Hyperlipidaemias

·        Role of lipoproteins in lipid transport.

·        Lipid transport in the body.

·        Modulation of cellular cholesterol.

·        Types of hyperlipidaemia.

·        Guiding principles in treatment.

Role of Lipoproteins in Lipid transport

1.    All lipids (fatty acids, triglycerides, phospholipids, free and esterified cholesterol) whether from dietary sources or synthesized by the liver have to be transported in plasma to various tissues for use or storage.

2.    The solubilization and transportation of these water-insoluble lipids is accomplished by their incorporation into lipoproteins.

3.    The lipoproteins carry the non-polar triglycerides and/or cholesterol esters in their core and this is covered by an outer later of amphipathic material consisting of apoproteins interlaced with phospholipids and free cholesterol.

4.    The apoproteins function as cofactor(s) to regulate enzyme activity and also play a vital role in the cellular uptake of lipoproteins by attachment to specific uptake receptors.

Transport of lipids in the body

1.       Chylomicrons:

a.    In the small intestine, ingested lipids emulsified by bile salts to form micelles, are hydrolyzed by pancreatic lipase, phospholipase and esterases, respectively and absorbed.

b.    In the intestinal mucosal cells, the absorbed long chain fatty acids are recombined as triglycerides which together with some reformed cholesterol ester form the core of the chylomicron.

c.    The chylomicrons are secreted into the lymph and carried by way of the thoracic duct to enter the blood circulation taking up small amounts of apo-E and apo-C from other lipoproteins.

d.    At the endothelial cells of the capillaries, the chylomicrons are digested by lipoprotein lipase (LPL) bound to the surface of the endothelial cells; apo-C and heparin act as cofactors.

e.    The liberated fatty acids cross the endothelium and enter adipocytes or muscle cells where they are either re-esterified to form triglycerides for storage or oxidized to provide energy.

f.     The chylomicron remnant dissociates from the endothelium and free cholesterol is transferred to HDL.

g.       Retention of apoE enable the chylomicron remnant to be recognized and taken up by the liver by receptor-mediated endocytosis.

h.    In the hepatocyte, the cholesterol esters in the remnant are hydrolyzed in lysosomes and the free cholesterol is either excreted in the bile, oxidized and excreted as bile acids or used to form VLDL which is then secreted into the plasma.

2.    Very low density lipoproteins (VLDL):

a.    The stimulus for synthesis of VLDL is a high caloric intake which induces the liver to assemble triglycerides for export.

b.       Triglycerides and cholesterol are transported to extra-hepatic tissues in VLDL secreted in the plasma.

c.       VLDL are digested to produce LDL which is taken up by the liver and other tissues.

d.       Circulating LDLs have a half-life of 1.5 days and are the major source of cholesterol in plasma (60 – 70% of total).

3.    High density lipoproteins (HDL):

a.       Nascent HDL are secreted by the liver as discoid particles of phospholipid with apo-A and –E and having high affinity for cholesterol.

b.    HDL take on free cholesterol from extra-hepatic tissues through desorption from plasma membranes and directly from other circulating lipoproteins by a cholesterol ester transfer protein (CETP).

c.    The cholesterol adsorbed onto HDL is esterified with a long-chain fatty acid by an enzyme in plasma, lecithin-cholesterol acyltransferase (LCAT).

d.       Disposal of cholesterol ester in HDL may occur either by direct transfer to hepatocytes or by apo-E receptor-mediated uptake of the whole particle.

e.    In this way, HDL function to transport cholesterol from peripheral tissues to the liver which prevents accumulation of cholesterol in tissues.

Modulation of cellular cholesterol

1.       When liver or extra-hepatic tissues require cholesterol they synthesize LDL receptors and obtain cholesterol from circulating LDL.

2.    Free cholesterol within the cell:

a.       Inhibits HMG-CoA reductase, thereby stopping de novo cholesterol synthesis.

b.       Inhibits synthesis of LDL receptors, thereby reducing cholesterol uptake.

c.       Activates acyl-CoA which esterifies cholesterol for storage.

3.    In this way a balance is established between cholesterol taken up by the cell via LDL and the amount made within the cell.

4.       Cholesterol is required for the synthesis of steroid hormones.

5.       Formation of bile acids is the major route by which cholesterol is eliminated.

Classification of Hyperlipidaemias

Guiding princples in Management

1.       Exclude any contributory causes of hyperlipidaemias:

a.    Liver and biliary disease.

b.       Obesity.

c.       Hypothyroidism.

d.       Diabetes.

e.    Diet.

f.       Alcohol excess.

g.       Drugs: beta-blockers, thiazides and oral contraceptives.

2.       Dietary adjustment:

a.       Those who are overweight should reduce their total caloric intake until they have returned to the weight that is appropriate for their height.

b.       Dietary control with reduced cholesterol and saturated fat intake and total fat not exceeding 35% of total calories can result in 10 to 15% reduction in plasma cholesterol.

c.       There is evidence that an average daily intake of as little as 30g of fish has a protective effect against death from coronary artery disease and that fish-oil (rich in eicosapentaenoic acid & docosahexanoic polyunsaturated fatty acids) markedly lower triglyceride-rich lipoproteins in plasma.

3.    The vast majority of cases of hyperlipidaemia can be managed by diet alone.

4.    Lipid lowering drugs should not usually be considered until other measures have failed – the basis to use them is made on the basis of the overall IHD risk, e.g. evidence of existing IHD, hypertension, diabetes mellitus, positive family history.

5.       Rationale for drug treatment:

a.    Lipid Research Clinics Coronary Primary Prevention trial (JAMA 1984) and Helsinki Heart Study (N Eng J Med, 1987): reducing asymptomatic hypercholesterolaemia reduces risk of myocardial infarction.

b.       Cholesterol Lowering Atherosclerosis Study (JAMA 1987): regression of coronary occlusion on lowering of plasma cholesterol levels.

6.       Treatment of specific hyperlipidaemias:

a.    Type I and some type V: reduce dietary fat to 10% of total caloric intake.

b.    Type IIa: usually responds to diet but those with familial hypercholesterolaemia almost always need an ion exchange resin and/or a statin.

c.    Type IIb and IV: Dietary control, fibrates or statins; resins should be avoided.

d.    Type III: usually diet-sensitive, failing which fibrates are the drugs of choice.