Lipids Metabolism

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 Lipids
 Lipids constitute a heterogeneous group of compounds of
biochemical importance.
 Lipids may be defined as compounds which are relatively
insoluble in water, but freely soluble in nonpolar organic
solvents like benzene, chloroform, ether, hot alcohol,
acetone, etc.
Major functions
• Fuel molecules
• Signal molecules
• Component of cell membranes
• Carrier of vitamin
• Thermal insulator
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• Cushion and lubrication
 Classifications of lipids:
Based on the chemical nature, lipids are classified as:

1- Simple Lipids: They are esters of fatty acids with glycerol

or other higher alcohols (e.g. triacylglycerols)

2- Compound Lipids: They are fatty acids esterified with

alcohol; but in addition, they contain other groups
(Phospholipids, Glycolipid ,Lipoproteins)

3- Derived Lipids: They are compounds which are derived

from lipids or precursors of lipids, e.g. fatty acids, sterols such
as: (cholesterol) and fat-soluble vitamins.
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 Fatty Acids:

 Fatty acids are simply linear chains of carbon hydrogen bonds ) C – H

bonds) that terminate with a carboxyl group.

 In plasma, only a relatively small amount of fatty acids exist in the free
unesterified form, most of which is bound to albumin.

 The majority of plasma fatty acids are instead found as a constituent of

triglycerides or phospholipids.

 Fatty acids are covalently attached to the glycerol backbone of

triglycerides and phospholipids by an ester bond that forms between the
carboxyl group on the fatty acid and the hydroxyl group (MOH) on
glycerol

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 Triglycerides:
Triglycerides contain three fatty acid molecules attached to
one molecule of glycerol by ester bonds.
Triglyceride is present in dietary fat (exogeneous source ) and
can be synthesized in the liver and adipose tissue
(endogenous ) to provide a source of stored energy.
95 % of body fat is triglycerides.
Cushion organs such as the eyes and kidneys
Triglyceride catabolism is regulated by lipase, epinephrine and
cortisol.
Triglycerides transported by Chylomicrons ( exogeneous ) and
VLDL ( endogenous ).

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 Phospholipids:
 phospholipids are similar in structure to triglycerides except
that they only have two esterified fatty acids.
 The third position on the glycerol backbone contains a
phospholipids head groups, such as: choline, inositol, serine,
and ethanolamine, which are all hydrophilic in nature.
Because phospholipids contain both hydrophobic fatty acids
(C – H chains) and a hydrophilic head group, they are by
definition amphipathic lipid molecules and as such are
found on the surface of lipid layers.
Part of cell membranes (lecithin).
Form the myelin sheath to provide electrical insulation for
neurons.
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 Cholesterol:

 Cholesterol is an unsaturated steroid alcohol containing

four rings (A,B,C, and D), and it has a single C – H side
chain tail similar to a fatty acids in its physical
properties.
 The only hydrophilic part of cholesterol is the hydroxyl
group in the A -ring. Cholesterol is, therefore, also an
amphipathic lipid and is found on the surface of lipid
layers along with phospholipids.
 Part of cell membranes.
 Converted to vitamin D in the skin on exposure to UV
rays of the sun.

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 Cholesterol:
 Converted by the liver to bile salts, which emulsify fats
during digestion.
 Precursor for the steroid hormones such as estrogen in
women (ovaries) or testosterone in men (testes).
 Exogeneous cholesterol comes from diet.
 Endogeneous cholesterol is synthesized by the liver.
 70 % of cholesterol associated with cellular components.
 30 % is in the plasma ( ⅓ free cholesterol , ⅔ esterified
cholesterol )
 Transported by high-density lipoprotein (HDL) and low-
density lipoprotein (LDL).

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 Physiology of lipids
Involves three phases
A- Digestive phase
 Triglycerides are digested by lipase, in the gut to form
fatty acids and diglycerides.
 In the small intestine cholesterol, fatty acids,
diglycerides, phospholipids becomes surrounded by bile
to form a micelle package that triglycerides in the
micelles are broken down into fatty acids, glycerols and
monoglycerides by action of pancreatic lipase and bile
acids.

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 B- Absorptive phase
 Occurs in the small intestine (enterocytes) as
components of triglycerides reassembled.
 Triglycerides, Cholesterol, phospholipids packaged
with apo B-48 to form chylomicrons (for transport)
and enter the lymphatic system and eventually reach
circulation.
 Short fatty acids enter the blood bound to albumin,
and these head to all tissues, including adipose
tissue.
C- Transport phase
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 Lipoprotein
Lipoproteins are typically spherical in shape and
composed of both lipids and proteins, called
apolipoproteins.
The lipoprotein system evolved to solve the problem of
transporting fats around the body in the aqueous
environment of the plasma.
The amphipathic cholesterol and phospholipid
molecules are primarily found on the surface of
lipoproteins, whereas the hydrophobic and neutral
triglyceride and cholesteryl ester molecules are found
in the central or core region.
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 Classification of Lipoproteins

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 Based on density
The size of the lipoprotein particle correlates with its
lipid content.
The larger lipoprotein particles contain more lipid
relative to protein and thus are lighter (lower) in
density.
The various lipoprotein particles were originally
separated by ultracentrifugation into different density
fractions (chylomicrons, VLDL, LDL, and HDL),
which still form the basis for the most commonly used
lipoprotein classification system.

