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A lipoprotein is a biochemical assembly whose primary function is to transport hydrophobic lipid (also known as fat) molecules in water, as in blood plasma or other extracellular fluids. They consist of a Triglyceride and Cholesterol center, surrounded by a phospholipid outer shell, with the hydrophilic portions oriented outward toward the surrounding water and lipophilic portions oriented inward toward the lipid center. A special kind of protein, called apolipoprotein, is embedded in the outer shell, both stabilizing the complex and giving it a functional identity that determines its fate.
Lipoproteins are complex particles that have a central hydrophobic core of non-polar lipids, primarily cholesterol esters, and triglycerides. This hydrophobic core is surrounded by a hydrophilic membrane consisting of phospholipids, free cholesterol, and apolipoproteins. Plasma lipoproteins are divided into seven classes based on size, lipid composition, and apolipoproteins.
Lipoprotein any member of a group of substances containing both lipid (fat) and protein. They occur in both soluble complexes as in egg yolk and mammalian blood plasma and insoluble ones, as in cell membranes. Lipoproteins in blood plasma have been intensively studied because they are the mode of transport for cholesterol through the bloodstream and lymphatic fluid.
Types of Lipoprotein
- Chylomicrons – These are large triglyceride-rich particles made by the intestine, which are involved in the transport of dietary triglycerides and cholesterol to peripheral tissues and the liver. These particles contain apolipoproteins A-I, A-II, A-IV, A-V, B-48, C-II, C-III, and E. Apo B-48 is the core structural protein and each chylomicron particle contains one Apo B-48 molecule. The size of chylomicrons varies depending on the amount of fat ingested. A high-fat meal leads to the formation of large chylomicron particles due to the increased amount of triglyceride being transported whereas in the fasting state the chylomicron particles are small carrying decreased quantities of triglyceride.
- Chylomicron remnants – The removal of triglyceride from chylomicrons by peripheral tissues results in smaller particles called chylomicron remnants. Compared to chylomicrons these particles are enriched in cholesterol and are pro-atherogenic.
- Very low-density lipoproteins (VLDL) – These particles are produced by the liver and are triglyceride-rich. They contain apolipoprotein B-100, C-I, C-II, C-III, and E. Apo B-100 is the core structural protein and each VLDL particle contains one Apo B-100 molecule. Similar to chylomicrons the size of the VLDL particles can vary depending on the quantity of triglyceride carried in the particle. When triglyceride production in the liver is increased, the secreted VLDL particles are large. However, VLDL particles are smaller than chylomicrons.
- Intermediate density lipoproteins (IDL; VLDL remnants) – The removal of triglycerides from VLDL by muscle and adipose tissue results in the formation of IDL particles which are enriched in cholesterol. These particles contain apolipoprotein B-100 and E. These IDL particles are pro-atherogenic.
- Low-density lipoproteins (LDL) – These particles are derived from VLDL and IDL particles and they are even further enriched in cholesterol. LDL carries the majority of the cholesterol that is in the circulation. The predominant apolipoprotein is B-100 and each LDL particle contains one Apo B-100 molecule. LDL consists of a spectrum of particles varying in size and density. An abundance of small dense LDL particles are seen in association with hypertriglyceridemia, low HDL levels, obesity, type 2 diabetes (i.e. patients with metabolic syndrome), and infectious and inflammatory states. These small dense LDL particles are considered to be more pro-atherogenic than large LDL particles for a number of reasons. Small dense LDL particles have a decreased affinity for the LDL receptor resulting in a prolonged retention time in the circulation. Additionally, they more easily enter the arterial wall and bind more avidly to intra-arterial proteoglycans, which traps them in the arterial wall. Finally, small dense LDL particles are more susceptible to oxidation, which could result in an enhanced uptake by macrophages.
- High-density lipoproteins (HDL) – These particles play an important role in reverse cholesterol transport from peripheral tissues to the liver, which is one potential mechanism by which HDL may be anti-atherogenic. In addition, HDL particles have anti-oxidant, anti-inflammatory, anti-thrombotic, and anti-apoptotic properties, which may also contribute to their ability to inhibit atherosclerosis. HDL particles are enriched in cholesterol and phospholipids. Apolipoproteins A-I, A-II, A-IV, C-I, C-II, C-III, and E are associated with these particles. Apo A-I is the core structural protein and each HDL particle may contain multiple Apo A-I molecules. HDL particles are very heterogeneous and can be classified based on density, size, charge, or apolipoprotein composition.
