Lipids

Defined on the basis of solubility.

Lipids are heterogeneous group of water insoluble
(hydrophobic) organic molecules, they are
chemically diverse compound but have one
feature: water insoluble

Functions

The biological functions of lipids are divers as their

chemistry
1. Lipids in form of a bilayer are essential components
of biological membranes.
2. Lipids containing hydrocarbon side chains serve as
energy stores.
3. Many intra-and intercellular signaling events
involve lipid molecules.

* dietary fats are absorbed in the small

intestine
- dietary lipids are not digested to any extent in
the mouth or stomach in adults.
The rate of action of acid-stable lipase is very
slow in adults, because it is active only at neutral
pH.
In the duodenum : emulsification of the dietary
lipids occurs.
* Lipids are insoluble hydrolysis occurs only at
the interfaces emulsification increase surface
area of lipid droplets .
- this occurs by:

1- bile salts act as detergents.

bile salt = bile acid (steroid nucleus) + glycin or
taurine.
2- mechanical mixing due to peristalsis Forming
of micelles

* Absorption of lipids by intestinal mucosal cells

The primary products of dietary lipid degradation with the bile salts from mixed micelles.
Short and medium chain length F.A dont need micelles formation to be absorbed (pass
directly)
Effect of unsaturated fatty acid on the absorption of Cholesterol !!!!
hydrophilic

Hydrophobic
core

Brush membrane

Resynthesis of triacylglycerol and cholesteryl esters by the

intestinal mucosal cell

Formation of micelles increase

the surface of lipids exposed to
the enzymes which is water
soluble.
Free Fatty acid are
transported via albumin

T.G lipase 2-monogycerol

+ 2 F.A

Cholesterol ester
cholesterol

Triacylglycerol is hydrolyzed by
Hormone sensitive lipase
Free fatty acid are transported
to muscle cells carried by
Albumin

* Cholesterol and other lipids are carried on plasma lipoproteins:

- cholesterol, cholesterol esters and other lipids are essentially

insoluble in water. To be moved from one part to another they
should carried as plasma lipoprotein.
Plasma lipoproteins
- Macromolecular complexes of lipids and specific proteins called
apolipoprotein with a various combination of phospholipids,
cholesterol, cholesterol esters and TG.
* Function : to keep the lipid soluble for transporting them between
organs and also provide efficient mechanism for delivering their
lipid contents to the tissues.

Chylomicrons

* Composition of plasma lipoproteins

- TG and cholesterol esters are mainly carried by lipoprotein (In the
core : TG + cholesterol ester, In the surface : hydrophilic parts of
cholesterol, phospholipids and hydrophilic parts of apolipoproteins
Each class of lipoprotein has specific function determined by point of
synthesis, lipid composition and apolipoprotein content.
The composition of the circulating lipoproteins is not static. They are
in dynamic state with continuous exchange of components between the
various types

* Size and density of lipoprotein particles

different combinations of lipids and proteins produce different densities
- can be separated by ultra centrifugation.

Classification and characteristics of lipoproteins

Functions of apolipoproteins

Apolipoproteins : the free

form, have several functions,
structural component,
recognition sites, activators
or coenzymes.

The composition of circulating lipoproteins are in dynamic state with

continuous exchange of components between the various types.
*TG-rich particles
Chylomicrons-exogenous TG
VLDL: endogenous lipids from liver to cells
IDL: normally it is transient intermediate lipoprotein undetectable in
plasma, formed during the conversion of VLDL into LDL
These particles, because of their large size reflect light and plasma
containing high concentration appears turbid or milky (lipemia), it a turbid
plasma sample is left standing for 18 hr at 4C the larger chylomicrons(
lowest density) form a creamy layer on the surface
Lipemia: presence of high amount of TG in plasma and it appears turbid
because these particles are large in size so they scatter light

* Lipoproteins that contain mostly cholesterol

LDL formed from VLDL
HDL
These lipoproteins of small size do not scatter light, even at high
concentration in plasma do not produce lipaemia.
*The small chylomicron remnants are composed mainly of cholesterol,
apoB and apoE
Endogenous Lipid pathway
- the liver is the main source of endogenous lipids
These lipids are transported from the liver in VLDL
Plasma taken from a fasting subject contains only LDL, VLDL, and HDL,
CM and IDL are not seen in fasting normal subjects.
70% of plasma cholesterol is incorporated in LDL and only 20% in HDL,
the measured plasma cholesterol conc. primarily reflects LDL conc. and TG
conc. those of VLDL

The Exogenous and Endogenous lipid cycle.

