Highdensity lipoprotein structure and composition

In contrast to LDL, HDL particles (Figure 3) remove excess cholesterol from the periphery and return it to the liver either by the direct uptake of HDL particles via hepatic HDL scavenger receptor type B-1 (SR-B1) or indirectly by CETP-mediated transfer of cholesteryl ester from HDL to LDL or VLDL and hepatic uptake of these apoB particles via the LDLr. The process of collecting excess peripheral cholesterol by HDL for disposal via the liver is the reverse cholesterol transport (RCT) pathway. This is an extremely important process to maintain cholesterol homeostasis since most cells do not have the capability to metabolize excess cholesterol. The key role that HDL plays in mediating cholesterol efflux from cholesterol-rich macrophages and foam cells in the atherosclerotic lesion is regarded as the primary mechanism by which HDL reduces or reverses atherosclerosis.16

With an average diameter of approximately 10 nm, HDL particles have a smaller overall surface size and higher density than LDL particles. The major HDL structural protein is apolipoprotein-AI (apoA-I) which is occasionally accompanied by apoA-II. In contrast to apoB-100 in LDL, apoA-I is much smaller (243 amino acids, ~28kDa), primarily a-helical, and found in both lipid-free and lipid-associated states. However, circulating, lipid-free apoA-I

Cholesterol (red)

Phospholipid

Cholesteryl ester (red)

Apolipoprotein B-100 ß-sheet

Lipoprotein Structure

Figure 2 An illustrated model of a low-density lipoprotein (LDL) particle depicting the spherical surface composed primarily of phospholipids (PLs) with their polar head groups held together by non-covalent interactions on the surface and their associated hydrophobic fatty acid ester tails pointing inward toward the interior of the particle. Free cholesterol (FC) molecules are occasionally interspersed among the PLs on the surface. The interior core of the particle is composed of neutral lipids, primarily cholesteryl ester (CE), with smaller amounts of triglycerides (TGs). Nearly 50% of the surface of the LDL particle is covered with the tightly associated, large (MW >550kDa) apolipoprotein, apoB-100, either as a wide ribbon with b-sheet secondary structure or defined a-helical loops. ApoB-100 occasionally dips below the PL surface to penetrate the interior core. a-Helical regions of apoB-100 also form ligand recognition loops for various receptors, including the hepatic LDL receptor. (Reprinted with permission by Keith Kasnot.)

Triglyceride (green)

LDL receptor ligand

Figure 2 An illustrated model of a low-density lipoprotein (LDL) particle depicting the spherical surface composed primarily of phospholipids (PLs) with their polar head groups held together by non-covalent interactions on the surface and their associated hydrophobic fatty acid ester tails pointing inward toward the interior of the particle. Free cholesterol (FC) molecules are occasionally interspersed among the PLs on the surface. The interior core of the particle is composed of neutral lipids, primarily cholesteryl ester (CE), with smaller amounts of triglycerides (TGs). Nearly 50% of the surface of the LDL particle is covered with the tightly associated, large (MW >550kDa) apolipoprotein, apoB-100, either as a wide ribbon with b-sheet secondary structure or defined a-helical loops. ApoB-100 occasionally dips below the PL surface to penetrate the interior core. a-Helical regions of apoB-100 also form ligand recognition loops for various receptors, including the hepatic LDL receptor. (Reprinted with permission by Keith Kasnot.)

Table 3 Average human plasma concentrations of Lp(a), LDL, and HDL components in normal subjects

Lipoprotein

Average human plasma concentration in normal subjects in (mgdL )

Lipoprotein cholesterol (mgdL )

ldl12,13

HDL315

HDL215

apoB-100 apoA-I apoA-I apoA-I

apo(a)-apoB-100

Highly variable

106+ 13 Negligible 31 18

represents an extremely small percentage ( <5%) of apoA-I found in human plasma where discoidal and spherical forms of HDL predominate.

As a result, mature HDL particle assembly (Figure 4) is a complex process involving several intermediates that occurs throughout the circulation. As shown in Table 2, several subclasses of HDL particles have been observed which can be separated by gel filtration or size exclusion chromatography, including a discoidal pre-b-HDL, and two spherical subclasses, HDL2 and HDL3. HDL3 particles have higher densities and smaller diameters than HDL2 particles.15 Pre-b-HDL particles contain mostly apoA (>90%) and have only a small relative percentage of cholesteryl ester and FC. In contrast to LDL particles, the spherical HDL particle subclasses also have a higher overall apolipoprotein content (40-55%) and correspondingly lower cholesteryl ester and FC mass percentages.

