previous table (B48, CII, CIII,

E, A-1).

Reactions: TAG is hydrolyzed under the catalysis of

lipoprotein lipase (LPL) to form FFAs and glycerol, which are
taken up by tissues.

Function: Transport exogenous lipids from the intestine to

other parts of the body.
 VLDLs .5.3.2

VLDLs ------ IDLs ------ LDLs

 5.3.2. VLDLs
Origin: Hepatic cells.
Major lipid: TG
Apolipoprotein: Shown in the previous table (B100,
CII, CIII, E)
The reaction: Under a LPL catalyst, TG is hydrolyzed
to form FAs and glycerol. VLDL is converted to IDL,
and has an equal amount of cholesterol and TG. 50%
of IDL is captured by the liver and the other half
further undergoes the same procedure as VLDL does.
The last remnant is LDL.
Function: Transport endogenous lipid from the liver
to extra-hepatic tissues.
 5.3.3. LDLs (“Bad cholesterol”)
Origin: VLDL
Major lipids: Cholesterol
Apo: Shown in the previous table (B100, C-II,
C-III, E)
Reaction: 50% of LDL is degraded in the
liver and 50% of LDL is captured by
extrahepatic tissues.
Function: Transport endogenous lipids from
the liver to extra-hepatic tissues.
Functions of LDL in the cells:
Cholesterol metabolism:

1.Inhibit HMG-CoA reductase to inhibit Cholesterol

synthesis.

2.Inhibit biosynthesis of LDL receptors at the transcription

level.

3.Stimulate acyl CoA: cholesterol acyl transferase (ACAT)

activity, stimulating the formation of cholesterol esters from
free cholesterol and accumulate in plasma.

4.Construct cell membranes.

 5.3.4. HDLs (“Good cholesterol”)

Origin: liver (major), intestine, CM and VLDL.

Major lipids: cholesterol esters and phospholipids.

Apolipoprotein: Shown in previous table (C-II, C-III,

E, A-1)

Reaction: Lecithin: cholesterol acyltransferase

(LCAT) catalyzes cholesterol’s conversion to
cholesterol esters. Cholesterol esters from the
surface move into the hydrophobic interior of HDL.
 Function
1. Reservoir for apo C-II & E
2. Uptake of unesterified Cholesterol
3. Esterification of cholesterol
4. Transport cholesterol from peripheral
tissues to liver
 6. Lipids metabolism

6.1. Triglyceride Metabolism

a- Esterification (Biosynthesis)
b- Lipolysis (Break down)

The catabolism and anabolism are not the

forward and reverse processes of the same
pathway. They are entirely different
pathways, involving different reactants and
enzymes.
A- Esterification: (Synthesis of TG)

For TGs biosynthesis, 2 substrates are

required
 Acyl Co-A

 α-Glycerol phosphate
a.1- Conversion of a FFAs to it is activated form:
FFA Thiokinase CoA synthetase acyl CoA

a.2- The source of α–glycerol phosphate:

There are mainly two sources:
1. Conversion of glycerol to α-glycerol-P by glycerol
kinase in the presence of ATP
2. From glucose oxidation: dihydroxyacetone-
phosphate is converted to α-glycerol-P without ATP
Note:
 Glycerol kinase (GK) is absent in adipose tissue

 Glycerol produced by lipolysis in adipose tissue therefore

can not be utilized for the provision of α-glycerol-P.
 Glycerol from the liver, kidney and other tissues, which
possess GK, is utilized for α-glycerol phosphate
synthesis.
B- lipolysis (Breakdown of Triglycerides)

TG in adipose tissue and the liver undergoes

hydrolysis by hormone-sensitive TG lipase
(HSL) to form FFAs and glycerol. HSL
removes a FA from C1 and/or C3. Additional
lipases specific for diacyl or monoacyl
glycerol removes the remaining fatty acids.
Hormonal regulation of triglycerol degradation in the
adipocyte
Mobilization of TAG
b.1. the Fate of glycerol:

