LIPIDS

Goals/ objectives

These lectures will provide an understanding and
knowledge of the classification of lipids; their
structures and functions; essential and long chain
polyunsaturates; digestion, absorption and
storage; mobilisation, catabolism and ketone
synthesis; plasma lipoproteins; control of lipid
metabolism; synthesis of lipids, sterols and
steroids; eicosanoids; lipidoses and lipid-related
diseases.
LIPIDS 1

At the end of this lecture students be able to:

Define lipids;
Describe the different types of lipids;
Describe the structures of lipids and fatty acids;
and
Define and describe essential fatty acids and long
chain polyunsaturates.
Unlike proteins and carbohydrates, lipids cannot
be defined from the perspective of common
structural properties, but merely on the basis of
very broad common chemical similarities.

Classically lipids were defined as being soluble in
other lipids.

A better definition is that they are a chemically
heterogeneous group sharing insolubility in water
and solubility in organic solvents. Even this is not
true for all lipids, but it does hold true for lipids
from vertebrates, including mammals.

Within the mammalia most lipids are esters of
long chain fatty acids with glycerol, sphingosine or
a sterol.

Mammalian lipids can be
divided into:
Neutral (visible fat), and
Polar (invisible fat).
Neutral lipids are triacylglycerols (triglycerides),
diacylglycerols (diglycerides), monoacylglycerols
(monoglycerides), sterols and sterol esters.

Tri-, di- and mono-acylglycerols are esters of 3, 2
or 1 fatty acid(s) with glycerol.

Sterols are polycyclic alcohols.

Sterol esters are esters of polycyclic alcohols with a
fatty acid.


Triacylglycerols (TAGs) are the predominant
lipid fuel for metabolism.
Sterols form a major part of all cell
membranes to increase membrane stiffness
as well as forming the precursors for all the
steroid hormones.
H
2
C-O-R (R = any fatty acid)
|
HC-O-R
|
H
2
C-O-R

Triacylglycerol (triglyceride)

H
2
C-O-R
|
HC-O-R
|
H
2
C-O-H

Diacylglycerol (diglyceride)

H
2
C-O-H
|
HC-O-R
|
H
2
C-O-H

Monoacylglycerol (monoglyceride)

In acylglycerides the fatty acids in the 1 and/or 3
(outer) position(s) are sometimes unsaturated.
H
3
C H
2
C H
2
C CH
3
H
2
C H
2
C CH
H
2
C H
3
C CH CH
3
H
2
C C CH
2
H
2
C H
3
C HC HC CH
2
HC HC CH
HC C CH
2
HO H
2
C HC
CHOLESTEROL
H
3
C H
2
C H
2
C CH
3
H
2
C H
2
C CH
H
2
C H
3
C CH CH
3
H
2
C C CH
2
H
2
C H
3
C HC HC CH
2
HC HC CH
HC C CH
2
RO H
2
C HC
CHOLESTEROL ESTER
The range of triacylglycerols is enormous:

More than 25 possible fatty acids and in any
combination in threes - equates to thousands of
possible types.

Conversely, the range of cholesterol esters is limited
- only a single fatty acid from more than 25
possible.

Polar lipids are phosphoglycerides (phospholipids),
lysophosphoglycerides (lysophospholipids) and
sphingolipids.

Phosphoglycerides are esters of 2 fatty acids with
glycerol but with a phosphate and base group
attached to the 3 position of the glycerol.

Lysophosphoglycerides are esters of 1 fatty acid
with glycerol but with a phosphate and base group
also attached to the 3 position of the glycerol.

Sphingolipids are esters of a fatty acid with
sphingosine. Sphingolipids in a vast variety of types
form the basis for the structure and function of
neural tissues.

H
2
C-O-R (R = any fatty acid)
|
HC-O-R
|
H
2
C-O-PO
4
-X


Phosphoglyceride (phospholipid)

H
2
C-O-R
|
HC-O-H
|
H
2
C-O-PO
4
-X

Lysophosphoglyceride (lysophospholipid)

X = H, phosphatidic acid
Serine, serine phosphoglyceride
Choline, choline phosphoglyceride
Ethanolamine, ethanolamine phosphoglyceride
Inositol, inositol phosphoglyceride

In phosphoglycerides a fatty acid in the 2 (middle) postion is
usually a polyunsaturated fatty acid.
PHOSPHATIDIC ACID:



CHOLINE PHOSPHOGLYCERIDE:




ETHANOLAMINE PHOSPHOGLYCERIDE:
H
SERINE PHOSPHOGLYCERIDE:



LYSO SERINE PHOSPHOGLYCERIDE:


INOSITOL PHOSPHOGLYCERIDE:




INOSITOL PHOSPHOGLYCERIDE
BISPHOSPHATE:


CARDIOLIPIN:




The range of phosphoglycerides is huge:

6 different base groups and more than 25 possible
fatty acids - in pairs or singles this equates to
thousands of possible types.