|Lipoprotein||Density (g/ml)||Size (nm)||Major Lipids||Major Apoproteins|
|Chylomicrons||<0.930||75-1200||Triglycerides||Apo B-48, Apo C, Apo E, Apo A-I, A-II, A-IV|
|Chylomicron Remnants||0.930- 1.006||30-80||Triglycerides Cholesterol||Apo B-48, Apo E|
|VLDL||0.930- 1.006||30-80||Triglycerides||Apo B-100, Apo E, Apo C|
|IDL||1.006- 1.019||25-35||Triglycerides Cholesterol||Apo B-100, Apo E, Apo C|
|LDL||1.019- 1.063||18- 25||Cholesterol||Apo B-100|
|HDL||1.063- 1.210||5- 12||Cholesterol Phospholipids||Apo A-I, Apo A-II, Apo C, Apo E|
|Lp (a)||1.055- 1.085||~30||Cholesterol||Apo B-100, Apo (a)|
Basic Characteristics of Lipoproteins
|Types of Lipoprotein||Density (g/mL)||Primary Components||Diameter (µm)|
|Chylomicrons||<0.95||Dietary triacylglycerols (90%) and cholesterol||75–1200|
|Very-low-density lipoprotein||0.95–1.006||Endogenous triacylglycerols and cholesterol||30–80|
|Intermediate-density lipoproteins||1.006–1.019||Triacylglycerols and cholesterol||25|
|High-density lipoproteins||1.063–1.210||Phospholipid and protein||5–12|
Functions of Lipoprotein
Lipids are one of the four main biological molecules of the human body, along with carbohydrates, proteins, and nucleic acids.
- Lipids are essential components of life on a cellular level, as they are involved in multiple processes such as storing energy, serving as chemical messengers, and forming cell membranes, and transporting fat-soluble vitamins such as VitaminE.
- For lipids to carry out these roles in the cell, however, they must travel to their destination cells after being absorbed in the gastrointestinal tract. Without lipoproteins, this transport would not be possible, as the hydrophilic environment of the blood is not compatible with the hydrophobic nature of lipids like cholesterol.
- Therefore, lipoproteins play an integral role in the ability of the human body to utilize lipids, and the metabolism of these lipoproteins has a direct effect on the level of lipids in the serum and on the subsequent processes that involve lipids within the cell.
- The handling of lipoprotein particles in the body is referred to as lipoprotein particle metabolism. It is divided into two pathways, exogenous and endogenous, depending in large part on whether the lipoprotein particles in question are composed chiefly of dietary (exogenous) lipids or whether they originated in the liver (endogenous), through de novo synthesis of triacylglycerols.
- The hepatocytes are the main platform for the handling of triacylglycerols and cholesterol; the liver can also store certain amounts of glycogen and triacylglycerols. While adipocytes are the main storage cells for triacylglycerols, they do not produce any lipoproteins.
- Bile emulsifies fats contained in the chyme, then pancreatic lipase cleaves triacylglycerol molecules into two fatty acids and one 2-monoacylglycerol. Enterocytes readily absorb the small molecules from the chymus. Inside of the enterocytes, fatty acids and monoacylglycerides are transformed again into triacylglycerides. Then these lipids are assembled with apolipoprotein B-48 into nascent chylomicrons. These particles are then secreted into the lacteals in a process that depends heavily on apolipoprotein B-48. As they circulate through the lymphatic vessels, nascent chylomicrons bypass the liver circulation and are drained via the thoracic duct into the bloodstream.
- In the bloodstream, nascent chylomicron particles interact with HDL particles, resulting in HDL donation of apolipoprotein C-II and apolipoprotein E to the nascent chylomicron. The chylomicron at this stage is then considered mature. Via apolipoprotein C-II, mature chylomicrons activate lipoprotein lipase (LPL), an enzyme on endothelial cells lining the blood vessels. LPL catalyzes the hydrolysis of triacylglycerol that ultimately releases glycerol and fatty acids from the chylomicrons. Glycerol and fatty acids can then be absorbed in peripheral tissues, especially adipose and muscle, for energy and storage.
Apolipoproteins have four major functions including 1) serving a structural role, 2) acting as ligands for lipoprotein receptors, 3) guiding the formation of lipoproteins, and 4) serving as activators or inhibitors of enzymes involved in the metabolism of lipoproteins (Table 3). Apolipoproteins thus play a crucial role in lipoprotein metabolism.
- Apolipoprotein A-I – Apo A-I is synthesized in the liver and intestine and is the major structural protein of HDL accounting for approximately 70% of HDL protein. It also plays a role in the interaction of HDL with ATP-binding cassette protein A1 (ABCA1), ABCG1, and class B, type I scavenger receptor (SR-B1). Apo A-I is an activator of lecithin: cholesterol acyltransferase (LCAT), an enzyme that converts free cholesterol into cholesteryl ester.