The glycerol released during lipolysis is

transported through the blood to the liver, where
it can be phosphorylated and used to form TAG
in the liver or can be converted to DHAP, which
can participate in glycolysis or gluconeogenesis
b. 2. the fate of fatty acids

FFAs move through the cell membrane of the

adipocyte and immediately bind to albumin in the
plasma. They are transported to the tissues,
where the FAs that enter the cells get activated to
their CoA derivatives and are oxidized for energy.
 Fatty acids metabolism:
FAs are water-insoluble long chain
hydrocarbons with one carboxyl group at the
end of the chain and may be:
•Saturated fatty acids: Do not have double
bonds in the chain
•Unsaturated fatty acid: Have one or more
double bonds
•Branched chain fatty acids like phytanic acid
 
Fatty acids Nomenclature

1. The systematic name (“n” system): IUPAC

2. Trivial Names: These names are typically

derived from a common source of the compound
or the source from which it was first isolated.
3. Two abbreviation Systems:
a. Alpha (α) Nomenclature (delta (Δ) numbering
system)
b. Omega (ω) Nomenclature
Common name No.of carbons: No of Formula
double bond
Saturated FA CH3(CH2)nCOOH
Formic acid 1 HCOOH
Acetic acid 2:0 CH3COOH
Butyric acid 4:0 CH3(CH2)2COOH
Caproic acid 6:0 CH3(CH2)4COOH
Caprylic acid 8:0 CH3(CH2)6COOH
Capric acid 10:0 CH3(CH2)8COOH
Lauric acid 12:0 CH3(CH2)10COOH
Myristic acid 14:0 CH3(CH2)12COOH
Palmitic acid 16:0 CH3(CH2)14COOH
Stearic acid 18:0  CH3(CH2)16COOH
Arachidic acid 20:0 CH3(CH2)18COOH
Behenic acid 22:0 CH3(CH2)20COOH
Lignocericacid 24:0 CH3(CH2)22COOH
 Unsaturated FA
Palmitoleic acid 16:1 Δ9 ω-7
Oleic acid 18:1 Δ9  ω-9
Linoleic acid 18:2 Δ9,12 Essential ω-6
Linolenic acid 18:3 Δ9,12,15  FAs ω-3
Arachidonic acid 20:4 Δ5,8,11,14  ω-6
Eicosapentaenoic acid 20:5 Δ5,8,11,14,17  ω-3
 The truth about fats: The good, the bad, and the in-
between
Saturated FFAs
1. Are a source of energy
2. In food: are usually accompanied by cholesterol
3. They enhance the levels of total cholesterol and
LDL
4. Stability: their auto-oxidation takes place at higher
Temperature
5. They promote obesity and atherosclerosis
Note: Diet must be limited in the amounts of saturated fatty
acids to reduce the above disadvantages.
 Unsaturated FFAs
A Source of energy
In the food: are usually accompanied with
cholesterol
Resists oxidation (?)
Are essential nutrients that are important in
preventing and managing heart disease
(TXA3*).
Are a primary structural component of the
human brain.
cerebral cortex, skin, and retina.
*talked about in the next slide
 Note (extra): TXA3, eicosapentaeonic acid
and decreased heart attack risk
In vivo, eicosapentaeonic acid (EPA) is incorporated into platelet
phospholipids, to some extent replacing arachidonic acid. Thus,
following phospholipase A2 activation, EPA as well as arachidonic acid
can be released. As both acids are substrates for cyclooxygenase,
there will be some trienoic prostaglandins (prostaglandins with 3
double bonds) generated from EPA. These have important differences
in biological activity, in that prostaglandin I3 is equipotent to
prostacyclin (prostaglandin I2α) in preventing platelet aggregation, but
thromboxane A3 is much less active than thromboxane A2 in causing
platelets to clump. Thus, when EPA is available as a precursor,
platelets are less prone to aggregate without substantial reduction of
endothelial thromboresistance. Thus, people who eat more fish or take
fish oil containing EPA have a shift in their eicosanoid formation
towards the antithrombotic side. This shift is the simplest scientific
explanation for decreased heart attacks in fish eaters.
 Omega-3 fatty acids (fish oil), which may help to:
 Lower blood pressure
 Reduce TGs
 Decreased LDL and VLDL
 Slow the development of plaque in the arteries
 Reduce the chance of abnormal heart rhythm
 Reduce the likelihood of heart attack and stroke
 Lessen the chance of sudden cardiac death in people with heart
disease
 Vasodilator
 Anti-inflammatory effects
 Inhibition platelet aggregation (linolenic acid- 18: 3Δ9.12.15, ω3- can
be converted to eicosapentaeonic acid)
 Omega-6 FFAs

