Denefil Olha Volodymyrivna Disorder of lipoprotein metabolism. Atherosclerosis.

Denefil Olha Volodymyrivna

Disorder of lipoprotein metabolism. Atherosclerosis

• Plasma lipoproteins are produced and secreted by the liver parenchymal cells and epithelial cells of the small intestine.

General structure of lipoprotein.There is a lipid drop inside (nucleus),

which contains triglycerides (TG) and cholesterol esters (ACh).

Membrane covers the nucleus and consists of protein (apoprotein, or apo-), phospholipids (PhL) and non-ester cholesterol (NACh).

The outer membrane of lipoprotein is hydrophilic and inner core is hydrophobic.

Lipoproteins are soluble in water, it is a transport form of lipids in the blood.

• In plasma of healthy people is

• 4-8 g/l - total lipids

• 0.8-1.5 g/l - VLD

• 3,2-4,5 g/l - LDL• 2,7-4,3 g / l -

HDL• 3,9-6,5 mmol/l -

general chylomicrons

Kinds of the lipoproteins

Indexes Chylomicron VLDL, pre--LP

LDL, -LP HDL, -LP

Diameter, nm 500-1000 25-75 19-24 6-12

Chemical structure (%):

Cholesterol 0,5- 3 15-17 35-48 20-37

% Cholesterol esters

46 57 66-70 78

Phospholipids 3-9 13-20 11-30 24-40

Triglycerides 80-95 50-70 5-10 3-5

Protein 1-2 5-12 14-25 45-55

Apoproteins A, B, C, E B, C B, C, E A, C, D, E

The value of cholesterol

• 1. Necessary for maintaining of cell shape

• 2. Together with PL and proteins provides selective permeability of cells to different substances

• 3. Source of sex and steroid hormones

• 4. Source of bile acids

• 5. Necessary for growth of the organism and cell division

Balance of cholesterol

• One day in the human body• 450 mg of cholesterol oxidized to bile acids• 450 mg of cholesterol excreted with faeces• 100 mg of cholesterol excreted with dermal fat

• 300 mg of cholesterol derived from food• 700 mg of cholesterol is synthesized from acetyl-CoA in

the cells of various organs, the highest in the liver and small intestine

• In adult is about 140 grams of cholesterol (93% is in the cells, 7% is transported in the form of LP mainly LDL in plasma).

Аpо-В-receptorАpо-Е-receptor(receptor connects the LDL, depends on Cholesterol needs of the cell)

Role of LP in Cholesterol transport inside the cell. That is due to receptor-mediated mechanism.

It was discovered by American scientists M.Brown and J.Goldstein in 1973-1975

(Nobel Prize in 1985)

Skin fibroblast

Smooth muscles

cell of artery

Lymphocyte

Macrophage

Receptor-mediated endocytosis

Regulation of cholesterol contents• Except the receptor-mediated cholesterol

admission into the cell to regulate the content exists by removing cholesterol from the cell membrane surface. This is done by HDL.

• In blood this cholesterol undergoes etherification

under influence of lecithin-cholesterol-acetyltransferase, is transported to the liver, where partially oxidized to bile acids.

• Normally, these two processes are balanced.

• 10% of the population have congenital molecular abnormalities in cholesterol metabolism or LP:

• 1) increased synthesis of cholesterol, atherogenic LP in the liver and small intestine

• 2) the prevalence of violations outlet of atherogenic LP in the bloodstream by help of HDL

Violation of regulating processes of cholesterol metabolism

Inherited defects in exchange of LP (cause early atherosclerosis and coronary artery disease)

• 1) Tangier disease - (also known as "Familial alpha-lipoprotein deficiency") or Hypoalphalipoproteinemia is a rare inherited disorder characterized by a severe reduction in the amount of high density lipoprotein (HDL), often referred to as "good cholesterol," in the bloodstream.