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 Based on electrophoresis mobility

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 Based on core composition
 Triglyceride rich lipoproteins:
1- Chylomicrons (CM)
2- Very low-density lipoprotein (VLDL)
3- Intermediate density lipoprotein (IDL)
 Cholesterol rich lipoproteins:
1- Low density lipoprotein (LDL)
2- High density lipoprotein (HDL)

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Chylomicrons:
Chylomicrons, which contain apo
B-48, are the largest and the least
dense of the lipoprotein particles.
Because of their large size, they
reflect light and account for the
turbidity of postprandial plasma.
Because they are so light, they
also readily float to the top of
stored plasma and form a creamy
layer, which is a hallmark for the
presence of chylomicrons.

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 Metabolism of Chylomicron:
The newly synthesized chylomicrons in the intestine are
initially secreted into the lymphatic ducts and eventually enter
the circulation.
Chylomicrons are the major transport form of exogenous
(dietary) fat (principally triglycerides 90%, but also
cholesterol).
Triglycerides are removed from chylomicrons by the action of
the enzyme lipoprotein lipase (LPL), located on adipose tissue,
skeletal and cardiac muscle, with the result that FFAs are
delivered to these tissues to be used either as energy substrates
or, after re-esterification to triglyceride, for energy storage.

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 Metabolism of Chylomicrons:
LPL is activated by apo C-II. Apo A and apo B-48 are
synthesized in the gut and are present in newly formed
chylomicrons; apo C-II and apo E are transferred to
chylomicrons from HDL.
As triglycerides are removed from chylomicrons by the
action of LPL, they become smaller; cholesterol,
phospholipids, apo A and apo C-II are released from the
surface of the particles and taken up by HDL.
Esterified cholesterol is transferred to the chylomicron
remnants from HDL, in exchange for triglyceride, by
cholesteryl ester transfer protein.
The chylomicron remnants, depleted of triglyceride and
enriched in cholesteryl esters, are cleared rapidly from the
circulation by the liver.
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 VLDL
VLDL is produced by the liver and
contains apo B-100, apo E, and apo Cs;
like chylomicrons, they are also rich in
triglycerides.
They are the major carriers of endogenous
(hepatic-derived) triglycerides and
transfer triglycerides from the liver to
peripheral tissue. Like chylomicrons, they
also reflect light and account for most of
the turbidity observed in fasting
hyperlipidemic plasma specimens,
although they do not form a creamy top
layer like chylomicrons, because they are
smaller and less buoyant.
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 Metabolism of VLDL:
Most triglycerides in the liver that are packaged into VLDL
are derived from the diet after recirculation from adipose
tissue.
 Only a small fraction is synthesized de novo in the liver
from dietary carbohydrate.
VLDL particles, once secreted into the circulation, undergo
a lipolytic process similar to that of chylomicrons.
Triglycerides being removed by the action of LPL.
 As the VLDL particles become smaller, phospholipids,
free cholesterol and apolipoproteins are released from their
surfaces and taken up by HDL, thus converting the VLDL
to denser particles, IDL.
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 Metabolism of IDL:

Cholesterol that has been

transferred to HDL is esterified and
the cholesteryl ester is transferred
back to IDL by cholesteryl ester
transfer protein in exchange for
triglyceride. More triglycerides are
removed by hepatic triglyceride
lipase, located on hepatic
endothelial cells, and IDLs are
thereby converted to LDL,
composed mainly of cholesteryl
esters, apo B-100 and phospholipid.

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 Metabolism of LDL:
LDL is the principal carrier of cholesterol,
mainly in the form of cholesteryl esters.
LDL is formed from VLDL via IDL.
Catabolism of LDL takes place in the
liver and peripheral tissues via receptor
mediated endocytosis
 apo B100 of LDL binds to a specific
B100 receptor located on plasma
membrane of cells.
 Once they bound to LDL receptors,
they are endocytosed by cells and
transported to the lysosome, where
they are degraded.

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 Metabolism of LDL:
The cholesterol derived from LDL affect cholesterol content by
several ways:
 de novo cholesterol synthesis decreases due to inhibition of
HMG CoA reductase ((hydroxymethylglutaryl coenzyme A
reductase) gene expression
 Decrease LDL receptor gene expression
 If cholesterol is not required immediately, its stored in the cell
as cholesterol ester by the action of acyl CoA:cholesterol
acyltransferase (ACAT).

 LDL Transport cholesterol from the liver to all tissues. So, LDL
is regarded as bad cholesterol (High levels of LDL -
cholesterol increase the risk of atherosclerosis).
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 HDL
 HDL, the smallest and most
dense lipoprotein particle, is
synthesized by both the liver and
intestine.
 It is also called good cholesterol
(anti- atherogenic in nature).
 One of the major roles of HDL is
to maintain the equilibrium of
cholesterol in peripheral cells by
the reverse cholesterol transport
pathway.
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 Metabolism of HDL:
Cholesterol , is converted to cholesteryl ester by lecithin-
cholesterol acyltransferase (LCAT), which is activated by
apo A1.
Cholesteryl esters are transferred from HDL to remnant
particles by cholesteryl ester transfer protein (CETP) which
are taken up by the liver.
Delivering these cholesteryl esters to the liver (reverse
cholesterol transport) for uptake via scavenger receptor-B1
(SR-B1), carry good cholesterol.
Cholesterol that reaches the liver is then directly excreted
into the bile or first converted to a bile acid before excretion.

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