Atherosclerosis and lipid metabolism Flashcards
What is important to remember about fats
They are insoluble in water and therefore need to be packaged into proteins (lipoproteins).
Summarise the basic structure of lipoproteins
These consist of a central core of hydrophobic lipid (including triglycerides and cholesteryl esters) encased in a hydrophilic coat of polar phospholipid, free cholesterol and apoprotein.
What are apoproteins
Apoproteins bind to specific receptors that mediate uptake of lipoprotein particles into liver, blood or other tissues.
Describe how the different lipoproteins differ
There are four main classes of lipoprotein, differing in the relative proportion of the core lipids and in the type of apoprotein (various kinds of apoA and apoB)
Lipoproteins differ in size and density, and this latter property, measured originally by ultracentrifugation but now commonly estimated by simpler methods, is the basis for their classification
Name the different lipoproteins
HDL particles (contain apoA1 and apoA2), diameter 7–20 nm
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LDL particles (contain apoB-100), diameter 20–30 nm
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very-low-density lipoprotein (VLDL) particles (contain apoB-100), diameter 30–80 nm
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chylomicrons (contain apoB-48), diameter 100–1000 nm
Describe the exogenous pathway of lipid metabolism
The exogenous metabolic pathway is concerned with the transport and utilisation of dietary fats. Dietary fat is broken down in the gastrointestinal tract into cholesterol, fatty acids and mono- and diglycerides. These molecules, together with bile acids, form water-soluble micelles that carry the lipid to absorptive sites in the duodenum.1
Normally, virtually all triglyceride (TG) is absorbed, compared with only 50% of cholesterol. Following absorption in the duodenum, chylomicrons are formed which enter the bloodstream via intestinal lymphatics and the thoracic duct. On entering the plasma, rapid changes take place in the chylomicron. It is hydrolysed by the enzyme lipoprotein (LP) lipase releasing the triglyceride core, free fatty acids and mono- and diglycerides for energy production or storage. The residual chylomicron undergoes further delipidation, resulting in the formation of chylomicron remnants. These are taken up by a number of tissues. In the liver they undergo lysomal degradation, and are either used for a variety of purposes including remanufacture into new lipoproteins, production of cell membranes or excretion as bile salts.1
Where is lipoprotein lipase found
On the vascular endothelium of capillaries
Which two tissues can the FFAs released by lipoprotein lipase enter
Skeletal muscle (minority) Adipose tissue (majority)
What else can happen to the chylomicron remnants
They are very good at getting into the tunica intima and so can cause atheroma (normally cleared an hour after a fatty mea l)
What do the chylomicron remnants contain
Cholesterol esters.
Describe what happens to the chylomicron remnants upon entering the liver
pass to the liver, bind to receptors (remnant receptors) on hepatocytes and undergo endocytosis. Cholesterol liberated in hepatocytes is stored, oxidised to bile acids, secreted unaltered in bile, or can enter the endogenous pathway.
Describe the endogenous pathway of lipid metabolism
Whilst chylomicrons transport triglyceride from the gut to the liver, VLDL is the analogous particle that transports triglycerides from the liver to the rest of the body. Triglycerides together with cholesterol, cholesterol ester and other lipoprotein particles are transported in VLDL in the bloodstream, where VLDL undergoes delipidation with the enzyme lipoprotein lipase in a similar way to chylomicrons; this is the endogenous pathway of lipid metabolism. During this process, triglyceride is removed from the core and exchanged for cholesterol esters, principally from HDL. Whilst most VLDL is transformed into LDL, the larger VLDL particles are lipolysed to IDL, which is then removed from the plasma directly. Lipoprotein lipase is the main enzyme used in the lipolysis of large VLDL particles, whereas hepatic lipase reacts with the small VLDL and IDL particles.1 IDL is highly atherogenic.