• Omega-6 FFAs are used for reducing the risk of

heart disease, lowering total cholesterol levels,
lowering "bad" (LDL-C) levels, raising "good"
(HDL) Cholesterol levels, and reducing cancer risk.
• Are vasoconstrictors
• Have pro-inflammatory effects
• Enhance platelet aggregation
6.2.2. Anabolism of FFAs- General features

1. Glucose is the primary substrate for lipogenesis.

2. The major sites of FA synthesis are in the liver
3. The enzymes that synthesize FAs are localized in
the cytosol and are completely different from
the mitochondrial enzymes that catalyze fatty
acid degradation
4. The major pathway for synthesis involves the
polymerization of two carbon units derived from
acetyl CoA.
5. NADPH, Mn+2, CO2 & ATP are required for FA
synthesis.
 De novo FFA biosynthesis

1- Production of cytosolic acetyl CoA:

The transfer of acetate units from mitochondrial
acetyl-CoA to the cytosol. This process is observed
by the translocation of citrate from the
mitochondrion to the cytosol.
Notes:
• Citrate is produced by the condensation of
oxaloacetate(OAA) and acetyl CoA
• Acetyl CoA cannot cross the mitochondrial
membrane; only the acetyl portion is transported
Note (extra)
 2. Carboxylation of acetyl CoA to form malonyl
CoA
 

Acetyl CoA
Carboxylase
Acetyl CoA + ATP + HCO3- Malonyl CoA + ADP + Pi + H+
Note:
1.Essential FFAs must be obtained from the diet
because there is no human enzyme that can
introduce a double bond beyond the ninth carbon
atom.
2.The major product of FA synthetase is palmitate.
The elongation of FAs can occur either in the
endoplasmic reticulum or mitochondria.
Note (extra): Fatty acid synthase is a multi-enzyme protein
that catalyzes fatty acid synthesis. It is not a single enzyme
but a whole enzymatic system composed of two identical
multifunctional polypeptides, in which substrates are
handed from one functional domain to the next.
3. In the endoplasmic reticulum, the sequence of the
reaction is similar to the cytosol synthetic system. The
elongation needs malonyl CoA and NADPH, but acyl
carrier protein (ACP) is not required.

4. In mitochondria, palmitate may enter by a carnitine-

transport system. The elongation of FFAs is simply the
reversal of β-oxidation, with the exception that FAD is
replaced by NADPH.
Synthesis of unsaturated FAs:

The liver and adipose tissue contain the necessary

enzymes for converting palmitic to palmitoleic acid
(16:0 to 16: 1∆9) and stearic to oleic acid (18: 1∆9).
The enzymes are termed lipoxygenases or mixed
function oxygenases, requiring molecular O2, NADH,
and cytochrome b5.
 Oxidation of FFAs .6.2.3

The principle pathways by which FAs are oxidized

in the body are:
• α –oxidation

• β -oxidation

• ω -oxidation
The Oxidation of FFAs involve 3 stages:

1. Activation of FFAs

2. Transport into the mitochondria

3. Degradation to two-carbon fragments (such as

acetyl CoA) in the mitochondrial matrix
1- Fatty acid activation

FA must be converted to active form before it’s

further metabolized

Note: Pyrophosphate is then hydrolyzed to 2

molecules of phosphate. 2 high-energy P
bonds are expended during the activation of
each FA molecule (So the catabolism of each
fatty acid has a loss of 2 ATPs).
 Note (extra): ATP expenditure during FA
activation

