Download sheet l .06 slide 2 (lipids)

SHEET L .06 SLIDE 2 (LIPIDS) 2017
Clinical Biochem 2
Lipids:
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SHEET L .06 SLIDE 2 (LIPIDS) 2017
During fasting, activation of hormone-sensitive lipase at the adipose tissue occurs & the hydrolysis of
TGs begins.
“Lipoproteins differ in density, size, components and other things”
*LPL hydrolyzes TG at the chylomicrons into glycerol, free fatty acid &the remaining of the
chylomicrons. (Called chylomicron remnants)
These remnants are composed of : cholesterol esters  which move to the liver .
**VLDL is a carrier of TG that is endogenously synthesized at the liver and then released into the
circulation.
LPL digests VLDL into IDL which gets further broken down into LDL.
-LDL is rich in cholesterol esters which get uptaken by receptor-mediated endocytosis.
*formation of Foam cells  Macrophages derived from monocytes can uptake LDL via specific
receptors, as a result of this macrophages will contain cholesterol.
- LDL receptors are susceptible to down regulation based on the cholesterol levels. So, as cholesterol
goes up, LDL receptors go down.
When LDL got oxidized by free radicals it become more atherogenic.
**how do they get exposed to free radicals??
-if the person is exposed to oxidative stress or to some molecules such as: oxygen, hydrogen
peroxide, or toxic chemicals.
**what are free radicals??
-highly reactive molecules that can oxidize body substrates like: proteins and LDL.
BUT, why does LDL become more atherogenic??
-
Because when it got oxidized, its structure changes! This leads to its uptake by
macrophages and not by receptor-mediated endocytosis.
 The oxidized LDL gets engulfed by the macrophages & will release the cholesterol , hence
increasing the macrophages content of cholesterol (these what we call FOAM CELLS).
-foam cells adsorb to vessels wall and precipitate triggering platelets aggregation.
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SHEET L .06 SLIDE 2 (LIPIDS) 2017
**the amount of cholesterol we obtain from diet forms a very high proportion of total cholesterol. So,
we advice patients to lower cholesterol intake. Why is that?
-
Because dietary cholesterol will move to the liver! this would trigger down the regulation
of LDL receptors & increase cholesterol in the circulation  which is associated with an
increased risk of atherosclerosis
HDL:
It has phospholipids chain & responsible for the transfer of cholesterol from tissues to the liver.
-
Cholesterol that is esterified with acyl group forms phospholipids and produce cholesterol
esters. this process is mediated by LCAT ( lecithin-cholesterol acyl transferase ) , also
called phosphatidylcholine-sterol-O-acyltransferase .
*cholesterol can’t be hydrolyzed or degraded because there is no endogenous enzyme to do. So, the
body gets rid of it either by secretion or by converting it into bile acid and excretes it with feces.
*disorders of lipids metabolism:
Mostly hyperlipidemia
 When there is an elevation of lipids , some particles will precipitate because lipids are insoluble in
water.
**When there is an increase in the cholesterol level either by hypercholesterolemia or increase in VLDL
concentration, there will be an accumulation of lipids in subcutaneous tissue which causes
Xanthomatosis.
Xanthomas are yellow itchy nodule plaques (also called eruptive Xanthomata), these appear over the
elbows, knees, back and buttocks.
-Xanthomas will no longer appear if the Cholesterol levels go back to normal.
●
Hypercholesterolemia leads to multiple consequences, and the most important one is
atherosclerosis.
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SHEET L .06 SLIDE 2 (LIPIDS) 2017
The pathogenesis of atherosclerosis arises from the formation of foam cells as we mentioned earlier.
Foam cells will precipitate at the internal lumen of the vessels, followed by Ca+2 precipitation and platelet
aggregation. As a result, the vessels will become narrower and blood flow is obstructed.
-If the obstruction is complete, tissue necrosis will occur. (Myocardial Infarction of the heart as an
example)
These plaques that form at the lumen of blood vessels are called atheromatous plaques and they are
caused by an increase in LDL and IDL levels.
*These cholesterol plaques might also appear on the eyelids as soft yellow-orange plaque, due to the
increase of LDL cholesterol concentration (xanthelasma), these plaques might appear on other places as
well.
