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Lipoproteins - PowerPoint PPT Presentation

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Yıldırım Beyazıt University Medical Faculty Biochemistry Department. Lipoproteins. Prof. Dr. Fatma Meriç YILMAZ [email protected] Lipids in the Blood. Fatty Acids Bound to albumin. Cholesterol, Triglycerides and Phospholipids Transported by lipoproteins

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lipids in the blood
Lipids in the Blood
  • Fatty Acids
    • Bound to albumin
  • Cholesterol, Triglycerides and Phospholipids
    • Transported by lipoproteins
    • Cholesterol can be free or esterified
  • particles found in plasma that transport lipids including cholesterol
  • lipoprotein classes:
  • Chylomicrons are the LP particles lowest in density and largest in size

(Contain highest percentage of lipids and lowest percentage of proteins)

  • IDLs and LDLs are denser, having higher ratios of protein to lipid
  • HDLs are the densest LP particles with the highest protein contents
  • Structural determinants of lipoproteins
  • Enzyme cofactors
  • Ligands for binding to lipoprotein receptors
functions of apolipoproteins
Functions of Apolipoproteins

Provide recognition sites for cell-surface receptors

Serve as activators or coenzymes for enzymes involved in lipoprotein metabolism

Some of lipoproteins are essential structural components and cannot be removed

Some of them are transferred freely between lipoproteins

Apolipoproteins are divided into five groups by structure and function (A to E)

Most classes have subclasses like Apo A-I, Apo C-II etc.

Functions of all apolipoproteins are not yet known


HDL structural protein; LCAT activator;RCT


Hepatic Lipase activation


Tg metabolism; LCAT activator; dietresponse


Structural protein of all LP except HDL

Binding to LDL receptor



Inhibit Lp binding to LDL R; LCAT activator


LpL activator


LpL inhibitor; antagonizes apoE


B/E receptor ligand

enzymes and transfer proteins
Enzymes and Transfer Proteins
  • LCAT(Lecithin:CholesterolAcyltransferase)
    • Formation of cholesterol esters in lipoproteins (HDL)
  • ACAT(Acyl-CoA:CholesterolAcyltransferase)
    • Formation of cholesterol esters in cells
  • CETP(Cholesterol Ester Transfer Protein)
  • Transfer of CE from HDL to VLDL and
  • transfer of TG from VLDL to HDL
  • particles consisting of phospholipids, Chol/CE

triacylglycerols and apolipoproteins

  • Apolipoproteins (Apo B48, Apo CII, Apo E)

Chylomicrons are synthesized in intestinal epithelial cells, secreted into the lymph, pass into the blood, andbecome mature chylomicrons

On capillary walls in adipose tissue and muscle, lipoprotein lipase (LPL) activated by ApoCIIdigests the triacylglycerols (TG) of chylomicrons to fatty acids and glycerol.

Fatty acids (FA) are oxidized in muscle or stored in adipose cellsas triacylglycerols.

The remnants of the chylomicrons are taken up by the liver by receptor-mediated endocytosis (Apo E receptors). Lysosomal enzymes within thehepatocyte digest the remnants, releasing the amino acids, free cholesterol and fatty acidsinto the cytosol.

chylomicron circulation

Apo-B48 is uniquetochylomicrons

Theparticlereleasedfromintestinalcellsarenamed as nascent CM andcarriesonlyApo B48

When it reachestotheplasma is has beenmodified; Apo C II andApo E particlesaretransferredfromHDL

Apo C II activates LPL enzyme

As thechylomicroncirculates, morethan 90% of TG in itscore is degradedby LPL, theparticledecreases in size, increases in density

C apoproteinsreturnto HDL andtheparticle is called a remnant CM

Remnant CM stillcontainsApo E andbindstotheliverthroughApo E receptors





Mature CM

CM Remnant



Nascent CM










Blood Vessel








CM Remnants are taken to the liver and hydrolized

Apo E receptor

very low density lipoproteins vldl
VeryLowDensityLipoproteins (VLDL)

VLDLs are produced in the liver

They are composed of predominantly of endogeneous triacylglycerol (60%)

The main function of VLDL is to carry this lipid from the liver to the peripheral tissues

The TG of VLDL, produced in the liver, isdigested by lipoprotein lipase (LPL) present on the lining cells of the capillaries in adiposeand skeletal muscle tissue. Fatty acids are released and either oxidized or stored in tissues asTG.

vldl circulation
VLDL Circulation

VLDL is secreteddirectlyintothebloodbytheliver as nascent VLDL particlescontainingApo B-100