Because AMP (rather than ADP) is the product from

the reaction, acyl-CoA synthetase uses the
equivalent of two ATP molecules to supply energy for
the process; The regeneration of ATP from AMP must
occur in two steps. The first is the reversible reaction
catalyzed by adenylate kinase that uses an ATP to
phosphorylate the AMP, producing two ADP
molecules. These must then both be converted back
to ATP.
2-Transport of acyl-CoA into mitochondria
Most acyl-CoA are formed outside the mitochondria. The
oxidation of acyl-CoA occurs inside the inner membrane
of the mitochondria. The membrane is impermeable to
CoA and its derivatives. This problem is overcome by an
efficient shuttle system called the Carnitine shuttle.
Carnitine is used as a carrier of the acyl group across the
membrane.
6.2.3.1. β- oxidation
The principle pathway by which FAs are oxidized is
called β-oxidation. The circulating FAs are taken by
various tissues and oxidized. Tissues like the liver,
heart, kidney, muscle, lung, testis and adipose
tissue have the ability to oxidize long chain FAs. In
cardiac muscle, FAs are an important fuel of
respiration.
β-oxidation of fatty acyl CoA includes a
recurring sequence of 4 reactions:
1.Dehydrogenation linked to FAD
2.Hydration
3.Re-dehydrogenation linked to NAD+
4.Thiolysis by CoA-SH
 1-The first dehydrogenation of β-oxidation is
catalyzed by acyl CoA dehydrogenase to give an enoyl
CoA with a trans-double bond between C-2 and C-3.
ATP

2-The next step is the hydration of the double bond between C-2 and C-3 by enoyl CoA hydratase.
The hydration of enoyl CoA is stereo-specific; only the L-isomer of β-hydroxyacyl CoA is formed

3- The third step is dehydrogenation again, catalyzed

ATP by L-β-hydroxyacyl CoA dehydrogenase. The products
are ketoacyl CoA and NADH.

4-The final step is the cleavage of β-ketoacyl CoA by the thiol

group of a second molecule of CoASH. The products are acetyl
CoA and an acyl CoA shortened by two carbon atoms. The
shortened acyl CoA then undergoes another cycle of β-oxidation.
6.2.4. The energetics of FA oxidation

E.g., Palmitic acid (16: 0)

1. In each reaction cycle of β-Oxidation, an acyl CoA is

shortened by 2 carbons.

2. Completely degrading palmitoyl CoA would require 7 rounds

of β oxidation

3. After the 7th round, you’re left with an 8th acetyl CoA (CH2-
CO-CoA).
What is the ATP yield from oxidation of palmitate?
Note: each FADH2 molecule produces 2 ATPs, and each NADH
produces 3. Each acetyl CoA entering the TCA cycle produces 3
NADH molecule, 1 FADH2 molecule and a GTP molecule.
•8 acetyl CoA molecules enter TCA cycle. 12 ATPs are produced
for each acetyl CoA in the TCA cycle; 8*12 = 96 ATP molecules:
24 NADH = 72 ATP (by oxidative phosphorylation)
8 FADH2 = 16 ATP (by oxidative phosphorylation)
8 GTP = 8 ATP
• In each cycle of β-Oxidation, 1 FADH2, 1 NADH and 1 acetyl CoA are
produced.
 7 NADH = 21 ATP

 7 FADH2 = 14 ATP
• The total No. of ATPs produced from 1 molecule of
palmitate = 72 + 16 + 8 + 21 + 14 = 131.
• But remember, 2 high energy phosphate bonds (equivalent to 2
ATPs) were used to activate palmitate by converting it into
palmitoyl CoA. Therefore, the ATP yield is 129.
Note: 1 ATP produces 7.6 Kcal/mole. The Amount
of energy produced in the form of Kcal = 129* 7.6 =
980.4 kcal/mole

1 gram fat = 9 kcal. Theoretically, the yield of

energy from 1 mole of palmitic acid is equal to =
M.wt * 9 (= 259 *9 = 2304 Kcal)
Theoretically, the yield of energy is potential E +
Kinetic energy (Heat E). The Efficiency of conversion
= (980/2304)*100= 42%:
•42% of energy is converted into the form of ATP

•58% of energy is released in the form of heat

6.2.4. Oxidation of odd-chain FAs

The oxidation of FAs with an odd number of carbons proceeds

exactly as β-oxidation of FAs, but the final product is a molecule of
propionyl CoA. Propionyl CoA further undergoes carboxylation,
molecular arrangement, and conversion to succinyl CoA.