-In the familial hyper cholesterolemia tendinous xanthomata and usually Achilles tendons of the
Trans
• Cornea:
Corneal arcus under the age of 40 may be caused by the deposition of lipids and associated with high
plasma (LDL-Cholesterol) concentration.
Arcus Senilis presents in order subjects.
** Classification of disordered-lipid metabolism: 1ry and 2ry :
1- 1ry: idiopathic genetic disorder
2- 2ry: due to known causes, whenever we treat it the disorder will disappear
Primary lipid disorders:
• Genetic classification
• A mutation occurs (in the LDL Gene for example) and this classification has limitations
• Different mutations are discovered that cause Familial hypercholesterolemia (FH)
• May be due to over 500 different mutations of the LDL-receptor gene
• The same genotype can be expressed as more than one phenotype in different
Individuals; this means that different clinical manifestations (signs and symptoms) in different
individuals for the same disorder and there might be the same phenotype but at different genotype.
• We don’t have gene therapy to treat these mutations so this type of classification is not preferred.
*WHO classification is based on Fredrickson’s work which is based on the obstruction pattern of the
lipoprotein abnormality.
-It classifies lipids disorders according to serum appearance & according to lipids profile ( LDL, VLDL,
HDL, IDL, TG).
Whenever we test lipids that have high TGs due to high VLDL there will be condensation for the particles
at the serum, and because those particles are large they will do light reflection and appear milky color.
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SHEET L .06 SLIDE 2 (LIPIDS) 2017
This classification divide dyslipidemia into 6 types I/ IIa/ IIb/ III/ IV/ V
- Most common types are II (a and b) and type IV
● Type I
Increase in chylomicrons in serum appears as creamy top layer. TG is elevated while cholesterol is
normal. This type’s prevalence is very low.
● Type IIa
Increase in LDL, hence an increase in cholesterol will occur while the TG will be normal. The serum will
appear clear.
● Type IIb
Increase in LDL and VLDL leading to even higher increase in cholesterol and a slight increase in TG.
Serum appears turbid.
● Type III :
Fare (less than 1%), IDL elevation leads to turbid appearance (because it is an intermediate between IDL
and VLDL)
● Type IV:
Increase in VLDL leads to increase in turbidity, cholesterol or elevated, turbid appearance
● Type V :
Increase in VLDL leads to increase in chylomicron thus turbidity will be elevated, and cholesterol will be
elevated.
Its appearance will be à creamy top and turbid bottom (occurs in diabetes)
**1ry and 2ry Hypercholesterolemia causes  mainly the cause is 1ry , while in hypertriglyceridemia 
the 2ry causes are the main causes .
-Hypercholesterolemia => 1ry and 2ry causes
-Hypertriglyceridemia => mainly 2ry causes
What are the causes for 2ry Hypercholesterolemia?
1.
DM
2.
Primary hypothyroidism (decrease in T3 AND T4)
3. Nephrotic syndrome => loss of large proteins from the glomerulus, as a reflex the liver will start
synthesizing plasma proteins including Apolipoproteins - as Apo100- which will increase VLDL & LDL.
4. Cholestasis => reduced flow of the bile due to obstruction by tumors, stones, etc.
5.
Drugs as Thiazide diuretics.
** In FH , there is a mutation in the genes as in LDL synthesis process of transport, ligand binding to
hypercholesterolemia.
-It is familial (inherited) means that more than one member of the family can have this disorder.
-The risk differs from male to female and age.
**Familial (monogenic) hypercholesterolemia:
Is a defect in the LDL receptor gene
-The gene has two alleles if there was a defect in both alleles we call it homozygote, virtually there is no
LDL, the receptors are absent , and LDL cholesterol is 3 to 4 times higher than those in the normal
patients.
- Heterozygous ( defect in one alleles )
- LDL is reduced by 50%
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SHEET L .06 SLIDE 2 (LIPIDS) 2017
‫حاول أن تصل إلى أبعد مما تستطيع‬
‫الوصول إليه‬.
Sara’a Al-rayuushi
Seema Al- Shalabi
Anwar Asfour
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