Metabolism of lipoproteins

* Metabolism of Chylomicrons
* The nascent chylomicron that released by intestinal mucosal cells contain
apo B48 (unique for chylomicrons) then this nascent chylomicron is rapidly modified receiving
apo E and apo C.II from circulating HDL.
* Function: transport dietary TG to adipocysts and muscle and also to transport
Cholesterol and lipid soluble vitamin to the liver
* Degradation of chylomicrons
lipoprotein lipase : (activated by apo C.II) hydrolyses TG in these particles into free
fatty acids and glycerol.
*Chylomicrons lipoprotein lipase chylomicron remnants (decrease size, increase density)
- apolipoprotein C NOT E is returned to HDL and the remnant is taken up by
hepatocytes.
- Receptors of hepatocytes recognize the remnant through apo E activation of up
taking by endocytosis degradation by lysosomes release cholesterol.
- The release of cholesterol regulate the cholesterol synthesis in the liver by decrease
HMG CoA reductase and also inhibit allosterically this enzyme.
*The small chylomicron remnants are composed mainly of cholesterol, apoB and apoE
The remnants enter to the liver cells (apo E is binds to its receptors) release chol
and degrade proteins
*Dietary TG have been delivered to adipose tissue and muscle and cholesterol to liver
The uptake of Cholesterol remnants, unlike of LDL, is not influenced by the amount of
Cho in hepatic cells.

* Metabolism of Chylomicrons
- The largest in size and least density of lipoproteins.
- Synthesized in the endoplasmic reticulum of epithelial cells that line the small
intestine, then they are packaged in secretary vesicles by Golgi and exported to
lymphatic system then enter the blood stream.

* Metabolism of very low density lipoprotein (VLDL)

* VLDL : produced in liver and composed mainly of TG and their function to

carry lipids from liver to peripheral tissues and are degraded by
lipoprotein lipase
VLDL are the principal transport form of endogenous TG TG are removed by

lipoprotein lipase (LPL).

- Excess of F.A can be converted into TG in the liver and packaged with
specific apolipoprotein to form VLDL.
- Excess CHO can be converted into F A in the liver and converted into TG

packaged as VLDL
VLDL contain TG , some cholesterol, apo B100, apo CII and apo E
Apo E and some apo CII is transferred from the circulating HDL

* VLDL are transported in the blood from the liver to muscle and adipose
tissue.
VLDL lipoprotein lipase free F.A
- oxidation (myocytes) OR resynthesis of
TG (adipocytes)

Metabolism of very low density lipoprotein (VLDL)

* Cholesterol that was transferred to

HDL is esterified and then is
transferred to VLDL which became
denser and smaller (IDL)

*Cholesterol esters transfer from

HDL to VLDL by cholesterol ester
binding protein CEPT in exchange with
TG and PL

*Some IDL taken up by liver via LDL

receptors
Further TG in IDL is removed by
hepatic triglyceride lipase located on
the hepatic endothelial cells and IDL
is converted into LDL

Metabolism of LDL
* LDL are the principal carriers of cholesterol mainly in the cholesterol ester.
* They are formed from VLDL via IDL
-LDL particles have apo B-100, contain less TG, high concentration of cholesterol
and cholesterol esters.
- The primary function of LDL is to provide the peripheral tissue with cholesterol
by known mechanism called Receptor- mediated endocytosis.
* apo B-100 is recognized by LDL- receptor internalization and lysosomal
degradation with release of free cholesterol
- VLDL contains apo B-100, but cant bind to LDL receptors. (the conversion of
VLDL into LDL) exposes of the receptor- binding domain of apo B-100
* Fate of cholesterol
- cholesterol that enter the cell can be incorporated into the cell membrane or
can be re-esterified by acyl-CoA:cholesterol tansferase (ACAT) for storage as
form of cholesterol esters.
* LDL also con be up taken by liver cells mediated by apo E.

