Cell Signaling/ Biosignalling

 Biochemistry & Genetics-II

 Course Code: SHS.109
 Pre-requisite: 103
 Credit Hours: 3
Lecture by

Dr. Naveed Munir

PhD Biochemistry (GCUF & KCL, UK)
M.Phil, M.Sc Biochemistry (UAF)
B. Sc Med. Lab Technology (UHS)
Member Pakistan Association of Medical Lab scientists (MPAMLS)

REFERENCE TEXT BOOK:

Lippincott’s Illustrated Review of Biochemistry by Pamela C. Champe and Richard A. Harvey Latest Ed.
Essential of Medical Biochemistry, Mushtaq Ahmed Vol. I
 OUTLINES:
• Chylomicrons
• Introduction to lipoproteins
• Structure of lipoprotein
• Classification of lipoprotein
• Apolipoproteins
• Degradation of triacylglycerol by lipoprotein lipase
• Metabolism of VLDL
• Metabolism of LDL
• Receptors of LDL
• Function and metabolism of HDL
• Disorders of lipoproteins

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 Introduction

Lipids (Greek: lipos, means fat or hard)

are a heterogeneous class of naturally occurring
organic substances.
have a distinguished functional group or structural
features.
are insoluble in water and highly soluble in one or
more of the following solvents: ether, chloroform,
benzene and acetone. are widely distributed in the
biological world.
 Introduction

• Because of their insolubility in aqueous solutions, body lipids

are generally found compartmentalized,
• as in the case of membrane-associated lipids or droplets of
triacylglycerol in white adipocytes,
• or transported in plasma in association with protein, as in
lipoprotein particles or on albumin
 Functions of Lipids
• Storage of energy
–Reduced compounds: lots of available energy
–Hydrophobic nature: good packing

• Insulation from environment

–Low thermal conductivity
–High heat capacity (can “absorb” heat)
–Mechanical protection (can absorb shocks)
 Functions of Lipids

• Water repellant
–Hydrophobic nature: keeps surface of the organism
dry
•Prevents excessive wetting
•Prevents loss of water via evaporation

• Membrane structure
–Main structure of cell membranes
 More Functions
• Cofactors for enzymes
–Vitamin K (fat soluble): blood clot formation
–Coenzyme Q: ATP synthesis in mitochondria
• Signaling molecules
–Paracrine hormones (act locally)
–Steroid hormones (act body-wide)
–Growth factors
–Vitamins A and D (hormone precursors)
• Antioxidants
–Vitamin E (Fat Soluble)
 Dietary lipids

• The average daily intake of lipids by U.S. adults is about 81g,

of which more than 90% is normally triacylglycerol (TAG,
formerly called triglyceride).
Dietary lipids
 Lipoproteins- Structure,
classification, metabolism and
significance

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 General Structure of Lipoproteins

• Surrounded by a single surface layer of amphipathic

phospholipid and cholesterol molecules
• These are oriented so that their polar groups face outward
to the aqueous medium.
• The protein moiety of a lipoprotein is known as an
apolipoprotein or apoprotein.

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 General Structure of Lipoproteins

Some apolipoproteins are integral and cannot be removed, whereas

others can be freely transferred to other lipoproteins.
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 Apolipoproteins
The apolipoproteins associated with lipoprotein particles have a
number of diverse functions:
Recognition sites for cell-surface receptors

Activators or coenzymes for enzymes involved in lipoprotein

metabolism.
As essential structural components of the particles and cannot be
removed
Whereas others are transferred freely between lipoproteins.

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 Classes of lipoproteins
Divided by structure and function into five major
classes.

•A through E, with most classes having subclasses, for

example,
•Apolipoprotein (or apo) A-I and apo C-II.
•They are enzyme cofactors.

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 Classification of Lipoproteins

• There are various types of lipoproteins:

• They differ in
–lipid and
–protein composition
and therefore, they differ in:
- Size and density
- Electrophoretic mobility

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 Classification of Lipoproteins

1. Chylomicons:

Derived from intestinal absorption of triacylglycerol and

other lipids.
•Density is generally less than 0.95 g/dL

•while the mean diameter lies between 100- 500 nm

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 Classification of Lipoproteins

2. Very low density lipoproteins (VLDL), derived from the

liver for the export of triacylglycerol

3. Intermediate density lipoproteins (IDL) are derived

from the catabolism of VLDL, with a density ranging
intermediate between Very low density and Low density
lipoproteins

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 Classification of Lipoproteins

4. Low-density lipoproteins (LDL), representing a

final stage in the catabolism of VLDL

5. High-density lipoproteins (HDL), involved in

cholesterol transport and also in VLDL and
chylomicron metabolism.

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 Classification of
Lipoproteins

Types, density,
Composition and Sizes
of
Lipoproteins

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 Chylomicrons
Types and
Composition
of Very low density
Lipoproteins Lipoprotein (VLDL)

Low density
Lipoprotein (LDL)

High density
Lipoprotein (HDL)

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 Classification of Lipoproteins

Based on electrophoretic mobility's

Lipoproteins may be separated according to their
electrophoretic properties into - α, pre β, β, and
broad beta lipoproteins.

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 Classification of Lipoproteins

• The mobility of a lipoprotein is mainly dependent

upon protein content.
• Those with higher protein content will move faster
towards the anode and those with minimum protein
content will have minimum mobility.

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 Lipoprotein Electrophoresis

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 Metabolism of chylomicrons

• The particle released by the intestinal mucosal cell

is called a “nascent” chylomicron because it is
functionally incomplete.
• When it reaches the plasma, the particle is rapidly
modified, receiving apolipoprotein E (which is
recognized by hepatic receptors) and C

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 Metabolism of chylomicrons

• Apolipoprotein-C (apo C-II), which is necessary for

the activation of lipoprotein lipase, the enzyme that
degrades the triacylglycerol contained in the
chylomicron.
• The source of these apolipoproteins is circulating
HDL.