As illustrated in Figure 4, mature HDL assembly begins when lipid-free apoA-I accepts FC at sites in the liver, intestine, endothelial cells, or macrophages by a receptor-mediated process involving adenosine triphosphate-binding cassette (ABC) transporters, primarily ABCA1.17 The resulting FC associated with apoA-I is esterified to cholesteryl ester by the action of lecithyl cholesterol acyl transferase (LCAT) which utilizes apoA-I as a cofactor. This LCAT-assisted fatty acid esterification process drives the formation of the discoidal pre-b-HDL particles. The pre-b-HDL

Spherical HDL

Lipoprotein Structure

Figure 3 An illustrated model of mature spherical high-density lipoprotein (HDL) and discoidal pre-|3-HDL. Discoidal pre-|3-HDL forms as an intermediate in mature HDL particle assembly (Figure 4), as the small, helical apolipoprotein AI (apoA-I) accumulates phospholipid (PL) and free cholesterol (FC) which is further esterified to cholesteryl ester (CE) following the action of lecithyl cholesterol acyl transferase (LCAT). Like LDL, mature, spherical HDL is composed primarily of PLs with their polar head groups held together by non-covalent interactions on the surface and their associated hydrophobic fatty acid ester tails pointing inward toward the interior of the particle. FC molecules are occasionally interspersed among the PLs on the spherical surface. In contrast to LDL, the neutral lipids in the interior core of the HDL particle are composed primarily of triglycerides (TGs) with smaller amounts of CE. The surface of the HDL particle is covered with the loosely associated braids of small (MW = 28 kDa), a-helical apoA-I. The flexibility of this helical protein provides multiple opportunities for ligand recognition loops for various receptors, including scavenger receptors and adenosine triphosphate-binding cassette (ABC) transporters. (Reprinted with permission by Keith Kasnot.)

Figure 3 An illustrated model of mature spherical high-density lipoprotein (HDL) and discoidal pre-|3-HDL. Discoidal pre-|3-HDL forms as an intermediate in mature HDL particle assembly (Figure 4), as the small, helical apolipoprotein AI (apoA-I) accumulates phospholipid (PL) and free cholesterol (FC) which is further esterified to cholesteryl ester (CE) following the action of lecithyl cholesterol acyl transferase (LCAT). Like LDL, mature, spherical HDL is composed primarily of PLs with their polar head groups held together by non-covalent interactions on the surface and their associated hydrophobic fatty acid ester tails pointing inward toward the interior of the particle. FC molecules are occasionally interspersed among the PLs on the spherical surface. In contrast to LDL, the neutral lipids in the interior core of the HDL particle are composed primarily of triglycerides (TGs) with smaller amounts of CE. The surface of the HDL particle is covered with the loosely associated braids of small (MW = 28 kDa), a-helical apoA-I. The flexibility of this helical protein provides multiple opportunities for ligand recognition loops for various receptors, including scavenger receptors and adenosine triphosphate-binding cassette (ABC) transporters. (Reprinted with permission by Keith Kasnot.)

particles also accept more FC from ABCA1 and develop further into spherical HDL2 and HDL3 particles, following the action of LCAT Spherical HDL2 and HDL3 particles and mature HDL do not interact well with ABCA1, but can access additional FC through apoA-I-mediated interaction with related specific macrophage ABCG1 transporters or the SR-B1 scavenger receptors found in peripheral cells. Intact spherical HDL2 and HDL3 particles and mature HDL can deliver FC and cholesteryl ester to the liver by a similar apoA-I-mediated interaction with the hepatic SR-B1 receptor. While ABCA1 and ABCG1 promote cholesterol efflux from cells to the various forms of HDL, the SR-B1 receptors mediate bidirectional transport of cholesterol in both the liver and the periphery.

While the heterogeneity of the HDL particle population precludes detailed structural studies by protein crystallography, a spherical model for mature HDL has been developed.15 As illustrated in Figure 3, the smaller helical apoA-I surrounds the sphere in a loosely held braid. The flexibility of the apoA-I helix affords multiple opportunities for the formation of exposed loops that can act as ligand sites for ABC transporters or SR-BI receptors.

As shown in Table 3, much lower plasma levels of apoA-I are found in healthy humans than apoB-100. Similarly, HDL cholesterol (HDLc) represents a smaller overall percentage of total cholesterol. Comparing HDLc levels of 45-50 mgdL _ 1 with a total cholesterol concentration of 170-180 mgdL_ 1 indicates that HDLc represents ~30% of total cholesterol in normal subjects.15

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Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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