*Receptor- mediated endocytosis

Cholesterol is delivered from LDL
into the peripheral cells.

* LDL receptors
deficiency
elevation of plasma
LDL
increase
plasma cholesterol.

Peripheral
cells uptake
cholesterol.

How can the body distinguish between the exogenous or endogenous

cholesterol

Practically the live can distinguish the particles that carry the cholesterol;
Endogenous: carried by LDL and the uptake of LDL by the liver or other
cells is highly regulated.
Exogenous (from diet): carried by chylomicrons, the chylomicron remnants
transport dietary cholesterol to the liver.
High level of exogenous cholesterol increase its entrance to the liver
decrease the synthesis of cholesterol and decrease the synthesis of
LDL receptors decrease the uptake and increase the level of circulating
cholesterol.
* Exercises increase the LDL receptors reduce the LDL-cholesterol level
* Estrogens also increase the LDL receptors reduce the circulating
cholesterol level LDL of female is less than male
* thyroid hormones (T3) has +ve effect on the binding of LDL to its
receptors hypothyroidism is a common cause of Hypercholesterolemia

Role of oxidized lipoproteins in plaque formation in arterial wall

Pathogenesis of atherosclerosis

Macrophages derived from monocytes can take up LDL via specific receptors
The uptake will be
activated when
LDL will be
oxidized via nonspecific
receptors
oveloading with CE
foam cells
component of
plaques
atherosclerosis

Factors influencing plasma LDL concentrations

-The plasma LDL concentration (the measured plasma cholesterol
concentration), is determined mainly by the rate of uptake by LDL
receptors.
*The liver has a central role in cholesterol metabolism because it:
1. Contains most of the LDL receptors
2. Synthesizes most of the endogenous cholesterol
3. Receives cholesterol from the diet and from lipoproteins
4. Is the only organ that can excrete cholesterol from the body in the bile
*The concentration of LDL receptors on hepatic cell surfaces depends on
the amount of cholesterol accumulated in the liver cells.
High intracellular cholesterol level number of receptors is reduced
increase the circulating cholesterol.
*Factors that lead to the accumulation of cholesterol in the liver will, by reducing
receptor numbers, increase plasma LDL concentrations.

Cholesterol absorption from the intestine is increased if the diet is rich in

saturated fat, efficient micelle formation chylomicrons transported

to the liver in chylomicron remnant particles that are taken up by chylomicronremnant receptors.
These receptors are not down regulated as LDL receptors
Inhibition of hepatic cholesterol synthesis, by suppression of the enzyme HMG

CoA reductase, may not prevent intracellular accumulation if dietary intake is

excessive.
Intracellular cholesterol accumulation leads to a reduction in LDL receptor
activity. LDL entry into cells therefore falls and plasma concentrations rise.
Cholesterol can be excreted from the body in bile either as cholesterol or
as bile salts. Some bile acids are reabsorbed from the intestinal lumen. Any
interruption to the enterohepatic circulation results in an increased conversion
of cholesterol to bile acids reduction in hepatic cholesterol stores
increase in the number of LDL receptors.
*The rate of hepatic LDL receptor synthesis is also increased by estrogens and
by thyroid hormones.