• 2) familial hypercholesterolemia - genetically caused by the absence or deficiency of receptors on the surface of parenchymatous and connective tissue-type cells

Receptor-mediated and nonreceptor (unregulated) endocytosis (basis of atherosclerosis

development)

Atherosclerosis is the variable combination of changes in arteries intimae, which consists of focal accumulation of lipids, complicated carbohydrates, blood substances, fibrous tissue and calcium, and associated with changes in media (WHO definition)

First experimental model of atherosclerosis was created on rabbits in 1913. Every day

within 3-4 months A.Anichkov added 10 g of Cholesterol in rabbits ration.

“Atherosclerosis is impossible without cholesterol”.

А.N.Аnichkov

Ways of LDL transport in the arterial wall

• 1. Nonspecific unregulated endocytosis

• 2. Through the intercellular channels of endothelial monolayer (action of adrenaline, noradrenaline, serotonin, angiotensin II, histamine)

• 3. Through the damaged endothelial monolayer (nicotine, autoimmune complexes, high blood pressure, turbulent blood flow, push of pulse wave, the tension shift)

Cholesterol metabolism violation

1. Hypercholesterolemia

2. Dislipoproteinemia

а) LDL concentration

b) Kch = (LDL+VLDL)/HDL (high coefficient correlates to higher probability of atherosclerosis)

Endothelium damage 1. Action of Hemodynamic

factorsа) arterial pressure stroke

volume blood push endotheliocytes

displacement and damage

b) Turbulent moving of blood(arch of aorta, bifurcation of

arteries, branching of arteries, winding section - in these places often formed

plaques)

2. Damage by immune complexes

ЕТHIOLOGY

Peculiarities Are produced- in blood- extra cellular space- in arterial wall

Modified LDL

Properties1. They do not interact with

аpоВ- and аpоЕ-receptors 2. They interact with “scavenger

– receptors ”. Entrance of LDL inside the cell results from the gradient concentration (uncontrolled еndocytosis)

3. Supply cholesterol in cells and stimulate put-off of cholesterol in artery walls

Peroxides modified LDL

LDL+Glucose

LDL+protein

LDL+Ig

LDL+glycosaminoglycan

Their accumulation promotes the forming of foam cells

There are persons who have normal concentration of LDL, but suffer from atherosclerosis!

Reducing of HDL concentration is important

Anti atherosclerosis role of HDL

1. Very easy penetration inside the intimae (due to apоprotein-А) and take out cholesterol

2. Reduce coming up of LDL inside endotheliocytes3. Retention of LDL damage by free radicals

4. Increase prostacyclin synthesis and and decrease thrombocytes aggregation

5. Decrease proliferation of the smooth muscle cells, which is induced by LDL

6. Decrease synthesis of glycosaminoglycans by smooth muscle cells

In the occurrence of atherosclerosis there are 4 defining mechanisms:

• 1. Hereditary factors (lipid metabolism associated with mutation of genes, which encoding receptor of cells to low-density lipoprotein: decreasing the quantity of receptors for LDL on the surface of hepatocytes or they are absent; hereditary hyperlipoproteinemy; deficiency of lipoprotein lipase, enzymes of β-oxidation of fatty acids; defects of NO-synthase genes, polymorphisms of genes encoding of angiotensinogen, angiotensin receptors, angiotensin-converting enzyme, and endothelin receptors to them, growth factor of platelets and fibroblasts).

• 2. Lipid metabolism disorders (increase level of total cholesterol above 5.2 mmol/l; serum cholesterol LDL above 4 mmol/l; decrease serum level of high density lipoprotein cholesterol below 0.9 mmol/l).

• 3. Changes in the vascular wall of arteries.• 4. Violation receptors of cells (E.I. Chazov, 1998).