Phosphoglycerides, mainly choline and ethanolamine,
form the major components of the cell membrane
lipid bilayer structure.
Serine and inositol phosphoglycerides and
cardiolipin are minor, but functionally important,
membrane components.
This model has been shown to be too simplistic.
There are now known to be specialised areas within
the membrane structure that are where most of the
membrane functions are located. These are known as
lipid rafts as they remain coherent within
themselves. They can often move within the overall
membrane structure, effectively float around, but in
a controlled manner not randomly.

They contain high concentrations of more complex
phosphoglycerides (inositol phosphoglyceride,
cardiolipin), sphingolipids (sphingomyelin, ceramides),
cholesterol and proteins.
They are where most of the internal and external
links to a cell occur, ie. the cytoskeleton and
extracellular matrix, as well as active
transmembrane proteins (channels, receptors).
Sphingolipids are a complex group of polar lipids,
based on the amino alcohol, sphingosine. This is
usually synthesised from palmitate (C16:0) and
serine, an amino acid. They are combined, but with
the loss of a carbon from serine. This is sphingosine.

Recently, sphingolipids made from myristate (C14:0)
and laurate (C12:0) have also been identified, but
their significance is still an area of debate.


PALMITATE SERINE
H H
CH
3
(CH
2
)
12
C = C COOH HOOC C - CH
2

H NH
2



H H H
CH
3
(CH
2
)
12
C = C C C - CH
2

H OH NH


SPHINGOSINE


The amine group now has a long chain fatty acid
attached, usually between 16 and 24 carbons in
length, and with zero or one double bond. This is
now ceramide and is the basis for all the many and
varied sphingolipids.
SPHINGOSINE

H H H
CH
3
(CH
2
)
12
C = C C C - CH
2

H OH NH

C = O
(CH
2
)
16-24
LONG CHAIN FATTY ACID

CH
3

CERAMIDE

Probably the most important sphingolipid
quantitatively is sphingomyelin. This has a
phosphocholine group attached to the serine residue.
Sphingomyelin is found in practically all membranes,
including plasma and subcellular organelles. It makes
up 5-20% of the polar lipids of most cell types.

Sphingomyelin is the only sphingolipid that contains
phosphate, and functionally in most cells acts to
stabilise membrane structure. In neural tissues it
also forms the major part of the lipid of the myelin
sheath.


SPHINGOSINE
PALMITATE SERINE PHOSPHOCHOLINE
H H H O
CH
3
(CH
2
)
12
C = C C C - CH
2
- O P O CH
2
CH
2
N
+
(CH
3
)
3

H OH NH O
-
C = O
(CH
2
)
16-24
LONG CHAIN FATTY ACID

CH
3

CERAMIDE

SPHINGOMYELIN

Other sphingolipids do not have phosphocholine
attached but rather have monosaccharides linked to
the same carbon.

The type of sphingolipid depends on the type of
saccharide attached, and this characterises them
into cerebrosides, sulphatides, globosides or
gangliosides.

Initially 1 glucose or 1 galactose is attached to form
gluco- and galactocerebrosides.



SPHINGOSINE
PALMITATE SERINE SACCHARIDE
H H H
CH
3
(CH
2
)
12
C = C C C - CH
2
- GLUCOSE/GALACTOSE
H OH NH

C = O
(CH
2
)
16-24
LONG CHAIN FATTY ACID

CH
3

CERAMIDE

CEREBROSIDE
Attachment of a sulphate to any of these forms a
sulphatide.

SPHINGOSINE
PALMITATE SERINE SACCHARIDE
H H H
CH
3
(CH
2
)
12
C = C C C - CH
2
- GLUCOSE/GALACTOSE-SO
4

H OH NH

C = O
(CH
2
)
16-24
LONG CHAIN FATTY ACID

CH
3

CERAMIDE

CEREBROSIDE
If no sulphate, further saccharides can then be
attached up to about 4 in some cases. Its rare for a
cerebroside with more than 1 saccharide to have all
the same type, thus most cerebrosides of higher
numbers of saccharides are mixed.

The most common cerebrosides have 1 glucose and 2
galactoses attached.

If one of the attached groups is galactosamine
(galNAc) then this is a globoside.

