Title of the lecture:

LIPID METABOLISM
By:
Asst. Professor

Dr. Salar A. Ahmed

PhD. Aristotle University of Thessaloniki – Greece

2018-2019

Tel: 0750 4101917

Email: salar.adnan@med.hmu.edu.krd
 6. Lipids metabolism

6.1. Triglyceride Metabolism

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

The catabolism and anabolism are not the forward and

reverse process of the same ,they are entirely different pathway
involving different reactant 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 acylCoA

a.2- Source of α – glycerol phosphate:

Mainly two source
1. Conversion of glycerol to α – glycerol-P by gly. kinase in the
presence of ATP
2. From glucose oxidation :dihydroxy acetone phosphate is
converted to α – gly.-P without ATP
Note :

 Glycerol kinase is absent in A.T

 Glycerol produced by lipolysis in AT can not be utilized for

provision of α-gly-P in AT.

 Glycerol From liver, kidney and other tissues which possess GK

utilized for α-glycerol phosphate synthesis
B- lipolysis( Breakdown of Triglycerid )

TG in AT and liver undergoes hydrolysis by hormone

sensitive TG lipase to form free FFAs and glycerol , HSL
remove FA from carbon No.1 and or C3 additional lipase
specific for diacyl or monoacyl glycerol removes the remaining
fatty acids
Hormonal regulation of triglycerol degradation in the
adipocyte
Mobilization of TAG
b.1. Fate of glycerol:

Glycerol release during lipolysis is transported through the

blood to the liver where it can be phosphorelated , used to form
TAG in the liver or can be converted to DHAP which can be
participate in glycolysis or gluconeogenesis
b. 2. Fate of fatty acids

Free FFAs move through the cell membrane of the

adipocyte and immediately bind to albumin in the plasma they
transport to the tissues , where the FA 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 which may be

• Saturated fatty acids : Do not have double bond 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 : The names typically derive

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(9) ω -7

Oleic acid 18:1 Δ9 ω-9
Linoleic acid 18:2 Δ9,12 Essential ω -6
Linonlenic acid 18:3 Δ9,12,15 FAs ω -3

Arachidonic acid 20:4 Δ5,8,11,14 ω -6

Eicosapentaenoic 20:5 Δ5,8,11,14,17 ω -3
acid
 The truth about fats:
The good, the bad, and the in-between
Saturated FFAs
1- Source of energy
2- In the food: usually accompanied with ch.
3- Enhance the level of T.ch. and LDL
4- Stability : Autooxidation takes place at higher T
5- Promote obesity and atherosclerosis

Note: Diet must be limited amount of saturated fatty

acids to reduce the above disadvantages.
 Unsaturated FFAs
Source of energy
In the food: usually accompanied with ch.
Resists to oxidation
Are essential nutrients that are important in preventing and
managing heart disease
is a primary structural component of the human brain,
cerebral cortex, skin, and retina.
 Omega-3 fatty acids (fish oil) which may helps 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
 Omega-6 FFAs

1- Omega-6 FFAs are used for reducing the risk of heart disease,
lowering T.ch. levels, lowering "bad" (LDL-C levels, raising
"good" (HDL) Ch. levels, and reducing cancer risk.
2- Vasoconstrictor
3- Pro inflammatory effects
4- Enhanced platelet aggregation
6.2.2. Anabolism of FFAs
General features

 Glucose is the primary substrate for lipogenesis.

 The major sites of FA synthesis is in the liver

 The enzymes that synthesized FA 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.
Note : Essential FFAs :
1. Essential FFAs must be obtained from 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 FA can occur either in endoplasmic reticulum or
mitochondria.
3. In endopasmic reticulum, the sequence of reaction is similar to
cytosol synthetic system. The elongation needs malonyl CoA and
NADPH, but ACP is not required.

4. In mitochondria, palmitate may enter mitochondrial by

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

The liver and AT contain the necessary enzymes for converting

palmitic to palmitoleic acid, 16:0 , 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.
 6.2.3. Oxidation of FA

Principle pathway by which FAs are oxidized in the body are

6.2.3.1. α –oxidation

6.2.3.2. β -oxidation

6.2.3.2. ω -oxidation
 Oxidation of FAs involve 3 stages

1. Activation of FAs

2. Transport into the mitochondria

3. Degradation to two-carbon fragments (as acetyl CoA) in the

mitochondrial matrix
1- FA activation

FA must be converted to active form before further metabolized

Note : Pyrophosphate then is hydrolyzed to 2 molecules of

phosphate., 2 high-energy P bonds are expended during the
activation of each FA molecule.
2-Transport of acyl-CoA into mitochondria

Most acyl-CoA are formed outside the mitochondria. The oxi. of

acyl-CoA is inside the inner membrane. The membrane is
impermeable to CoA and its derivatives.

This problem is overcome by an efficient shuttle system called

Carnitine shuttle .