TheymustobtainApo C-II andApo Efromcirculating HDL

Apo C-II activates LPL and as VLDL passthroughthecirculation, TGsaredegradedbylipoproteinlipase, causing VLDL todecrease in size andbecomedenser

Surfacecomponents, includingthe C and E apoproteinsarereturnedto HDL but theparticlesretainApo B-100

Finallysome TG aretransferredto HDL andcholesterolestersaretransferredfrom HDL to VLDL withCholesterol Ester Transfer Protein (CETP)

Withthesemodifications, VLDL is convertedto LDL in theplasma

intermediate density lipoprotein idl
IntermediateDensityLipoprotein (IDL)

Intermediate-density lipoproteins are formed from the degradation of VLDLs

Some of the IDL particles are rapidly taken up by the liver through Apo E receptors; others remain in circulation, where they undergo further triglyceride hydrolysis and are converted to LDL

Carry Apo E and Apo B-100

low density lipoprotein ldl
LowDensityLipoprotein (LDL)

LDL particles contain much less TG then their precursor VLDL and have a high concentration of cholesterol and cholesteryl esters

The primary function of LDL is to provide cholesterol to peripheral tissues

LDL particles contain Apo B100

which is the receptor binding site for LDL particles

These receptors can also bind Apo E and are named as Apo B100/Apo E receptors





Mature VLDL












Nascent VLDL

Blood Vessel









LDL is taken up with

LDL receptors

Apo B100 receptors

high density lipoprotein hdl
HighDensityLipoprotein (HDL)

HDL comprise a heterogeneous family of lipoproteins with a complex metabolism that is not completely understood.

HDL is a reservoir of apolipoproteins Apo C-II and Apo E

HDL takes up the cholesterol esters from peripheral tissues and returns it to the liver

It is responsible from esterification of cholesterol with LCAT enzyme

high density lipoprotein hdl1
HighDensityLipoprotein (HDL)

Nascent HDL are disk shaped particles containing primarily phospholipid and Apo A, C and E

They take up cholesterol from peripheral tissues and return it to liver as CE.

When chol is taken up by HDL, it is immediately esterified with LCAT

LCAT enzyme is synthesized by the liver.

LCAT binds to nascent HDL and is activated by Apo A-I

high density lipoprotein hdl2
HighDensityLipoprotein (HDL)

LCAT transfersthefattyacidfromcarbon 2 of phosphotidylcholintocholesterol

Thisproduces a hydrophobiccholesteryl ester which is transferredtothecore of thelipoprotein

As thediscoidalnascent HDL accumulatescholesterylesters, it firstbecomes a spherical, relativelycholesteryl ester poorHDL3 thenturnstoHDL2 which is cholesteryl ester rich HDL form.

hdl metabolism
HDL Metabolism




HDL receptor mediated

endocytosis in liver



Transfer of some CE


“used” cholesterol is

Transferred to HDL and converted

to cholesteryl esters (LCAT)


Cholesterol is secreted to bile or

repackaged to form VLDL







Lipoprotein(a), or Lp(a)
  • An atherogenic lipoproteincontaining apo(a) and apoB.
  • 20-30% of people have levelssuggesting CV risk.
  • Black subjects have Lp(a)normal range twice as highas white and Asiatic subjects.
  • Apo(a) sequence similar to plasminogen, and Lp(a)interferes with spontaneous thrombolysis.
  • Lp(a) levels highly genetic, resistant to diet and drugtherapy.




The function of the heart is to circulate blood throughout the body by:
  • Pumping blood through the lungs removes carbon dioxide and refreshes the blood with oxygen
  • The oxygenated blood is pumped to the body to provide oxygen and nutrients and to remove waste products.
  • The coronary arteries are the blood vessels that supply blood and oxygen to the heart muscle.
Atherosclerosiscan, and does, occur in almost any artery in the body. But in the heart it’s effects can be crucial.
  • The body depends on a strong pumping heart to circulate life-giving blood, and this includes to the heart muscle itself.
  • If the coronary arteries become blocked, the cardiac muscle begins to fail, and so the blood circulation decreases, which includes the circulation to the heart muscle itself.
clinical manifestations of atherosclerosis
Clinical Manifestations of Atherosclerosis
  • Coronary heart disease
    • Stable angina, acute myocardial infarction, sudden death, unstable angina
  • Cerebrovascular disease
    • Stroke, TIAs
  • Peripheral arterial disease
    • Intermittent claudication, increased risk of death from heart attack and stroke

American Heart Association, 2000.

old theory
  • High cholesterol causes plaque by building up on wall of arteries—therefore, focus was on lowering cholesterol as much as possible