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 Degradation of triacylglycerol by
lipoprotein lipase
• Lipoprotein lipase is an extracellular enzyme
predominantly those of adipose tissue and cardiac
and skeletal muscle.
• Lipoprotein lipase, activated by apo C-II on
circulating lipoprotein particles, hydrolyzes the
triacylglycerol contained in these particles to yield
fatty acids and glycerol.

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 Degradation of triacylglycerol by
lipoprotein lipase

•The fatty acids are stored (by the adipose) or used for
energy by the muscle.
•Glycerol is used by the liver, for example, in lipid
synthesis, glycolysis, or gluconeogenesis.

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 Degradation of triacylglycerol by
lipoprotein lipase

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 Metabolism of VLDL
• VLDLs are produced in the liver

• Composed predominantly of endogenous triacylglycerol

(approximately 60%), and their function is to carry this
lipid from the liver (site of synthesis) to the peripheral
tissues.
• There, the triacylglycerol is degraded by lipoprotein
lipase, as discussed for chylomicrons

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 Release from liver
• VLDL are secreted directly into the blood by the liver as
nascent VLDL particles containing apo B-100.
• They must obtain apo C-II and apo E from circulating
HDL.
• As with chylomicrons, apo C-II is required for activation
of lipoprotein lipase

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 Modification of circulating VLDL

• As VLDL pass through the circulation, triacylglycerol is

degraded by lipoprotein lipase, causing the VLDL to
decrease in size and become denser.

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 Production of LDL from VLDL in the
plasma
• With these modifications, the VLDL is converted in the
plasma to LDL.
• Intermediate sized particles, the intermediate-density
lipoproteins (IDL) or VLDL remnants, are observed
during this transition.

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 Metabolism of VLDL

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 Metabolism of LDL
• LDL particles contain much less triacylglycerol than their
VLDL
• High concentration of cholesterol and

• High cholesteryl esters.

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 Metabolism of LDL
Receptor-mediated endocytosis:
• The primary function of LDL particles is to provide
cholesterol to the peripheral tissues (or return it to the
liver).
• They do so by binding to cell surface membrane LDL
receptors that recognize apo B-100 (but not apo B-48).

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 Metabolism of LDL

• Because these LDL receptors can also bind apo E, they are
known as apo B-100/apo E receptors.
• A similar mechanism of receptor-mediated endocytosis is
used for the cellular uptake and degradation of
chylomicron remnants and IDLs by the liver.

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 Metabolism of LDL
• Negatively charged glycoproteins that are clustered in pits
on cell membranes
• The cytosolic side of the pit is coated with the protein
clathrin, which stabilizes the shape of the pit.

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 Metabolism of LDL
• After binding, the LDL-receptor complex is internalized
by endocytosis.
• The vesicle containing LDL loses its clathrin coat and
fuses with other similar vesicles, forming larger vesicles
called endosomes.
• The pH of the endosome falls (due to the proton-pumping
activity of endosomal ATPase), which allows separation
of the LDL from its receptor.
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 Metabolism of LDL
• The receptors can be recycled, whereas the lipoprotein
remnants in the vesicle are transferred to lysosomes and
degraded by lysosomal acid hydrolases.
• Releasing free cholesterol, amino acids, fatty acids, and
phospholipids.
• These compounds can be reutilized by the cell.

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 LDL: Receptor-Mediated Endocytosis

Acetyl-Coenzyme A acetyltransferase

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 Metabolism of HDL
• HDL comprise a heterogeneous family of lipoproteins
with a complex metabolism.
• HDL particles are formed in blood by the addition of lipid
to apo A-1, an apolipoprotein made by the liver and
intestine and secreted into blood
• Apo A-1 accounts for about 70% of the apoproteins in
HDL

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 Functions of HDL
• HDL is a reservoir of apolipoproteins:

• HDL particles serve as a circulating reservoir of apo C-II

(the apolipoprotein that is transferred to VLDL and
chylomicrons, and is an activator of lipoprotein lipase), and
• apo E (the apolipoprotein required for the receptor mediated
endocytosis of IDLs and chylomicron remnants).

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 Functions of HDL
HDL uptake of unesterified cholesterol:
• Nascent HDL are disk shaped particles containing
primarily phospholipid and apolipoproteins A, C, and E.

• They take up cholesterol from non-hepatic (peripheral)

tissues and return it to the liver as cholesteryl esters

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 Functions of HDL
Esterification of cholesterol:
•When cholesterol is taken up by HDL, it is immediately
esterified by the plasma enzyme lecithin: cholesterol
acyltransferase (LCAT).
•Phosphatidylecholine (PC) act as donor of fatty acid and
converted into lyso-PC

Esterification
•Maintains the cholesterol concentration gradient, allowing
continued
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efflux of cholesterol to HDL.
 Functions of HDL
Reverse cholesterol transport:
•The selective transfer of cholesterol from peripheral cells to
HDL, and from HDL to the liver for bile acid synthesis and
to steroidogenic cells for hormone synthesis, is a key
component of cholesterol homeostasis.

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 Metabolism of HDL
• This is, in part, the basis for the inverse relationship seen
between plasma HDL concentration and atherosclerosis,
and for HDL’s designation as the “good” cholesterol
carrier
• The efflux of cholesterol from peripheral cells is
mediated, at least in part, by the transport protein,
ABCA1.

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 ABCA1

• An ATP-binding cassette A1 (ABC) protein

• ABC proteins use energy from ATP hydrolysis to

transport materials, including lipids, in and out of cells
and across intracellular compartments

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 Metabolism of HDL

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