atherosclerosis, lipoproteins and lipid-lowering drugs

Question 1

describe the exogenous pathway of lipid metabolism

Answer 1

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

Question 2

what happens to the VLDL?

Answer 2

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

Question 3

reverse cholesterol transport

Answer 3

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.1

Question 4

endothelium dysfunction characteristics in atherosclerosis

Answer 4

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

Question 5

describe the formation of the fatty streak formation

Answer 5

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. Later lesions include smooth muscle cells. A complicated series of steps is involved, including smooth-muscle migration, T cell activation, foam cell formation and platelet adherence and aggregation.1
Fatty streaks are common; they may increase in size, remain static or even disappear.1

Question 6

formation of the complicated atherosclerotic plaque

Answer 6

The development of an atherosclerotic plaque indicates an advanced stage in the atherosclerotic process and results from death and rupture of the lipid-laden foam cells in the fatty streak. Migration of vascular smooth muscle cells (VSMCs) to the intima and laying down of collagen fibres results in the formation of a protective fibrous cap over the lipid core. The fibrous cap is a crucial component of the mature atherosclerotic plaque as it separates the highly thrombogenic lipid-rich core from circulating platelets and other coagulation factors. Stable atherosclerotic plaques are characterised by a necrotic lipid core covered by a thick VSM-rich fibrous cap. Lesions expand at the shoulders by continued leukocyte adhesion. 1