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The physiology of lipoproteins has been actively researched for the past few decades. Research has answered many questions about how this system works but even more questions have evolved as a result. Lipoprotein physiology is still a hot topic today.
Accordingly it has been very challenging to construct a diagram that shows the interactions among components. The information presented here is meant to give the general student a basic understanding of lipoprotein interactions and is not intended to show all that is understood about this complex system. Indeed, all is not understood.
September 2013
The most obvious reason that too much cholesterol is 'bad' is that it contributes to the formation of atherosclerotic plaques. As these enlarge they constrict the artery and imped blood flow. If a plaque ruptures small pieces of it (thrombi) enter the circulation and become lodged in small downstream vessels. If such a vessel is in the brain the result is a stroke; if in the heart the result is a heart attack.
Not so obvious is the effect excess cholesterol has on all body cells. Though cholesterol is a normal component of cell membranes and contributes to their stability, excess cholesterol causes rigidity. This impedes the normal and necessary lateral movements of membrane components affecting activities such as enzyme function, endocytosis, cell growth, etc.
Body cells can synthesize enough of their own cholesterol to keep pace with everyday demands. If they need more they position LDL receptors in their membranes and engulf cholesterol-rich LDLs to fulfill this need. If they have excess cholesterol they utilize SR-B1 and ABCA-1 transporters to move cholesterol to the outer leaflet of the cell membrane. From this locations HDL particles pick up cholesterol for transport to the liver where it will be secreted as bile.
In addition to being synthesized by body cells, dietary cholesterol is brought into the body as a minor component of chylomicrons; the major component is triglyceride. These largest of all lipoproteins deposit triglyceride in different regions of the body depending on when the individual has last eaten. Just after a meal triglycerides will be hydrolyzed into fatty acids and monoglycerides in adipose tissue for storage. When fasting this will occur in muscle tissue to be used for energy.
The now smaller chylomicrons called remnants will be taken into the liver and removed from circulation. The liver will recirculate most triglycerides and a small amount of cholesterol in VLDLs. This will maintain a supply of triglycerides for skeletal and heart muscle between meals. VLDL remnants bypassing the liver interact with other circulating lipoproteins and exchange triglycerides and cholesterol.
Why is cholesterol circulating around the body in chylomicrons and VLDs if it isn't deposited somewhere? And anyway, the smallest lipoproteins -- the remnants -- can't penetrate capillary walls to reach any body cell that does have LDL receptors displayed.
With the help of hepatic lipase the IDL (VLDL remnant) can lose its remaining triglyceride and become small enough to penetrate capillary walls. This is particularly important to body cells that require a good supply of cholesterol to synthesize steroids (testosterone, cortisone, aldosterone) However, hepatic lipase is bound to hepatocyte membranes in an inactive form and must be released, circulated and activated in order to convert IDLs to LDLs.
HDL2 particles, especially those that have picked up some triglyceride from lipoprotein-rich particles, are responsible for displacing inactive hepatic lipase from hepatocytes. They then transport the still inactive enzyme through the body until contacting triglyceride-rich lipoproteins. Hepatic lipase is transferred to these particles and thus becomes activated. This enzyme hydrolyzes any triglycerides in the particle and also breaks down excess phospholipids in the coat. If the triglyceride-rich lipoprotein is an intermediate density lipoprotein (IDL) the resulting smaller particle could be an LDL. LDLs are able to penetrate capillary walls.
They are also small enough to slip beneath the lining of arteries that have become become inflamed. Macrophages in these areas release chemicals that alter the LDLs causing them to become oxidized. The macrophages also have special SR-A receptors that specifically engulf oxidized LDLs. This cholesterol uptake by the macrophages converts them into foam cells that mark the early stages of atherosclerosis.
Now that the problem of delivering cholesterol to body cells -- and inflamed arteries -- has been solved the new problem is how to retrieve excess cholesterol. This is where HDL comes into play once more. This lipoprotein is small enough to pass through all capillary walls and also to reach foam cells. In addition to SR-B1 transporters, foam cells display ABCG-1 transporters both of which move intracellular excess cholesterol to the surface. Because HDLs don't have much free cholesterol in their coat there is a cholesterol gradient between their coat and cells displaying excess cholesterol. When in contact, this gradient facilitates cholesterol movement to HDLs. The HDLs return the cholesterol to the liver (reverse cholesterol transport) for secretion as bile.
This series of tutorials uses a flow diagram to capture the complex interactions involved in lipoprotein physiology. Sections of this main diagram are isolated and presented in a series of tutorials. These tutorials consider:
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