* Metabolism of HDL
- Synthesized in the liver and small intestine as small, protein- rich particles that
contain little cholesterol and no cholesterol esters. (nascent HDL, depleted HDL)
- Contain apo A.I, C.II, C.III and others and
LCAT (lecithin- cholesterol acyl transferase) which is called also
PCAT (phosphatidyl choline- cholesterol acyl transferase)
- LCAT is found at the surface of nascent HDL converts the cholesterol and PL
of chylomicron as VLDL remnant to cholesterol esters that forms the core of
HDL and formation of mature spherical HDL particle.
- Then the cholesterol rich HDL returns to the liver where the cholesterol is
unloaded that can be converted into bile salts.
* Depleted HDL can be pick up cholesterol stored in extra hepatic tissues and
carry it to the liver in Reverse Cholesterol Transport pathway.

Nascent HDL binding cholesterol rich cell

from cell to the HDL
goes to the liver.

passive movement of cholesterol

- up taking of cholesterol from cells by enzyme LCAT and storing of cholesterol

ester in the core of HDL.

* Metabolism of HDL
*Nascent HDL acquires free cholesterol from extrahepatic
cells, chylomicrons and VLDL, the nascent HDL is converted
into HDL3.
*Nascent HDL binding cholesterol rich cell passive
movement of cholesterol from cell to the HDL

*The cholesterol is esterified by LCAT and CE is transferred

to remnant lipoproteins by cholesteryl ester transfer protein
(CETP) in exchange for TG
* apo A is activator for LCAT
*Remnant particles are removed from circulation by the liver
*Cholesterol is excreted in bile as it is or as bile salts

* HDL is taken up by liver. Reverse

Cholesterol Transport pathway

Reverse Cholesterol Transport

HDL functions
1-HDL as reservoir of apolipoproteins
It act as circulating reservoir of apo C.II that can be transferred to VLDL
and chylomicron.
And also takes back the apoprotiens before VLDL remnants and
chylomicron remnants are taken by the liver.
2-Up taking of free cholesterol
3-Esterification of free cholesterol into CE by LCAT.
* CE (cholesterol esters) that stored in HDL can be transferred into VLDL
and exchanged by TG or PE by CE transfer protein.
VLDL

LDL

CE is utilized by cells.

* Fate of HDL
- HDL is taken by liver by receptor- mediated endocytosis. And CE are
degraded and cholesterol can be repackaged in lipoprotein, converted into bile
acids or secreted into bile.

* Role of lipoproteins in heart disease

- high levels of cholesterol

increase risk of atherosclerosis

linked to high level of LDL, decrease HDL.

Disorders of lipid metabolism

Clinical manifestation of hyperlipidaemia:
Prolonged hyperlipidaemia results in accumulation of
lipid in tissues and causes cell damage. Lipids may
accumulate in arterial wall, subcutaneous tissue,
tendons and cornea
Arterial walls.
-It is the most important manifestation of
lipid disorders.
-Cholesterol accumulation and associated
cellular proliferation and fibrous tissue
formation produces atheromatous plaques.
-Atherosclerosis is due to deformation and
obstruction of the artery that may result from
calcification and ulceration of plaques.
The small lipoproteins LDL and IDL are
atherogenic.

Xanthelasma
Soft yellow-orange plaques on the eyelids are lipid deposits under the
periorbital skin and may be associated with high plasma LDL-cholesterol
concentrations

Tendons
Tendinous Xanthomata and usually on Achilles tendons or the extensor tendons
of the hands occur in familial hypercholesterolaemia
Cornea:
Corneal arcus under the age of 40 may be
caused by the deposition of lipids and
associated with high plasma LDLcholesterol concentrations.

Subcutaneous tissue
The accumulation of lipids in subcutaneous

tissue causes xanthomatosis (xanthoma: is a

yellow nodule plaque). The nature of the lipid
fraction most affected usually determines the
clinical appearance:

Eruptive xanthomata are crops of small,

itchy, yellow nodules (1-4mm) yellowishbrown papules. They are associated with
very high plasma VLDL or chylomicron
(triglyceride) concentrations, which
disappear if plasma lipid concentrations
fall to normal.
Appear over extensors of the elbows
and knees, and on the back and
buttocks of patients with severe
hyperlipidaemia

Classification of Disorders of lipid metabolism

Currently there is no satisfactory comprehensive classification of lipoprotein
disorders.
In practice, lipoprotein disorders are classified as being:
1.