- Apolipoprotein A-II – Apo A-II is synthesized in the liver and is the second most abundant protein on HDL accounting for approximately 20% of HDL protein.
- Apolipoprotein A-IV (2) – Apo A-IV is synthesized in the intestine during fat absorption. Apo A-IV is associated with chylomicrons and high-density lipoproteins but is also found in the lipoprotein-free fraction. Its precise role in lipoprotein metabolism remains to be determined but studies have suggested a role for Apo A-IV in regulating food intake.
- Apolipoprotein A-V (3) – Apo A-V is synthesized in the liver and associates with triglyceride-rich lipoproteins. It is an activator of LPL mediated lipolysis and thereby plays an important role in the metabolism of triglyceride-rich lipoproteins.
- Apolipoprotein B-48 – Apo B-48 is synthesized in the intestine and is the major structural protein of chylomicrons and chylomicron remnants. There is a single molecule of apo B-48 per chylomicron particle. There is a single apolipoprotein B gene that is expressed in both the liver and intestine. The intestine expresses a protein that is approximately ½ the size of the liver due to mRNA editing. The aerobic-1 editing complex is expressed in the intestine and edits a specific cytidine to a uracil in the apo B mRNA in the intestine creating a stop codon that results in the cessation of protein translation and a shorter Apo B (Apo B-48). Notably, Apo B-48 is not recognized by the LDL receptor.
- Apolipoprotein B-100 – Apo B-100 is synthesized in the liver and is the major structural component of VLDL, IDL, and LDL. There is a single molecule of Apo B-100 per VLDL, IDL, and LDL particle. Apo B-100 is a ligand for the LDL receptor and therefore plays an important role in the clearance of lipoprotein particles.
- Apolipoprotein C – The C apolipoproteins are synthesized primarily in the liver and freely exchange between lipoprotein particles and therefore are found in association with chylomicrons, VLDL, and HDL.
- Apo C-II – is a co-factor for lipoprotein lipase (LPL) and thus stimulates triglyceride hydrolysis (4). Loss of function mutations in Apo C-II results in marked hypertriglyceridemia due to a failure to metabolize triglyceride-rich lipoproteins.
- Apo C-III is an inhibitor of LPL (5) – Additionally, Apo C-III inhibits the interaction of triglyceride-rich lipoproteins with their receptors. Recent studies have shown that loss of function mutations in Apo C-III lead to decreases in serum triglyceride levels and a reduced risk of cardiovascular disease. Interestingly, inhibition of Apo C-III expression results in a decrease in serum triglyceride levels even in patients deficient in lipoprotein lipase indicating that the ability of Apo C-III to modulate serum triglyceride levels is not dependent solely on regulating lipoprotein lipase activity.
- Apolipoprotein E (6) – Apolipoprotein E is synthesized in many tissues but the liver and intestine are the primary sources of circulating Apo E. Apo E exchanges between lipoprotein particles and is associated with chylomicrons, chylomicron remnants, VLDL, IDL, and a subgroup of HDL particles. There are three common genetic variants of Apo E (Apo E2, E3, and E4). ApoE2 differs from the most common isoform, Apo E3, by a single amino acid substitution where cysteine substitutes for arginine at residue 158. Apo E4 differs from Apo E3 at residue 112, where arginine substitutes for cysteine. Apo E3 and E4 are ligands for the LDL receptor while Apo E2 is poorly recognized by the LDL receptor. Patients who are homozygous for Apo E2 can develop familial dysbetalipoproteinemia. Apo E4 is associated with an increased risk of Alzheimer’s disease and an increased risk of atherosclerosis.
- Apolipoprotein (a) (7) – Apo (a) is synthesized in the liver. This protein is a homolog of plasminogen and its molecular weight varies from 300,000 to 800,000. It is attached to Apo B-100 via a disulfide bond. High levels of Apo (a) are associated with an increased risk of atherosclerosis. Apo (a) is an inhibitor of fibrinolysis and can also enhance the uptake of lipoproteins by macrophages, both of which could increase the risk of atherosclerosis. The physiologic function of Apo (a) is unknown. Interestingly this apolipoprotein is found in primates but not in other species.