Succinyl CoA can be metabolized via the TCA cycle, of which it is an

intermediate, or it could be a substrate for heme synthesis.
Metabolism of propionyl CoA
 6.2.5. Oxidation of unsaturated FAs

One of the intermediates of the β-oxidation of

saturated FAs is Δ2-trans-enoyl CoA, which can be
hydrated to form L-β-OH-acyl CoA.
However, the β-oxidation of unsaturated FAs will
produce Δ3-cis-enoyl CoA and Δ2-cis-enoyl CoA
molecules.
Δ3-cis-enoyl CoA can be converted to Δ2-trans-
enoyl CoA by the catalysis of Isomerase.

Δ2-cis-enoyl CoA can be hydrated to form D-β-

hydroxyacyl CoA, which then undergoes
epimerization to form L-β-OH-CoA under the
catalysis of Epimerase.
Δ3-cis-enoyl CoA Δ2-cis-enoyl CoA

Isomerase H2O

Δ2-trans-enoyl CoA D-β-hydroxyacyl CoA

epimerase
H2O
L-β-hydroxyacyl CoA
Note:
• Two additional enzymes are needed for the oxidation of
unsaturated FAs; isomerase and epimerase
• The presence of double bonds in the fatty acid makes it so that the
ATP production on oxidation is less by two for each double bond.
 Note (extra): this is because the initial dehydrogenation step to introduce a
double bond, which yields an FADH2 molecule (= 2 ATP), is not required
since the double bond is already present in the unsaturated FA.
6.2.3.2. ω- Oxidation:
An alternative pathway to β-oxidation which,
instead of involving the β-C, involves the oxidation
of the ω-C (by hydroxylase enzymes involving cyt
P450, and mono-oxygenase). This process is
normally a minor catabolic pathway for medium-
chain FAs, but becomes more important when β-
oxidation is defective
6.2.3.3. Alpha Oxidation
A process by which certain FAs are broken down
by removal of a single C from the COOH end. In
humans, alpha-oxidation is used in peroxisomes to
break down dietary phytanic acid (branched chain
FAs, which can’t oxidized by β-oxidation due to its
β-methyl branch (β-C atom blocked by methyl
group), formed from the break down of
chlorophyll)
 CH3 CH3
CH 3 (CHCH 2 CH 2 CH 2 )3 CHCH 2 CO 2H

Phytanic Acid (3,7,11,15-tetramethyl

hexadecanoic acid)
 1.Cholesterol Metabolism

The total amount of cholesterol in the human

body is about 2g/kg body weight.

Adrenal gland 100mg/g > brain 20mg/g > liver

3mg/g > skeletal muscle 1mg/g
The greatest part of the cholesterol of the body
arises by biosynthesis (about 1g/day), whereas
only about 0.3g/day are provided by diet.
Cholesterol is typically a product of animal
metabolism and occurs therefore in foods of
animal origin, such as meat, liver, brain, and
egg yolk.
6.3.1. Cholesterol biosynthesis
de novo biosynthesis of cholesterol occurs in
virtually all cells. This capacity is greater in liver,
intestine, adrenal cortex, and reproductive tissues,
including ovaries, testes, and placenta. 70-80 % of
endogenous cholesterol is formed in liver and 10%
in the intestines.
 The major sites: cytosol and endoplasmic reticulum
 The raw material: acetyl CoA
 The cofactors: ATP, NADPH, NADH
Cholesterol Biosynthesis is
• 26 steps
• 3 stages
 3 mol of acetyl CoA are used to synthesize 3-
hydroxy-3-methylglutaryl CoA (HMG CoA)
 HMG CoA to squalene
Rate limiting step is conversion of HMG CoA to
mevalonic acid by HMG CoA reductase
 Formation of cholesterol from squalene
 acetyl CoA diet
6.3.2. Metabolic conversion of cholesterol
biosynthesis
>1g/day ¡« 0.3g/day