Primary-when the disorder is not due to an identifiable underlying disease.

2.

Secondary-when the disorder is a manifestation of some other disease.

Primary lipid Disorders:

Genetic classifications: are becoming increasingly complex as different
mutations are discovered Familial hypercholesterolaemia (FH), may be due
to any of over 500 different mutations of the LDL receptor gene.
*The same genotype can be expressed as more than one phenotype in
different individuals. i.e different clinical manifestations (signs and
symptoms) in different individuals for the same genetic disorder.
*These manifestations depend on the severity of the case, and on the life
style
*Until gene therapy and/or specific substitution therapy become more
available, genetic classifications, are unlikely to prove very useful in
practice.

WHO classification of dyslipidemia: based on Fredrickson work and it

is phenotypic classification based on the observation pattern of
lipoprotein abnormality
*The Fredrickson or World Health Organization classification is the
most widely accepted for the primary hyperlipidaemias.
* It is based the appearance of fasting plasma sample after
standing for 12 hr at 4C and analysis of its cholesterol and TG
* As a result, patients with the same genetic defect may fall into
different groups, or may change grouping as the disease progresses or
treated.

* The major advantage of this classification is that it is widely accepted

and gives some guidance for treatment
*The six types by Fredrickson are not equally common. Type I and V are

rare, while types IIa, IIb and IV are very common.

Fredrickson (WHO) classification of dyslipidaemia

Fredrickson (WHO) classification of dyslipidaemia

Genetic classifications:
Genetic defect

Fredrickson

Risk

Familial
Hypercholesterolemia

Reduced number of
functional LDL receptors

IIa or IIb

CHD

Familial
hypertriglyceridemia

Possibly single gene

defect

IV or V

Familail combined
hyperlipidemia

Possibly single gene

defect

IIa, IIb, IV or V

CHD

Lipoprotein lipase
deficiency

Reduced levels of
functional LPL

Pancreatitis

Apo C-II deficiency

Inability to synthesize apo

C-II (cofactor of LPL)

Pancreatitis

Abetalipoproteinemia

Inability to synthesize apo

B

Normal

Fat soluble vitamins

deficiencies,
neurological deficit

Analphalipoproteinemia

Inability to synthesize apo

A

Normal

Neurological deficit,
CE storage in
abnormal places

Disease

Predominant hypercholesterolaemia
The risk of developing cardiovascular disease increases as the plasma cholesterol
concentration rises above 200 mg/dl in the absence of other risk factors this

value could be raised

Causes of hypercholesterolaemia
- Hypercholesterolaemia associated with little or no elevation of plasma
triglyceride concentration is almost always due to a raised plasma LDL

*The coexistence of an underlying genetic defect or other lipid disorders cause a

greater increase in plasma cholesterol with age.
Secondary hypercholesterolaemia.
Disorders that may produce a secondary increase in plasma total and LDL-

cholesterol
-primary hypothyroidism,
-diabetes mellitus,
-nephrotic syndrome,

-cholestasis
-drugs (e.g.; thiazides).

Primary hyperlipidaemias
Familial hypercholesterolaemia (FH)
* This condition is characterized by high plasma cholesterol

concentrations which are present from early childhood and do not

depend upon the presence of environmental factors
* Different mutations can affect LDL synthesis, transport, ligand
binding, and recycling but all cause a similar phenotype.
*The familial incidence of hypercholesterolaemia, often associated with
an increased risk of ischemic heart disease, suggests an inherited
disorder.

* Environmental and dietary factors may determine the expression of

the defect.
* The risk of developing cardiovascular disease is higher than normal,

compared with an age- and sex matched population.

Familial (monogenic) hypercholesterolaemia

Caused by a LDL receptor defect reduced cellular uptake of LDL,
particularly by the liver causes an increase in plasma total and LDLcholesterol concentrations.
Plasma triglyceride concentrations are either normal or only slightly

increased it is the most lethal of the inherited disorders.

