Disorders of Lipid Metabolism

PHYSIOLOGY

Lipids are insoluble in water, and are transported in the bloodstream as macromolecular complexes. In these complexes, lipids (principally triglyceride, cholesterol and cholesterol esters) are surrounded by a stabilizing coat of phospholipid. Proteins (called apoproteins) embedded into the surface of these ‘lipoprotein’ particles exert both a stabilizing function and allow the particles to be recognized by receptors in the liver and the peripheral tissues. The structure of a chylomicron (one type of lipoprotein particle) is illustrated.
The genes for all the major apoproteins and that for the low-density lipoprotein (LDL) receptor have been isolated, sequenced and their chromosomal sites mapped. Production of abnormal apoproteins is known to produce,  or predispose to, several types of lipid disorder, and it is likely that others will be discovered. Genetic abnormalities which affect the LDL receptor cause familial hyper cholesterolaemia.
Five principal types of lipoprotein particles are found in the blood . They are structurally different and can be separated in the laboratory by their density and electrophoretic mobility. The larger particles give postprandial plasma its cloudy appearance.

Chylomicrons

Chylomicrons are synthesized in the small intestine postprandially. They contain triglyceride and a small amount of cholesterol, and provide the main mechanism for transporting the digestion products of dietary fat to the liver and peripheral tissues. Each newly formed chylomicron contains several different apoproteins (B-48, A-I, AIr),  and acquires apoproteins C-II and E by transfer from high-density lipoprotein (HDL) particles in the bloodstream. Apoprotein C- II binds to specific receptors in the peripheral tissues and the liver and allows the endothelial enzyme, lipoprotein lipase, to remove triglyceride from the particle. The remaining chylomicron remnant particle, which contains most of the original cholesterol, is taken up by the liver by mechanisms which are still not fully understood, possibly mediated by apoprotein E. Very low density lipoprotein (VLDL) particles These are synthesized and secreted by the liver and contain most of the endogenously synthesized triglyceride and a smaller quantity of cholesterol. Apoprotein B-I00 is an essential component. Apoproteins C and E are later incorporated into VLOL by transfer from HOL particles. As they pass round the circulation VLOL particles bind  through apoprotein C allowing triglyceride to be progressively removed by lipoprotein lipase. This leaves a particle, now depleted of triglyceride and apoprotein C, called an intermediate-density lipoprotein (IDL) particle.

Intermediate-density lipoprotein particles

These also contain apoprotein B-lOO and can bind to the hepatocyte through apoprotein E. Once bound, IDL particles can be catabolized, or have further triglyceride removed (by the enzyme hepatic lipase) producing LOL particles.

Low-density lipoprotein particles

LOL particles are the main carrier of cholesterol, anddeliver it both to the liver and to peripheral cells. The  surface of the LOL particle contains a single apoprotein B-lOO, and also apoprotein E. The apoprotein B-lOO is the principal ligand for the LOL receptor. This receptor lies within coated pits on the surface of the hepatocyte. Once bound to the receptor, the coated pit invaginates and fuses with Iiposomes which destroy the LOL particle . The number of hepatic LOL receptors regulates the circulating LOL concentration. The circulating LOL concentration is also regulated by controlling the activity of the rate-limiting enzyme in the cholesterol synthetic pathway, hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase. Not all the cholesterol synthesized by the liver is packaged immediately into lipoprotein particles. Some is converted into bile salts. Both bile salts and cholesterol are excreted in the bile: both are then reabsorbed through the terminal ileum and recirculated (enterohepatic circulation).

High-density lipoprotein particles

HOL particles are produced in both the liver and intestine.The nascent particles are disc shaped, seemingly  inert and contain E apoproteins. They are modified by acquiring some surface components of chylomicron and VLOL particles as these are broken down into smaller particles. The materials gained by the nascent HOL  particles include phospholipids, and the A and C apoproteins. The more mature HOL particles take up cholesterol from cell membranes in the peripheral tissues. As it is taken up the enzyme lecithin-cholesterol acyltransferase (LeA T), activated by the apoprotein A on the particle’s surface, esterifies the sequestered cholesterol. The HOL particle is then capable of transporting this cholesterol away from the periphery to the liver (reverse cholesterol transport) where it binds through apoprotein E.
HOL particles carry 20-30% of the total quantity of cholesterol in the blood.
When a laboratory measures fasting serum lipids, the majority of the total cholesterol concentration consists of LOL particles with a 20-30% contribution from HOL particles. The triglyceride concentration largely reflects  the circulating number of VLOL particles, since chylomicrons are not normally present in the fasted state. If the patient is not fasted the total triglyceride concentration will be raised due to the presence of triglyceriderich chylomicrons as well as VLOL particles.

EVIDENCE FOR A RELATIONSHIP

BETWEEN LIPOPROTEIN

CONCENTRATIONS, ATHEROMA AND CARDIOVASCULAR RISK
LDL cholesterol.
EPIDEMIOLOGICAL LINKS BETWEEN CHOLESTEROL AND CORONARY HEART DISEASE. Population studies have repeatedly demonstrated a strong association between both total and LOL cholesterol concentration and coronary heart risk. There is a strong link between  mean fat consumption, mean serum cholesterol concentration and the prevalence of coronary heart disease between countries. The exception is France where the cardiovascular risk is only moderate-perhaps due to high alcohol consumption. Studies of migrants, particularly of Japanese men migrating to Hawaii, have shown that as diet changes, and cholesterol concentrations rise, so does the cardiovascular risk. Such studies show the importance of the environment rather than the genetic make-up of a population.

The Multiple Risk Factor Intervention Trial (MRFIT) screened one-third of a million American men for various cardiovascular risk factors and then followed them for 6 years. Data from this study have shown that although  cardiovascular risk rises progressively as total cholesterol concentration increases, the risk increase is modest for individuals with no other cardiovascular risk factors. With each additional risk factor, the effect produced by the same difference in cholesterol  concentration becomes greatly magnified. The Framingham Study has reproduced these findings in a separate population.
ANIMAL AND BIOCHEMICAL STUDIES. Diverse laboratory studies have shown a strong link between dietary fat intake, resultant elevation of LDL cholesterol concentrations and the development of atheroma .
PATIENTS WITH MONOGENIC INHERITED LIPID DISORDERS.
Young men with the monogenic disorder familial hypercholesterolaemia are normal apart from considerably
elevated LDL cholesterol concentrations, yet they die of premature cardiovascular disease, and only 20-30% reach retirement age.
PREVENTION TRIALS. Two large well-controlled primary prevention studies (the Lipid Research Clinics Trial and the Helsinki Heart Study) have shown an increasing improvement in cardiovascular risk with increasing duration of treatment for hyperlipidaemia. (Intervention trials).

HDL cholesterol

Epidemiological studies have shown that HDL particlesappear to protect against atheroma. This effect may be  due to the ability of the particle to transport cholesterol from the peripheral tissues to the liver. HDL particles have important effects on the function of platelets and of the haemostatic cascade. These properties may favourably influence thrombogenesis.

VLDL particles

There is a weaker independent link between raised concentrations of (triglyceride-rich) VLDL particles and cardiovascular risk. The evidence is only epidemiological so there is a weaker case for the treatment of hypertriglyceridaemia when it occurs alone.

Chylomicrons

Excess chylomicrons do not confer an excess cardiovascular risk, but raise the total plasma triglyceride concentration.