The product of this metabolic cascade, LDL, exists in the plasma in the form of a number of subfractions; LDL I–IV. It has been shown that small dense LDL particles are the most atherogenic. They are absorbed by macrophages within the arterial wall to form lipid-rich foam cells, the initial stage in the pathogenesis of atherosclerotic plaques.1
The enterohepatic circulation provides a route for the excretion of cholesterol and bile acids.1
What is the purpose of delivering LDL to cells
LDL provides the source of cholesterol for incorporation into cell membranes and for synthesis of steroids
Describe how cells take up LDL
Cells take up LDL by endocytosis via LDL receptors that recognise apoB-100. LDL receptors are critically important in determining the concentration of circulating LDL, and hence the development and progression of atheromatous disease; the most widely used drugs for the prevention of such disease, the statins, act by blocking the synthesis of cholesterol within hepatocytes which respond by increasing LDL receptor expression on their surface membranes
Where can IDL and LDLs be deposited
o IDL and LDLs are deposited in vessels to form atheroma
What happens to the size of the lipoprotein during endogenous lipid metabolism
During this process, the lipoprotein particles become smaller but retain a full complement of cholesteryl esters and become LDL particles.
They lose fat- but retain cholesterol esters- and thus increase in density
Describe reverse cholesterol transport
As cholesterol cannot be broken down within the body, it is eliminated intact. It is transported via HDL from the peripheral tissues to be excreted by the liver. HDL begins as a lipid-deficient precursor which transforms into lipid-rich lipoprotein. In this form it transfers cholesterol either directly to the liver or to other circulating lipoproteins to be transported to the liver for elimination.1
The observation that HDL acts as a vehicle for the transport of cholesterol for elimination has led to the identification of HDL as a protective factor against the development of atherosclerosis.
What is the purpose of reverse cholesterol transport
§ Reverse cholesterol transport – the removal of cholesterol from vessel walls back to the liver by HDL.
What else can happen to the HDL molecules in reverse cholesterol transport
Cholesterol can return to plasma from the tissues in HDL particles (reverse cholesterol transport). Cholesterol is esterified with long-chain fatty acids in HDL particles, and the resulting cholesteryl esters are transferred to VLDL or LDL particles by a transfer protein present in the plasma and known as cholesteryl ester transfer protein (CETP)
What type of disease can atherosclerosis be described as
“ Atherosclerosis is an inflammatory fibroproliferative disorder
Essentially, what is the issue in atherosclerosis
The endothelium of the tunica intima of large and medium sized arteries is damaged- making it leaky and allowing macrophages to enter.
Summarise the pathophysiology of atherosclerosis
- LDL enters endothelium (into tunica intima (media is VSMCs)).
- LDLs are oxidised by macrophages and VSMCs.
- Release of growth factors and cytokines.
- Additional monocytes/macrophages recruited.
- Foam cell accumulation.
- VSMC migration.
- VSMC proliferation.
- Plaque growth.
Describe endothelial dysfunction in atherosclerosis
Endothelial dysfunction in atherosclerosis is characterised by a series of early changes that precede lesion formation. The changes include greater permeability of the endothelium, up-regulation of leucocyte and endothelial adhesion molecules and migration of leucocytes into the artery wall.1
Summarise fatty streak formation
§ Migration of VSMCs.
§ Activation of T-cells.
§ Adherence & activation of platelets.
§ Formation of foam cells.
Describe the properties of fatty streaks
The ‘fatty streak’ is the earliest recognisable lesion of atherosclerosis and is caused by the aggregation of lipid-rich foam cells, derived from macrophages and T lymphocytes, within the intima, the inner most part of the artery wall
Fatty streaks are common; they may increase in size, remain static or even disappear.1
Explain the formation of fatty streaks
Monocytes adhere to the endothelium, migrate into the intima and differentiate into macrophages. Local oxidation of LDL (bound to proteoglycans) and once in the intima, macrophages take up the oxLDL and become foam cells.
Platelets adhere to the endothelial cells or areas of denuded matrix and become activated. Activated platelets, activated endothelial cells and macrophages release platelet-derived growth factor stimulating smooth muscle cell migration from the media to the intima.
Describe the uptake of oxLDL by macrophages
oxLDL uptake by macrophages via ‘scavenger’ receptors.
Uptake of oxLDL activates macrophages which release proinflammatory cytokines.
Summarise complicated plaque formation
§ Formation of fibrous cap.
§ Accumulation of macrophages.
§ Formation of necrotic core.
Describe the development of a lipid plaque
Smooth muscle proliferation and an increase in ECM occur in the intima. Additional cytokines and growth factors produced by activated macrophages and platelets promote additional monocyte and smooth muscle infilatration. Lipid may also be released from dying foam cells, contributing to extracellular free lipid pools.
This extracellular free lipid core is prone to calcification