structural component
fecal sterols CHOLESTEROL of biomembrane

skin liver

7-dehydrogen bile acids steroid hormones

cholesterol (40% of amount
of synthesis) gonad
ultraviolet light adrenal cortex
gonadal hormone
vitamin D3 glucocorticoid
androgen
(cholecaliferol) cortisol testosterone
cortisone estrogen
mineralocorticoid estradiol
aldosterone progestogen
progesterone
 Regulation of cholesterol metabolism

1. HMG-CoA reductase is the key enzyme, and catalyzes the

conversion of HMG-CoA to mevalonate. This enzyme can be
inhibited strongly by cholesterol.

2. Insulin and thyroid increase the activity of HMG-CoA reductase.

Glucagon and glucocorticoid decrease its activity.

3. The effect of diet: When diet contains 2% of cholesterol, the

endogenous production falls to 10-30 %. However, endogenous
production can not be completely suppressed by raising dietary
intake.
6.4. Formation and utilization of ketone bodies

The last product of FFAs in β-oxidation is acetyl CoA,

which in many tissues, except the liver, can be completely
oxidized to CO2 and water. However, in liver cells, the
significant amount of acetyl CoA is converted to so called
ketone bodies, Which include 3 substances:
Acetoacetate (HOOC-CH2-CO-CH3)
β-Hydroxybutyrate (CH3-CHOH-CH2-COOH)
Acetone ( CH3COCH3)
• Notes:

1. Acetoacetate & β-hydroxybutyrate are

synthesized from acetyl-CoA in the mitochondria
of liver cells; acetone is formed by spontaneous
decarboxylation of acetoacetate.

2. Ketone bodies are water soluble; the total

concentration of ketone bodies in blood is less
than 1 mg/dL.
3. In the early stages of fasting, the use of ketone
bodies by heart and skeletal muscle conserves
glucose for the support of the central nervous
system. With more prolonged starvation, the
brain can uptake more ketone bodies to spare
glucose consumption
4. High Concentrations of ketone bodies can induce
ketonemia and ketonuria, and even ketosis and
acidosis.
5. When carbohydrate catabolism is blocked by a
disease, e.g., DM, or a defect of sugar source, the
blood concentration of ketone bodies may increase.
6. Acetoacetate is chemically unstable and breaks
down to acetone, which is poorly metabolized, and
is excreted in the urine and in breathe.
6.5. Some important derivatives of polyunsaturated fatty
acids

Essential fatty acids serves as precursors of a group of

biochemical, active compounds, such as eicosanoids:
prostaglandins (PG), prostacyclin (PGI2), thromboxane

(TX) A2 and leukotriene (LT).

6.5.1. Prostaglandins: a family of compounds that have the 20-carbon skeleton of
prostanoic acid produced in response to a physiological trigger

Functions: It helps to regulate different activities, such as

Muscle Contraction
Blood flow
Wake-sleep cycle
Responsiveness of certain tissues to hormones such as epinephrine and
glucagons
Blood pressure
Elevate temperature, cause inflammation and pain
One of the more important signals, helps to regulate the synthesis of cyclic AMP.
6.5.2. Thromboxanes: Is a vasoconstrictor and a potent hypertensive agent,
and it facilitates platelet aggregation, which helps form blood clots and
reduce blood flow at the site of clots

6.5.3. Leukotrienes: are involved in functions such as the contraction of the

muscle lining of the airways to the lungs. Their overproduction is a major
cause of inflammation in asthma and allergic rhinitis
 
 7. Clinical disorders associated with lipid and
lipoprotein metabolism

7.1. Refsum’s Disease: A rare inherited disorder in

which phytanic acid accumulates in tissues.
• Possibly due to a defect or deficiency of the -
hydroxylase, which causes
– Nerve and retinal damage
– Bone and skin changes
 