Theories of atherosclerosis• 1. Hypothesis response

to injury

• 2. Monoclonal hypothesis

• 3. Lysosomal theory

Morphological stages of atherosclerosis1) lipid spots 2) fibrous plaques 3) complications: ulceration, calcification,

thrombosis

1 STAGE –

“FOAM CELLS” PATHOGENESIS

Macrophages have main role:

1. They have “scavenger”-

receptors so Cholesterol

comes in macrophage only

due to concentration

gradient

2. They can accumulate a lot

of Cholesterol inside the cell (process is

controlled by HDL)

3. Modified LDL stimulate

macrophages activity

1 STAGE –

“FOAM CELLS”

Migration of macrophage in intimae

Capture of LDL

Decrease of LDL

concentration in intimae

Many macrophages change into “foam cells”

Role of endotheliocytesThere is no deposit of LDL inside the endotheliocytes!!!!!!!!!а) Due to Аpо-В,Е-receptors entrants of LDL is controlledб) Using of scavenger receptors stimulates retroendocytosis

But!!!1. At hypercholesterolemia absorption of LDL is activated.

That causes endotheliocytes proliferation and accumulation of LDL in intimae.

2. Endothelium injury is common uncontrolled penetration of LDL inside the vessel wall.

3. On endothelium surface is activated lipoprotein lipase, which controls dissociation of VLDL into LDL and HDL

1 STAGE –

“FOAM CELLS”

Role of the smooth muscle cellsDeposit of LDL in intimae causes excretion of

hemotaxis factors by endotheliocytes, macrophages and fibroblasts. These substances conduce smooth muscle cell (SMC) hemotaxis into intimae (contractile cells have ability to change in secretory).

What do they do ???1. They absorb of LDL (they have Аpо-В and Аpо-Е

receptors)2. They proliferate (due to thrombocyte growth factor.

Their DNA synthesis activates and mitosis occurs)3. They synthesize collagen, elastin,

glycosaminoglucans (connective tissue matrix of plaque)

1 STAGE – “FOAM CELLS”

2 stage – LIPID SPOTS

They are formed on different parts of

arterial system (in elastic and elastic-muscle type of vessels):

They have different square in different age:

in aorta – 10 % in 10 years,

30-50% in 25-30 years

in coronary arteries are

appear in 15 years

in cerebral arteries are

appear in 35-45 years

There is proved that this stage can be reversible due to prolonged uncholesterol diet

Formation mechanismFoam cells overload by

cholesterol causes their damage. At this time hydrolytic lisosomal enzymes release, which causes necrosis of surround tissue.

2 stage – LIPID SPOTS

Contents of LIPID SPOTS:

- Foam cells

- Моnocytes/macrophages

- Smooth muscle cells

- Lymphocytes

- Free cholesterol

- Connective tissue

Main characteristic – don’t violate blood flow

3 stage – FIBROUS PLAQUE

Cholesterol and lisosomal enzymes

irritates intimae (because they are the foreign bodies)

Excreation of proliferation factors by macrophages, еndotheliocytes, lymphocytes and thrombocytes

SMC migration in intimae and active proliferation collagen and elastin (capsule that isolates place accumulation of cholesterol and damage of blood vessels by lysosomal enzymes)

characteristic- Contents: ЕChol, NEChol,

leavings of elastin and collagen, foam cells, Chol crystals, necrotic mass

- Vessel narrowing- Stage unalterable

- Partial regression (dilipidation) - diet without Cholesterol (150-160mg/dl) during 1,5-2 years

3 stage – FIBROUS PLAQUE

1. THROMBOSIS (due to endothelium

damage)

2. Ulceration(necrotic

disintegration content plaques leads to thinning of its walls)

3. Calcinations(deposit of insoluble

calcium salts)

4 stage - COMPLICATIONS

4 stage - COMPLICATIONS

Risk factors of atherosclerosis development• 1. Irreversible (endogenous)• Age (men over 40, women over 50 years)• Gender (male, anti-sclerotic effect of estrogen, cholesterol in the case of nonatherosclerotic α-

lipoprotein)• Genetic predisposition (sudden death, myocardial infarction or brain stroke in parents: at

age before 50 in men and before 55 in women)

• 2. Inverse (managed)• Smoking• Hypertension• Obesity

• 3. Potential or partially reverse• Hyperlipidemia - Hypercholesterolemia and / or hypertriglyceridemia• Hyperglycemia and diabetes mellitus• Low levels of high density lipoprotein

• 4. Other possible factors• Low physical activity• Emotional stress and / or personality type• Intoxication, infection

Thank you for your attention!