HDLs begin as small particles, become disc-shaped and mature to spheres. The newer, smaller spheres are most dense. HDLs pick up free cholesterol from cells and convert it into cholesterol ester (the 'not free' form of cholesterol). The cholesterol is taken back to the liver where it is used for bile.
Unlike a triglyceride-rich low density lipoprotein, a high density lipoprotein starts out as a very small, disorganized particle of no specific shape. It progresses through a series of changes becoming a disc-shaped particle then it becomes spherical. Unlike low density lipoproteins its job is to gather instead of lose; it picks up cholesterol from various cells throughout the body. Eventually it returns to the liver -- where it started -- and deposits its cholesterol load there.
The illustration at the right shows how an HDL begins as an apoprotein A1 (red) plus a few molecules of phospholipid (purple) and free cholesterol (orange) secreted into the space of Disse. It has no particular organization; it is called lipid-poor apoA1. It accumulates additional phospholipid and free cholesterol molecules as it circulates and becomes a bilayered disc called nacent HDL. As it continues to circulate it picks up additional free cholesterol and phospholipids but now the free cholesterol is converted into cholesterol ester that is stored between the two layers and this converts it to a small sphere called HDL3. This process continues until the sphere grows, becoming less dense, and is called HDL2.
The illustration at the left is extracted from the main diagram to focus on how an HDL lipoprotein matures. The curved line at the top is part of an hepatocyte membrane. The liver secretes apoprotein A1, accompanied by a few cholesterol and phospholipid molecules, producing a small disorganized particle is called lipid-poor apoA1.
This particles leaves the space of Disse and enters the circulatory system. It is extremely small and readily passes through capillary walls coming into direct contact with cells throughout the body. Cells with excess cholesterol (small circle with C) have ATP-binding cassette transporter (ABCA-1) on their surface. This protein transports free cholesterol to the outer leaflet of the cell membrane. ApoA1 of the lipid-poor particles binds with ABCA-1 resulting in the transferred of free cholesterol and phospholipid to the particle.
As phospholipid and free cholesterol are added to the particle, these molecules spontaneously arrange themselves with the hydrophobic (water-hating) sections facing each other and their hydrophilic (water-loving) sections facing outward. The arrangement is like a typical double-leaflet cell membrane as shown to the right. The edge of this structure is encircled by the apoprotein A1 molecule that stabilizes the structure known as nacent HDL.
The plasma enzyme lecithin-cholesterol acyltransferase (LCAT) also binds to apoA1 but at a different site. Activated by this binding, the enzyme converts accumulating free cholesterol to cholesterol ester. It does this by removing a fatty acid from a phospholipid and transferring it to a neighboring free cholesterol -- the cholesterol is no longer 'free'. Being extremely hydrophobic, cholesterol ester accumulates between the two layers of the disc. This converts nacent HDL to a small sphere called HDL3. The conformation of apoA1 is altered when the disc becomes spherical causing its detachment from the ABCA-1.
Cholesterol rich cells have scavenger receptor B-1 (SR-B1) transporters in addition to ABCA-1. Both function is essentially the same manner. As HDL particles contact these cells more cholesterol continues to accumulate and LCAT facilitates enlargement of the core.
To accommodate the expanding core, additional phospholipid and free cholesterol is also added to its coat by phospholipid transfer protein (PLTP). This protein accumulates sections of lipoprotein coat shed from other lipoproteins as they decrease in size. Included in these sections are also a variety of other apoproteins including additional apoA1s.
This ability of HDL to pick up cholesterol also applies to its encounter with cholesterol-rich foam cells. These cells reside just beneath the lining of inflamed arteries. SR-B1 transports cholesterol from intercellular droplets (circles with C) to the membrane. Additionally, foam cells have ABCG-1 transporters that do the same. HDL particles encountering these surfaces pick up more cholesterol and continue to enlarge. At some point the surface apoA1 becomes altered such that it no longer binds LCAT and no further enlargement can occur.
The density of the enlarging HDL eventually decreases to a point where it is called an HDL2. The '2' simply implies it is less dense than the '3' HDL. HDL1 particles are possible but they are rare in humans.
HDLs eventually pass through the liver sinusoids and enter the space of Disse. Here they encounter heparan sulfate proteoglycans (HSPG) bound to the hepatocyte membrane. These large, branched molecules have hepatic lipase (HL) bound to them. It appears that one of two things can happen when HDL and HL bind:
Continue to Lipoprotein Remodeling.
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