FAMILIAL HYPERCHOLESTEROLEMIA : CONSEQUENCES OF LOW DENSITY LIPOPROTEIN RECEPTOR DYSFUNCTION
Our knowledge of the LDL receptor originally came from studies of patients with a defective LDL receptor pathway. Some patients suffer from a genetic disease known as familial hypercholesterolemia (FH) in which a mutation affects the function of the LDL receptor and uptake of LDL particles by the liver and other tissues. It is characterised by three factors: (i) elevation of plasma levels of LDL; (ii) cholesterol deposits in abnormal sites particularly in tendons (formation of xanthomata) and in arteries (atheromata); and (iii) inheritance of an autosomal dominant trait with a gene affecting the quantitative inheritance. Thus the individuals who have inherited two alleles (FH homozygous) are more severely affected than those with one mutant allele (FH heterozymgous). The heterozygotas are present one in about 500 persons while one individual in one million inherits two mutant genes at the LDL receptor locus. Homozygous individuals are the outstanding example of a single gene mutation that produces obligatory atherosclerosis. There is progressive deposition of LDL-derived cholesterol in the major arteries followed by myocardial infarction, angina pectoris and sudden death usually before the age of 15. In heterozygous individuals there is much less severity in the symptoms developed. In heterozygous men the incidence of myocardial infarction before the age of 60 is about 75% while in normal men the risk is about 15%. The women show similar elevated levels of plasma cholesterol and LDL as men , but suffer much less from coronary heart disease. The heterozygous women run a risk of 45% while normal women show a risk of 10% in developing coronary heart disease before the age of 60.
Artherosclerosis is one of the most common diseases leading to mortality in humans. It is caused by the deposition of lipids (mainly free and esterified cholesterol) in blood vessels. Most of the cholesterol in the blood is transported in the form of LDL particles into the arterial intima, which is the site for atherogenesis. From the intima cholesterol is removed by HDL and put back in circulation in the plasma. Excessive deposition of lipids (mainly cholesterol) is caused by a disturbance between the influx and efflux of lipoproteins. The factors which cause this are the local modification of LDL particles (oxidation) leading to its uptake by scavenger cells, and insufficient removal of cholesterol by HDL particles. A schematic representation of these events is shown in Fig. 7.
PRESENT STATE OF KNOWLEDGE AND FUTURE RESEARCH
The mechanism for the removal of LDL particles from the plasma by the LDL receptor is at present best understood and it has influenced the thinking on the removal of other lipoproteins. There has been a natural tendency to look for similar systems of removal of other lipoproteins. But it is known that HDL particles are not metabolised as intact particles like LDL. In spite of the advances in chylomicron remnant removal there is still uncertainty whether the LDL receptor is responsible for chylomicron remnant removal or there is another specific receptor. The way the modified LDL particles are removed by scavenger receptors is not very clear. Finally the determination of human genome and the gene therapy will occupy much time for finding cures for atherosclerosis and hypercholesterolemia.
Fig. 7. The intimal traffic of cholesterol: schematic representation of processes leading to the formation of foam cells and extracellular cholesterol core. 1. Plasma LDL particles enter the intimal layer by crossing the endothelium. 2. LDL particles are bound to LDL receptors on the surface of smooth muscle cells (SMC) and are degraded within them. 3. Part of the excess LDL returns to the bloodstream. 4. Some of the nondegraded, nonreturned LDL becomes extracellularly modified by smooth muscle cells, mast cells, and macrophages, resulting in particles not recognised by the LDL receptor (mod. LDL). 5. Macrophages (Mf) remove modified LDL particles by scavenger receptors (Section 5.2) and are transformed into cholesterylester (CE)-loaded foam cells. 6. Some of the modified LDL might escape scavenging and form an extracellular cholesterol core trapped in the intima by the internal elastic lamina (int. el. lamina). 7. Some foam cells die, and their cholesterylester droplets fuse with the cholesterol core. 8. Parts of the cholesterol core may become phagocytosed by macrophages or foam cells. 9. Plasma HDL, possibly prebeta HDL particles, cross the endothelium; due to their small size they are more mobile than LDL particles, and 10. Interact with foam cells where they become loaded with cholesterol [this constitutes the initial step of reverse cholesterol transport]. A crucial function of HDL is to carry the cholesterol from the intima back to the bloodstream. Note that formation of foam cells and cholesterol core (characteristic of an atheroma) are due to an imbalance between cholesterol influx via LDL and cholesterol efflux via HDL Fatty streaks are clusters of foam cells without the extracellular cholesterol core found in atheromas. Adapted from (24)
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