In homozygotes LDL
receptors are virtually absent and plasma LDL-cholesterol is 3 to 4

times higher than those in normal subjects patients usually die before
the age of 20 from ischaemic heart disease.
In heterozygotes
The number of LDL receptors is reduced by 50% and the plasma
cholesterol concentrations are about twice those in normal subjects.
They have a 10 to 20-fold higher risk of developing ischaemic heart
disease than normal

Predominant hypertriglyceridaemia
* Elevated plasma triglyceride concentrations may be due to an increase in
plasma VLDL, or chylomicrons or both.
* Sustained and very high plasma concentrations of chylomicrons are
associated with abdominal pain and even acute pancreatitis, as well as
eruptive xanthomata.
* Many cases of hypertriglyceridaemia are symptom free. These large
lipoproteins are unlikely to cause artheroma, per se. However, many
patients with increased concentrations of VLDL-triglyceride have reduced
concentration of plasma HDL and increased plasma concentration of LDL or
IDL, which contain cholesterol.

* Hypertriglyceridaemia is usually secondary to another disease: obesity

and excessive carbohydrate intake, alcohol, drugs (thiazide diuretics) and
acute pancreatitis).

Familial endogenous hypertriglyceridaemia is caused by hepatic

triglyceride overproduction with increased VLDL secretion.

* The condition usually becomes apparent only after the fourth
decade.

* It may be associated with: obesity, glucose intolerance, decrease

in plasma HDL-cholesterol concentration and hyperuricaemia.
* Insulin resistance may be a common factor in the above conditions.
* High plasma triglyceride concentrations may cause eruptive
xanthomata.
* primary hypertriglyceridaemia is less than primary
hypercholesterolaemia

Familial combined hyperlipidaemia: Mixed hyperlipidaemia

It is common disorder
Associated with excessive hepatic production of apoB, increase LDL
and VLDL-triglyceride synthesis due to either a primary or secondary
disorder.
Family members have a variety of different phenotypes.
In one-third there is an increase in plasma LDL-cholesterol

In another third there is an increase in both LDL-cholesterol and

VLDL-triglycerides
The remaining third have VLDL-hypertriglyceridaemia.
The lipid abnormalities appear significantly in the after the age 30
The risk of ischaemic heart disease in all cases is higher
Raised plasma concentrations of both cholesterol and triglycerides are
commonest in patients with poorly controlled diabetes mellitus, severe
hypothyroidism or the nephrotic syndrome.

Hyperchylomicronaemia
* is usually due either to an acquired or inherited deficiency of
lipoprotein lipase.
* Insulin is needed for optimal enzyme activity hyperchylomiconaemia
may occur in poorly controlled diabetic patients.

Inherited lipoprotein lipase deficiency may be due to:

A) True deficiency of the enzyme
B) Reduced activity of the enzyme because of apo C-II deficiency.
Which is an activator for lipoprotein lipase
-The plasma is very turbid because of the accumulation of chylomicrons.
-True lipoprotein lipase deficiency usually presents during childhood, with
signs and symptoms due to an excess of fat at skin, liver (hepatomegaly)
retinal vessels and abdomen.
- Hyperchylomiconaemia due to apoC-II deficiency is most likely to
present in adults.

Rare disorders associated with lipid metabolism

-A few rare disorders, which are associated with reduced plasma lipid concentration
but with the accumulation of lipid in tissues
- Inherited disorder of HDL deficiency (Tangier disease):
-Called also Analphalipoproteinaemia

-Associated with premature coronary heart disease.