7.2. Xanthomatosis, which means accumulation
of lipids, usually cholesterol, in subcutaneous
tissue with large foam cells. It appear in
hyperlipoproteinemia, diabetes mellitus and
Von–Gierke's disease
 
7.3. Essential Fatty Acid Deficiency
 Irritated & flaky skin
 Gastrointestinal problems
 Compromised immune system
 Slow growth for children
 Skin lesion
 kidney damage
 Decreased resistance to stress
7.4. Atherosclerosis

The first step in the development of cardiovascular disease,

followed by arteriosclerosis which is where calcium deposits
accumulate along with cholesterol, fat, and other substances
found in the blood, forming hard plaques which are
associated with the thickening and hardening of arterial
walls.
a. Formation of plaque and arterial narrowing;
 The oxidants (like, O2-., NO, H2O2) and other oxidants
cause oxidation of blood LDL, which is taken up by
macrophages. The oxidized LDL accumulates in the
macrophages and other phagocytes, which are then known
as foam cells.
The endothelial cells of the artery wall are injured
either by oxidized LDL or mechanically. Damaged
endothelial cells cannot produce protaglandins I2
(PGI2), and prostacyclin (which inhibits platelet
aggregation) and platelets begin to aggregate and
release thromboxane A2 (TXA2); TXA2 stimulates
platelet aggregation.

Thus forms plaques that cause arterial narrowing

and leads to heart attacks. Atherosclerosis is the
main cause of ischemic heart disease (IHD) and
cardiovascular disease (stroke).
6. CARNITINE:
L-carnitine is an amino acid (AA) that is naturally produced in the
body. L-carnitine helps the body produce energy. It is important for
heart and brain function, muscle movement, and many other body
processes.
Carnitine deficiencies- Symptoms:
 Poor muscle tone
 Muscle weakness
 Brain dysfunction
 Heart dysfunction
Disorder of lipid transport and storage
Fatty liver
Fatty liver is the excessive accumulation of fat, primarily
TGs, in the liver parenchymal cells. Fat is mainly stored in
AT; the liver is not a storage organ. It contains about 5%
fat. In pathological conditions, this may be go up to 25-
30% and is known as fatty liver or fatty infiltration of the
liver.
When accumulation of lipid in the liver becomes chronic,
fibrotic changes occur in cells, which may finally lead to
cirrhosis and impairment of liver function.
Causes of fatty liver: It occurs in conditions in which there
is an imbalance between hepatic triacylglycerol synthesis
and the secretion of VLDL.
Conditions that cause fatty liver:
1.High fat diet
2.Starvation, uncontrolled diabetes mellitus, or insulin insufficiency
3.Alcoholism
4.High cholesterol intake
5.Use of certain chemicals
6.Dietary deficiency of
Essential fatty acids
Essential amino acids
Vitamin E and selenium
Lipotropic factors
 Lipotropic Factors
The substances that prevent the accumulation of fat in
the liver are known as lipotropic factors.
A dietary deficiency of these factors can result in fatty
liver
The various lipotropic agents are;
Choline
Methionine
Betaine
Vitamin B12 and folic acid are involved in the
formation of methionine from homocysteine.
 Hyper lipoproteinemia
Disorder Defect

Type I a) Deficiency of LPL

.familial Chy b) Production of abnormal LPL
c) apo-C deficiency
Type II LDL receptor defect
Familial Ch.

Type III (familial apo-E abnormality

Dysbetalipoproteinemia)

Type IV elevated production of VLDL

Familial Tg.
Type V elevated chylomicrons and
VLDLs due to unknown
cause

Familial hyper increased level of HDLs

alphalipoproteinemia

Familial LCAT absence of LCAT leads to

deficiency inability of HDLs to take up
cholesterol (reverse
cholesterol transport)
 Hypolipoproeinemia

Disorders Defect

Abetalipoproteinemia no chylomicrons, VLDLs or

LDLs due to defect in apo-
B expression

Familial hypobetalipoprot apoB gene mutations

einemia

Familial alpha-lipoprotein apoA-I and apoC-III

deficiency