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Transcript of Defined on the basis of solubility. Lipids are heterogeneous group of water insoluble (hydrophobic)...
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
FunctionsThe 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.
Lipids
* 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 cellsThe primary products of dietary lipid degradation with the bile salts from mixed
micelles.
Short and medium chain length F.A don’t need micelles formation to be absorbed (pass directly)
Effect of unsaturated fatty acid on the absorption of Cholesterol !!!!Effect of unsaturated fatty acid on the absorption of Cholesterol !!!!
Hydro-phobic core
hydrophilic
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 lipoproteinsPlasma 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 staticThe 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 4°C the larger chylomicrons( lowest density) form a creamy layer on the surface
Lipemia: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 ChylomicronsMetabolism of Chylomicrons* The “nascent chylomicron” that released by intestinal mucosal cells contain apo B-48 (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 apoEThe 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 liverThe 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 lipaseVLDL 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 can’t 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.
Peripheral cells uptake cholesterol.
* LDL receptors deficiency elevation of plasma LDL increase plasma 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 wallPathogenesis of atherosclerosis
Macrophages derived from monocytes can take up LDL via specific receptors
The uptake will
be activated
when LDL will be
oxidized via non-
specific
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 chylomicron-remnant 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 passive movement of cholesterol from cell to the HDL goes to the liver.
- 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
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.
HDL functions HDL functions
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.
Disorders of lipid metabolismClinical 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
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
TendonsTendons
Tendinous Xanthomata and usually on Achilles tendons or the extensor
tendons of the hands occur in familial hypercholesterolaemia
Cornea:Cornea:
Corneal arcus under the age of 40 may
be caused by the deposition of lipids and
associated with high plasma LDL-
cholesterol concentrations.
Appear over extensors of the
elbows and knees, and on the back
and buttocks of patients with
severe hyperlipidaemia
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)
yellowish-brown papules. They are
associated with very high plasma VLDL
or chylomicron (triglyceride)
concentrations, which disappear if
plasma lipid concentrations fall to
normal.
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*These manifestations depend on the severity of the case, and on the
life style
*Until gene therapy*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 4°C 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:
Disease 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
I Pancreatitis
Apo C-II deficiency Inability to synthesize apo C-II (cofactor of LPL)
I 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
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).
Predominant hypercholesterolaemia
Primary hyperlipidaemiasFamilial 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) hypercholesterolaemiaFamilial (monogenic) hypercholesterolaemia
Caused by a LDL receptor defect reduced cellular uptake of
LDL, particularly by the liver causes an increase in plasma
total and LDL- cholesterol 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 hypertriglyceridaemiaPredominant 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 hyperlipidaemiaMixed 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 profileEffect 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
Acetaladehyde
Acetate
Alcohol dehydrogenase
Aldehyde dehydrogenase
NADH
NADH
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 profileLDL-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 FactorsNegative Risk Factors
• HDL cholesterol concentration 60 mg/dL ( 1.6 mmol/L)
• LDL cholesterol < 100 mg/dL (2.6 < mmol/L)
Multiple metabolic risk Multiple metabolic risk
factorsfactors
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
33
02
14
Means 20 of 100 people with this level of risk will have a heart attack in the next 10 years.
http://hp2010.nhlbihin.net/atpiii/calculator.asp
Risk Assessment Tool for Estimating Your 10-year Risk of Having a Heart Attack
10-Year Risk Calculator Results
10-Year Risk Calculator
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
Intermediate10 –20% < 100 ≥160
Low< 10% < 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 LDL-receptor 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 cholesterolAlso 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