-An abnormal apoA leads to an increased rate of catabolism of HDL.
-Plasma HDL concentrations are low and cholesterol esters accumulate in the
reticuloendothelial system.
Abetalipoproteinaemia (ApoB deficiency):
- absence of Apo B
- results in impaired synthesis of chylomicrons and VLDL, and therefore of LDL.
-lipids cannot be transported from the intestine to the liver.
- risk: decrease in fat soluble vitamins lead to neurological defects, for treatment
vitamins are given I. V is given
Hypobetalipoproteinaemia
In this condition there is partial deficiency of apo B; CM, VLDL and LDL are present,
but in low concentrations.
LCAT deficiency:
results in accumulation of free, mostly unesterified, cholesterol in tissues

Secondary lipid disorders

Secondary hyperlipoproteina is a well recognized feature of a number
of diseases
Common causes of secondary hyperlipidaemia including obesity and
diabetes mellitus.
Management should be directed towards the cause.

Effect of Alcohol on Lipid profile

Large quantity of Ethanol increases the synthesis of Fatty acid,

because of production of NADH and acetate

Fatty acid TG VLDL

Ethanol

NADH

Alcohol
dehydrogenase

Acetaladehyde
NADH

Aldehyde
dehydrogenase

Acetate

Lipoprotein metabolism in diabetes mellitus

Insulin has a major role in the control of fat metabolism. Both type I and type 2
DM are associated with abnormalities of plasma lipids
In uncontrolled type I DM
* Marked hypertriglyceridaemia, increase in VLDL and often chylomicronaemia as a
result of decreased activity of lipoprotein lipase and increased activity of
hormone-sensitive lipase leading to increased flux of free fatty acids from
adipose tissue that act as a substrate for hepatic triglyceride synthesis
VLDL synthesis and accumulation increase LDL.

* Both VLDL and chylomicrones need insulin for optimum catalysis.

The degree of hypertriglyceridaemia correlates well with glycaemic control and
insulin treatment can reverse the hypertriglyceidaemia.
* LDL can also be increased, and HDL is decreased.
*The VLDL contains increased triglyceride and cholesteryl ester in relation to the
amount of apolipoptotein
* Glycation of apolipoprotein B may enhance the atherogenicity of LDL by reducing
its affinity for the LDL receptor, so leading to increased uptake by macrophage
scavenger receptors.
* Treatment with lipid-lowering drugs may be appropriate, to reduce the risk of
vascular disease

Investigation of lipid disorders

Plasma sampling
Plasma lipid concentrations and lipoprotein patterns are affected by
eating, smoking, alcohol intake, stress and changes in posture.
It is essential that the samples are taken under standard conditions. The
following points are important:
1) Plasma cholesterol concentrations are not significantly affected after a
fatty meal while plasma triglyceride concentrations are affected.
Therefore, specimens for analysis of both should be taken after the
patient has fasted for 12 hours.
2) The patient should be taking a 'normal' diet and his weight should have
remained constant for about two weeks before the tests.
3) Unless treatment is being monitored, the patient must not be on any
drugs designed to lower plasma lipid concentrations

Investigation of lipid disorders

Plasma sampling
3) Unless treatment is being monitored, the patient must not be on any
drugs designed to lower plasma lipid concentrations
4) Lipoprotein concentrations, like those of all large particles, are
affected by venous stasis and posture. A standardized collection
procedure is important if serial estimations to assess the effect of

treatment are used.

5) Stress may affect plasma lipid concentrations like myocardial
infarct, major operation, or any serious illness.

6) The blood sample should not be heparinized and plasma or serum

must be separated from cells as soon as possible

Lipid profile
LDL-cholesterol is most commonly estimated from quantitative
measurements of total and HDL-cholesterol and plasma triglycerides (TG)
using the empirical relationship of Friedewald et al. (1972)
[LDL-chol] = [Total chol] - [HDL-chol] - ([TG]/5)
where all concentrations are given in mg/dL
The ([TG]/5) is used as an estimate of VLDL-cholesterol concentration. It
assumes, first, that virtually all of the plasma TG is carried on VLDL, and
second, that the TG:cholesterol ratio of VLDL is constant at about 5:1
(Friedewald et al. 1972).
Neither assumption is strictly true.
Limitations of the Friedewald equation:
The Friedewald equation should not be used under the following
circumstances:
When chylomicrons are present.
When plasma triglyceride concentration exceeds 400 mg/dL (4.52 mmol/L).
In circumstances in which these conditions apply, LDL-cholesterol should
be measured directly.