  • 1) In 10 year study period on island of Crete, there were no recorded heart attacks despite high cholesterols
  • 2) French study showed reduced risk of second heart attack or cardiac-related death in those following the “Mediterranean Diet” compared to those on a low fat “cardiac” diet, despite similar cholesterol levels in both groups
new theory
  • Atherosclerosis is the result of damage to the endothelium (inner lining of arteries) and inflammation causing progressive damage
  • This then allows cholesterol (especially “oxidized” LDL) to enter the artery wall-causing more damage and reaction from the immune system-builds plaque
  • Creates cycle of inflammation and plaque
  • Progressively narrows the artery and it becomes stiffer, interfering with blood to vital organs
pathology and p athogenesis
Pathology and pathogenesis
  • The lesions associated with atherosclerosis are of three types:
    • The fatty streak
    • The fibrous atheromatous plaque
    • Complicatedlesion
  • The latter two are responsible for the clinicallysignificant manifestations of the disease.
  • There is increasing evidence that atherosclerosis is at leastpartially the result of:
    • (1) endothelial injury with leukocyte(lymphocyte and monocyte) adhesion and platelet adherence
    • (2) smooth muscle cell emigration and proliferation
    • (3) lipid depositionof activated macrophages
    • (4) subsequent developmentof an atherosclerotic plaque with lipid core
  • One hypothesis of plaque formation suggests that injury to the endothelial vessel layer is the initiating factor in the development of atherosclerosis.
    • Possible injurious agents are:
      • Products associated with smoking;
      • Immune mechanisms;
      • Mechanical stress, such as that associated with hypertension.
  • Hyperlipidemia, particularly LDL with its high cholesterol content, is also believed to play an active role in the pathogenesis of the atherosclerotic lesion.
ldl cholesterol and atherosclerosis
LDL – cholesterolandAtherosclerosis
  • The LDLis removed from the circulation by either LDL receptors or byscavenger cells such as monocytes or macrophages.
  • Approximately70% of LDL is removed by way of the LDL receptordependentpathway.
  • Although LDL receptors are widely distributed,approximately 75% are located on hepatocytes; thusthe liver plays an extremely important role in LDL metabolism.
  • Tissues with LDL receptors can control their cholesterol intakeby adding or removing LDL receptors.
ldl cholesterol and atherosclerosis1
LDL – cholesterolandAtherosclerosis
  • The scavenger cells, such as the monocytes and macrophages,have receptors that bind LDL that has been oxidized orchemically modified.
  • Theuptake of LDL by macrophages in the arterial wall can result inthe accumulation of insoluble cholesterol esters, the formationof foam cells, and the development of atherosclerosis.
mechanisms of atherosclerosis
Mechanisms of Atherosclerosis
  • One of the earliest responses to endothelial disfunction is the attachment of monocytes to theendothelium.
  • The monocytes emigratethrough the cell-to-cell attachments of the endothelial layerinto the subendothelial spaces, where they are transformedinto macrophages.
  • Activated macrophages release free radicalsthat oxidize LDL.
  • Oxidized LDL is not recognized at the cell receptor level and so, it can not be internalized and it longer remains into the blood stream.
Endothelial disruption leads to platelet adhesionand aggregation and fibrin deposition.
  • Platelets and activatedmacrophages release various factors that are thought to promotegrowth factors that modulate the proliferation of smoothmuscle cells and deposition of extracellular matrix in the lesions: elastin, collagen, proteoglycans.
  • Activated macrophages also ingest oxidized LDL to becomefoam cells, which are present in all stages of atheroscleroticplaque formation.
  • Lipids released from necrotic foamcells accumulate to form the lipid core of unstable plaques.
  • Connective tissue synthesis determinates stiffness, calcium fixation and further ulceration of atheromatous plaque.
modern theory of atherosclerosis
Modern theory of atherosclerosis
  • Multifactor theory:
    • Structural and functional injury of vascular endothelium;
    • Response to injury of immune cells and smooth muscle cells;
    • The role of lipoproteins in initiation and progression of lesions;
    • The role of growth factors and cytokines;
    • The role of repeated thrombosis in lesions progression.

It is also known as hyperlipidemia or hyperlipoproteinemia

It is defined as a presence of raised or abnormal levels of lipids and/or lipoproteins in the blood

This abnormality is common in the general population, and is one of the important modifiable risk factors for coronary heart disease (CHD).