Gangliosides are more complex again.
SPHINGOSINE
PALMITATE SERINE SACCHARIDE
H H H
CH
3
(CH
2
)
12
C = C C C - CH
2
- GLUCOSE/GALACTOSE-NANA
H OH NH

C = O
(CH
2
)
16-24
LONG CHAIN FATTY ACID

CH
3

CERAMIDE

GANGLIOSIDE
Addition of sialic acid (N-acetyl neuraminic acid,
NANA) to the saccharide side chain produces a
ganglioside. Problems with ganglioside synthesis,
turnover and degradation form the basis of a range
of rare, genetic diseases.

The commonest gangliosides are:
CERAMIDE-GLUC-GAL-NANA GM3
CERAMIDE-GLUC-GAL-GALNAC GM2
NANA
CERAMIDE-GLUC-GAL-GALNAC-GAL GM1
CERAMIDE-GLUC-GAL-GALNAC-GAL GQ1b
NANA

Cholera toxin binds to intestinal GM1 as the first
stage of its uptake.

So, in summary:

Palmitic acid + serine = sphingosine
Sphingosine + long chain fatty acid = ceramide
Ceramide + phosphocholine = sphingomyelin
Ceramide + glucose/galactose = cerebroside
Cerebroside + sulphate = sulphatide
Cerebroside + galactosamine = globoside
Cerebroside + sialic acid = ganglioside


All the ABO blood group antigens are also
glycosphingolipids linked with cell surface proteins.


The range of sphingolipids is enormous:

3 possible fatty acids with serine and
10 possible fatty acids with sphingosine gives 30
different base sphingolipids.

4 classes of derivatives cerebrosides, sulphatides,
globosides and gangliosides so there are many
hundreds of possible types.



FATTY ACIDS

All fatty acids have a hydrocarbon backbone with a
carboxyl group at one end.
In mammals most fatty acids have an even number of
carbon atoms, usually between 12 and 24.
The term "acyl" refers to any fatty acid, thus
acylCoA is any fatty acid attached to coenzyme a
(CoASH).
Acyl is not the same as acetyl. Acyl can be any
chain length fatty acid, while acetyl is specifically
two carbons only.
Why attach coenzyme a to a fatty acid? Coenzyme A
cannot cross a cell membrane, thus attaching
coenzyme A to a fatty acid traps the fatty acid
inside the membrane. Also, most metabolism of fatty
acids requires them to be in the coenzyme A
derivative form, not the free fatty acid.




H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2
C C C C C C C C CH
3

H
3
C C C C C C C C C
H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2

UNSUBSTITUTED HYDROCARBON





H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2
C C C C C C C C COOH

H
3
C C C C C C C C C
H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2

GENERIC FATTY ACID

In energy metabolism saturated fatty acids are by
far the most important, while unsaturated fatty
acids are the most important for cell structure and
as specific hormone precursors.

A saturated fatty acid is one where all the possible
bonds have been filled up with hydrogen - it's
saturated.

An unsaturated fatty acid is one where one or more
double bonds have been inserted into the chain - so
it's not as full up with hydrogen as possible - it's
unsaturated.




H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2
C C C C C C C C COOH

H
3
C C C C C C C C C
H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2

SATURATED FATTY ACID





H
2
H
2
H
2
H
2
H H
2
H
2
H
2
C C C C C C C C COOH

H
3
C C C C C C C C C
H
2
H
2
H
2
H H
2
H
2
H
2
H
2

MONOUNSATURATED FATTY ACID

Within the unsaturated fatty acids there are two
groups - the monounsaturates with one double bond
and the polyunsaturates with two or more double
bonds.

Within the polyunsaturates there are two subclasses
- the omega 3 (N3) and omega 6 (N6) which will be
covered later.

Saturated and unsaturated fatty acids exhibit
distinctly different properties both in themselves and
in their functions in mammalian metabolism.




H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2
C C C C C C C C COOH

H
3
C C C C C C C C C
H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2

DIUNSATURATED FATTY ACID (POLYUNSATURATE)





H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2
C C C C C C C C COOH

H
3
C C C C C C C C C
H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2

TRIUNSATURATED FATTY ACID (POLYUNSATURATE)



Polyunsaturates occurring in cell structures, which is
the vast majority of them, have cis double bonds.
Processing of these in food production can
irreversibly convert cis double bonds to trans,
which are not usable for cell structures, only energy
supply.

Trans polyunsaturates cannot fulfil any of the roles
of cis polyunsaturates, but rather mimic saturated
fatty acids.

Cis double bonds introduce a curve to the chain of
the molecule, while trans mirror the straight chain
of a saturate.