Carnitine is used as a carrier of acyl group to across the membrane

 6.2.3.1. β- oxidation

The principle pathway by which FAs are oxidized is called β-

oxi. , the circulating FAs are taken by various tissues and
oxidized.

Tissues like liver , heart , kidney , muscle ,lung, testis and AT ,

have the ability to oxidize long chain FA, 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 ofβ-oxidation is catalyzed by acyl CoA
dehydrogenase to give an enoyl CoA with a trans-double bond between C-2 and
ATP C-3.

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 by L-β-hydroxyacyl CoA

ATP 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. 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 propionylCoA (3C). Propionyl-CoA further undergoes
carboxylation, molecular arrangement, and conversion to
succinyl CoA,

The succinyl coA can be metabolized via the TCA cycle, of

which it is an intermediate or it could be the substrate for heam
synthesis.
 6.2.5. Oxidation of unsaturated FAs

 One of the intermediate of β-oxidation of saturated FAs is Δ2-

trans-enoyl CoA, which can be hydrated to form L-β-OH-acyl
CoA.
 But the β-oxidation of unsaturated FAs will
produces Δ3-cis-enoylCoA and Δ2-cis-enoyl CoA.
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 :

1. Two additional enzymes are needed for the oxidation of un.

FAs: isomerase and epimerase

2. The presence of double bond in the fatty acid (The ATP

production on oxidation is less by two numbers”)
6.2.3.2. ω- Oxidation:

is an alternative pathway to β-oxi. that, 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

Is 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 chane FAs, which can’t oxidized by β-oxi. due to
its β-methyl branch (β-C atom blocked by methyl group), from
break down of chlorophyll.
 CH3 CH3
CH3(CHCH 2CH2CH2)3CHCH 2CO 2H

Phytanic Acid
 1.Cholesterol Metabolism
The total amount of ch. in human body is about 2g/kg body
weight.

Adrenal gland 100mg/g > brain20mg/g > liver 3mg/g > skeletal
muscle 1mg/g
The greatest part of the ch. of the body arises by biosynthesis (about
1g/day). Whereas only about 0.3g/day are provided by diet.

Ch. 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 ch. occurs in virtually all cells, this

capacity is greater in liver, intestine, adrenal cortex, and
reproductive tissues, including ovaries, testes, and placenta. But
70-80 % of endogenous ch. is formed in liver, 10 % in intestine.
 The major site: 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 of HMG CoA to mevalonic

acid by HMG CoA reductase

Formation of cholesterol from squalene

6.3.2. Metabolic conversion of cholesterol
 acetyl CoA diet
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 key enzyme, which catalyzes the

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

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 ch, 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-oxi. is acetyl CoA, which in many

tissues, except 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,

skeletal muscle conserves glucose for support of central nervous
system. With more prolonged starvation, brain can up take more
ketone bodies to spare glucose consumption
4. High Con. of ketone bodies can induce ketonemia and
ketonuria, and even ketosis and acidosis.
5. When carb. catabolism is blocked by a disease of D.M or
defect of sugar source, the blood con. 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 on the breath.
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, thromboxane (TX) A2 and
leukotriene (LT).)
 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 defect or deficiency of the -
hydroxylase which causes
• Nerve and retinal damage
• Bone and skin changes
7.2. Xanthomatosis : it 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

Is the first step in the development of cardiovascular disease,

followed by arteriosclerosis which is where Ca accumulate along with
ch., fat, and other substances found in the blood, forming hard plaques
which associated with thickening and hardening of arterial walls .

Formation of plaque and arterial narrowing;

Oxidative modification LDL: Oxidation of LDL by oxidants (like,

O2-. NO, H2O2)
Phagocytosis of oxidized LDL and foam cells formation
Endothelial cells injury either by oxidized LDL or mechanically
platelet aggregation arterial narrowing
6. CARNITINE :
L-carnitine is an AA. (a building block for proteins) 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.
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 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.
• 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.
•The vorious lipotropic agents are;
Choline
Methionine
Betaine
Vitamin B12 and folic acid are involved in the
formation of methionine from homocysteine.
Note:
Lipoprotien (a)
 Lipoprotein(a) was originally described as a new serum
lipoprotein particle by Kare Berg.
 is composed of a common LDL nucleus linked to
apolipoprotein(a) by disulfide bonds through apolipoprotein
B-100
 half-life of Lp(a) is approximately 3–4 days.
 its precise physiological function remains unclear.
 However, numerous epidemiological studies have
demonstrated that elevated plasma levels of Lp(a) are a
significant risk factor for the development of atherosclerotic
disease.
 is an independent predictor for atherosclerotic
cardiovascular disease (CVD) and peripheral arterial
disease
 it has been proposed that Lp(a) may compete with
plasminogen for binding sites, plasminogen, a protein
that promotes clot lyses,
 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

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

Familial hyper alpha increased level of HDLs

lipoproteinemia

Familial LCAT deficiency absence of LCAT leads to

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 apoB gene mutations
hypobetalipoproteinemia

Familial alpha-lipoprotein apo-A-I and -C-III

deficiency