Dyslipidemia is generally characterized by increased fasting concentrations of total cholesterol (TC), LDL cholesterol (LDL-C), and triglycerides (TG), in conjunction with decreased concentrations of HDL cholesterol (HDL-C)

Hereditary Hyperlipoproteinemias
  • On diagnosing hyperlipoproteinemia, hyperlipidemic status should be evaluated to determine whether it is primary lipoprotein disorder or secondary to any of a variety of metabolic diseases.
  • The diagnosis of primaryhyperlipoproteinemia is made after secondary causes have been excluded.
  • Primary hyperlipoproteinemias are genetic disorders and classified from I to V
Type I Hyperlipoproteinemia
  • Familial Lipoprotein lipase deficiency
  • Characterized by high levels of chylomicrons and triglycerides and a deficiency of lipoprotein lipase
  • Disease onset is usually in infancy.
  • Type 1 has a pure elevation of triglycerides in the chylomicron fraction.These people sometimes getpancreatitisand abdominal pains, but they do not seem to have an increase in vascular disease.
type ii familial hypecholesterolemia
Type II Familial hypecholesterolemia
  • Type II, broken into two subtypes, type II-a and type II-b.
  • Type II a. LDL Receptor/Apo B 100 deficiency
  • Type II b. Increased production of Apo B
  • The familial (genetic) versions of Type II often develop xanthomas, which are yellow fatty deposits under the skin of the knuckles, elbows, buttocks or heels. They may also have xanthelasmas, smaller yellow patches on the eyelids. Both subtypes display high levels of blood cholesterol. People with type II-b also have high levels of triglycerides in their blood. Disease onset is usually after age 20.
type iii dysbetalipoproteinemia
Type IIIDysbetalipoproteinemia
  • The disorder is caused by Apo-E or Apo-E receptor.
  • Also called as broad beta disease because of the broad beta band in electrophoresis
  • Accumulation of IDL, VLDL and chylomicron remnants.
  • Elevated level of total cholesterol and triglycerides.
  • Type 3 appears in one in 10,000 people and elevates both triglycerides and cholesterol with consequent vascular disease.
  • Disease onset is usually in adults.
Apo E receptor

Apo E receptor

type iv hypertriglyceridemia
Type IVHypertriglyceridemia
  • Overproduction of VLDL or decreased catabolism
  • VLDL and TG increase
  • Questionable as to whether this is an independent risk factor for atherosclerosis

Type VMixedHypertriglyceridemia

  • Overproduction of VLDL and LPL deficiency
  • Both TG and CM levelsareelevated
second a ry hyperlipoproteinemia
  • Diabetes mellitus, because it alters the way the body handles its energy needs, also affects the way it handles fats. The result is elevated triglycerides and reduced HDL cholesterol. This effect is amplified by obesity.
  • Hypothyroidism is a common cause of lipid abnormalities. The thyroid hormone affects the rate of many chemical processes in the body, including the clearing of fats from the blood. The consequence is usually an elevation of cholesterol.
  • Kidney disease affects the blood's proteins and consequently the composition of the fat packages. It usually raises the LDLs.
  • Liver disease, depending on its stage and severity, can raise or lower any of the blood fats.
  • Alcohol raises triglycerides. Cigarettes smokinglowers HDL cholesterol, as doesmalnutritionand obesity.

Usually high lipid levels are asymptomatic

Occasionally when fat levels are high, it can be deposited in skin and tendons forming bumps called xanthomas (eyes and Achilles tendon)

Very high triglyceride levels may cause liver to enlarge

High lipids increase the risk of developing pancreatitis, which causes severe abdominal pain and is sometimes fatal

lipid profile testing
Lipid Profile testing

Total Cholesterol


HDL Cholesterol

LDL Cholesterol

(Freidewald=TK-HDL-VLDL or direct LDL)

VLDL Cholesterol (TG/5)

ncep iii
  • National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III issued guidelines for detection, evaluation, and treatment of high blood cholesterol levels
what should my cholesterol level be




CHD Death Rate/1000
















Plasma Cholesterol (mg/dl)

What should my cholesterol level be?
i am healthy when should i have cholesterol testing
I am healthy. When should I have cholesterol testing?
  • Cholesterol levels should be checked after age 20 even if the person is healthy.
  • If the result is normal, it should be repeated 5 years later.
  • If there is a history of familial hypercholesterolemia children should be checked.
what does lipid profile mean can i have only cholesterol testing
What does lipid profile mean? Can I have only cholesterol testing?
  • NCEP advises to determine TC, HDL-C, LDL-C and TG together
  • In children, TC should be checked; if is abnormal lipid profile testing should be performed.
should i have cholesterol testing during fasting
Should I havecholesteroltestingduringfasting?
  • In cholesterol testing, fasting is not obligatory
  • If lipid profile is going to be checked, 9-12 hours fasting is necessary
i am taking cholesterol pills when should i have a test
I amtakingcholesterolpills. Whenshould I have a test?
  • 6. and 12. weeks after beginning to the pills, then with 4-6 month periods