C C
C
C C
C CIS
C

C
C C C C
TRANS
C C C C
Saturated and trans unsaturated fats are solid
at ambient temperatures, while cis unsaturated
fats are more liquid depending on the number of
double bonds in the fatty acid chains.
Why does this matter?

The greater the number of double bonds in a
fatty acid the lower its melting point and hence
the greater its fluidity at ambient temperatures.
A balance between polyunsaturates and saturates
controls the degree of fluidity of a membrane
and can be changed depending on the situation.
Only cis polyunsaturates can be metabolised to
the longer chain more unsaturated compounds
that mammals require.
ESSENTIAL FATTY ACIDS (EFAS)
Two polyunsaturated fatty acids are essential
in mammalian diets, that is cannot be
synthesised by mammals but are required for
normal health.
These two polyunsaturates are produced by
most plants, some fungi and some bacteria.
However, most humans dont eat much fungi or
bacteria, so the majority of our EFA
requirements are met by eating plants.
They, or their longer chain more unsaturated
derivatives, are important in membrane
structure, membrane fluidity, electrical
insulation, skin waterproofing, hormone
transmission and hormone production.
The two essential polyunsaturates are distinct
in the positions of their first double bond from
the methyl terminal end.
One has the first double bond between carbons
6 and 7, with a second between 9 and 10.
This is called N6 or omega 6.
The other has the first double bond between
carbons 3 and 4, with a second between 6 and
7, and third between 9 and 10. This is called
N3 or omega 3.





H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2
C C C C C C C C COOH

H
3
C C C C C C C C C
H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2

N6 EFA (CIS C18:2N6, LINOLEIC ACID)





H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2
C C C C C C C C COOH

H
3
C C C C C C C C C
H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2

N3 EFA (CIS C18:3N3, -LINOLENIC ACID)



Why name from the methyl terminal end?

Normal hydrocarbon nomenclature numbers
compounds from the end at which any
substitution has occurred, thus for fatty acids
this would be from the carboxyl end.

However, any chain elongation or shortening
always occurs at the carboxyl end, so if the
double bond positions were numbered from this
end then they would appear to move if the
chain length was increased or decreased.

Nothing ever happens closer to the methyl end
than the 9 carbon (omega 9, N9), hence
numbering from here gives a constancy of
double bond position. Any extra double bonds
are added towards the carboxyl end.

This allows for the inter-relationship of
polyunsaturates of the N6 or N3 series
derived from the respective plant parents to
be easily recognised.




H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2
C C C C C C C C COOH

H
3
C C C C C C C C C
H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2







H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2
C C C C C C C C C COOH

H
3
C C C C C C C C C C
H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2




METABOLISM OF EFAS
CIS C18:2N6 CIS C18:3N3
-6-DESATURASE
CIS C18:3N6 CIS C18:4N3
ELONGASE
CIS C20:3N6 CIS C20:4N3
-5-DESATURASE
CIS C20:4N6 CIS C20:5N3
ELONGASE
CIS C22:4N6 CIS C22:5N5
-4-DESATURASE
CIS C22:5N6 CIS C22:6N3
The first enzyme in the desaturase cascade is
the rate-limiting step, and also the site of
blockade of the pathway.
Many factors block the enzyme: high glucose,
high saturated fat, stress hormones, smoking,
alcohol.
To date no stimulators have been identified.
In humans, the activity of the enzyme
deteriorates with age and the above factors.
This implies an increasing requirement for the
cascade products in the diet with age.
Interestingly, one group of humans have lost
the expression of -6-desaturase because
they have an almost exclusively carnivorous diet
and are thus getting the products in plentiful
supply in their diet.
The inuit (eskimo) people have a diet very rich
in seal meat and seals eat fish very rich in
polyunsaturates.
The only other mammals proven to be obligate
carnivores are the felinae. All the cats lack -
6-desaturase, and thus ageing humans, and
especially westernised ones, are becoming
more and more like cats.
-6-desaturase deficiency and/or inhibition
has been implicated in many chronic health
conditions.

Polyunsaturate deficiency/imbalance has been
recognised as a contributor to many conditions,
either primarily or secondarily.
Signs include increased metabolic rate, poor hair
condition, hair loss, scaly dermatitis, open non-
healing sores and wounds, anoestrus and
infertility, poor sperm quality and infertility,
neuropathy and death.
Conditions known to involve or at least have a
component of polyunsaturate deficiency/imbalance:
Psoriasis, PMS, atherosclerosis, rheumatoid
arthritis, hyperactivity, cancers, diabetes
mellitus, cardiovascular disorders, obesity, hair
loss, dermatitis, atopic eczema, multiple sclerosis,
schizophrenia, aging, epilepsy.

THE END