Reference ranges and laboratory investigation

Plasma conc at birth is very low (total chol less than 100 mg/dL 2.6 mmol/L) and
there is rapid increase in in first year of life
Elevated plasma chol is a major risk
factor for CHD

There are many CHD risk factors

Smoking will increase the risk factor
There is an inverse correlation between
HDL cholesterol and CHD risk.
So it is inappropriate to define a
reference range for plasma chol
concentration.

But it is preferable to consider an

individual person's chol concentration
taking in consideration all other CHD risk
factors

Coronary Heart Disease Risk Factors Determined By The NCEP

(National Cholesterol Education Program) and Adult Treatment
Panels

Positive Risk Factors

Age: 45 years for men; 55 years or premature menopause for women

Family history of premature CHD

Current cigarette smoking

Hypertension (BP 140/90 mmHg or taking antihypertensive medication)

LDL cholesterol concentration 160 mg/dL ( 4.1mmol/L), with 1 risk factor

LDL cholesterol concentration 130 mg/dL (3.4 mmol/L), with 2 risk factors

LDL cholesterol concentration 100 mg/dL (2.6 mmol/L), with CHD or risk
equivalent

HDL cholesterol concentration < 40 mg/dL (< 1.0 mmol/L)

Diabetes mellitus = CHD risk equivalent

Negative Risk Factors

HDL cholesterol concentration 60 mg/dL ( 1.6 mmol/L)

LDL cholesterol < 100 mg/dL (2.6 < mmol/L)

Multiple metabolic risk factors

A diagnosis of metabolic
syndrome is made if a
patient has three or more of

the following:
1.

Abdominal obesity (a waist

circumference of more than
40 inches [men] or 35 inches
[women])

2. An elevated triglyceride level

(150 mg/dL or higher)

3. A low HDL level (less than 40 mg/dL [men] or 50 mg/dL [women])

4. A high-normal or high blood pressure level (130/85 mm Hg or
higher)
5. A high fasting glucose level (110 mg/dL or higher)

6
3
3
0
2
14

Means 20 of 100
people with this level
of risk will have a
heart attack in the
next 10 years.

Risk Assessment Tool for Estimating Your 10-year Risk of

Having a Heart Attack
10-Year Risk Calculator
http://hp2010.nhlbihin.net/atpiii/calculator.asp
10-Year Risk Calculator Results

Risk Factor Intervention

Target treatment based on risk
High: 10 year risk > 20%
Intermediate: 10 year risk 10 20%
Low: 10 year risk < 10%

Preventive strategies differ depending on risk category

Aspirin
Cholesterol lowering

Risk Level
LDL Goal (mg/dl)
Consider Drug Therapy
___________________________________________________
High
> 20%
< 70
100

Intermediate
10 20%

< 10%

< 100

160

Low
< 160

190

The End

 Drugs: Thiaziade diuertics and b-blockers hypertriglyceridaemia since these

drugs affect the homeostasis of K+ and Na+ which is important for the
conversion of proinsulin into insulin
low insulin levels similar events of diabetes
Hypothyrodism low of T3, T4 decrease the uptake of LDL by the LDLreceptor mediated mechanism
Nephrotic syndrome: increase the cholesterol level
NS is associated with loss of protein with the urine
This will trigger the body to increase the synthesis of protein including Apo B
and other lipoproteins which lead to increase the cholesterol
Also may be due to loss of proteins responsible for regulation of lipid
metabolism

* Metabolism of Chylomicrons

*Esterified cholesterol is transferred to the CM remnants from HDL, in

exchange for triglyceride, by cholesteryl ester transfer protein
*CM remnants depleted from TG and enriched in CE and taken up by liver

As the VLDL particles become smaller, PL, free cholesterol and apolipoproteins are
released from VLDL and taken up by HDL converting the VLDL into IDL