|Apolipoprotein||MW||Primary Source||Lipoprotein Association||Function|
|Apo A-I||28,000||Liver, Intestine||HDL, chylomicrons||Structural protein for HDL, Activates LCAT|
|Apo A-II||17,000||Liver||HDL, chylomicrons||Structural protein for HDL, Activates hepatic lipase|
|Apo A-IV||45,000||Intestine||HDL, chylomicrons||Unknown|
|Apo A-V||39,000||Liver||VLDL, chylomicrons, HDL||Promotes LPL mediated TG lipolysis|
|Apo B-48||241,000||Intestine||Chylomicrons||Structural protein for chylomicrons|
|Apo B-100||512,000||Liver||VLDL, IDL, LDL, Lp (a)||A structural protein, Ligand for LDL receptor|
|Apo C-I||6,600||Liver||Chylomicrons, VLDL, HDL||Activates LCAT|
|Apo C-II||8,800||Liver||Chylomicrons, VLDL, HDL||Co-factor for LPL|
|Apo C-II||8,800||Liver||Chylomicrons, VLDL, HDL||Inhibits LPL and uptake of lipoproteins|
|Apo E||34,000||Liver||Chylomicron remnants, IDL, HDL||Ligand for LDL receptor|
|Apo (a)||250,000- 800,00||Liver||Lp (a)||Inhibits plasminogen activation|
LIPOPROTEIN RECEPTORS AND LIPID TRANSPORTERS
There are several receptors and transporters that play a crucial role in lipoprotein metabolism.
- LDL receptor (8) – The LDL receptor is present in the liver and most other tissues. It recognizes Apo B-100 and Apo E and hence mediates the uptake of LDL, chylomicron remnants, and IDL, which occurs via endocytosis. After internalization, the lipoprotein particle is degraded in lysosomes and the cholesterol is released. The delivery of cholesterol to the cell decreases the activity of HMGCoA reductase, a key enzyme in the biosynthesis of cholesterol, and the expression of LDL receptors. LDL receptors in the liver play a major role in determining plasma LDL levels (a low number of receptors is associated with high plasma LDL levels while a high number of hepatic LDL receptors is associated with low plasma LDL levels). The number of LDL receptors is regulated by the cholesterol content of the cell. When cellular cholesterol levels are decreased the transcription factor SREBP is transported from the endoplasmic reticulum to the Golgi where proteases cleave and activate SREBP, which then migrates to the nucleus and stimulates the expression of LDL receptors (Figure 4). Conversely, when cellular cholesterol levels are high SREBP remains in the endoplasmic reticulum in an inactive form and the expression of LDL receptors is low.
- LDL receptor-related protein (LRP) (10) – LRP is a member of the LDL receptor family. It is expressed in multiple tissues including the liver. LRP recognizes Apo E and mediates the uptake of chylomicron remnants and IDL.
- Class B scavenger receptor B1 (SR-B1) (11) – SR-B1 is expressed in the liver, adrenal glands, ovaries, testes, macrophages, and other cells. In the liver and steroid producing cells, it mediates the selective uptake of cholesterol esters from HDL particles. In macrophages and other cells, it facilitates the efflux of cholesterol from the cell to HDL particles.
- ATP-binding cassette transporter A1 (ABCA1) (12) – ABCA1 is expressed in many cells including hepatocytes, enterocytes, and macrophages. It mediates the transport of cholesterol and phospholipids from the cell to lipid poor HDL particles (pre-beta-HDL).
- ATP-binding cassette transporter G1 (ABCG1) (13) – ABCG1 is expressed in many different cell types and mediates the efflux of cholesterol from the cell to HDL particles.
- ATP-binding cassette transporter G5 and G8 (ABCG5/ABCG8) (14) – ABCG5 and ABCG8 are expressed in the liver and intestine and form a heterodimer. In the intestine, these transporters mediate the movement of plant sterols and cholesterol from inside the enterocyte into the intestinal lumen thereby decreasing their absorption and limiting the uptake of dietary plant sterols. In the liver, these transporters play a role in the movement of cholesterol and plant sterols into the bile facilitating the excretion of plant sterols.
- Niemann-Pick C1-Like 1 (NPC1L1) (14) – NPC1L1 is expressed in the intestine and mediates the uptake of cholesterol and plant sterols from the intestinal lumen into the enterocyte.
ENZYMES AND TRANSFER PROTEINS INVOLVED IN LIPOPROTEIN METABOLISM
There are several enzymes and transfer proteins that play a key role in lipoprotein metabolism.
- Lipoprotein lipase (LPL) (15) – LPL is synthesized in muscle, heart, and adipose tissue, then secreted and attached to the endothelium of the adjacent blood capillaries. This enzyme hydrolyzes the triglycerides carried in chylomicrons and VLDL to fatty acids, which can be taken up by cells. The catabolism of triglycerides results in the conversion of chylomicrons into chylomicron remnants and VLDL into IDL. This enzyme requires Apo C-II as a cofactor. Apo A-V also plays a key role in the activation of this enzyme. In contrast, Apo C-III and Apo A-II inhibit the activity of LPL. Insulin stimulates LPL expression and LPL activity is reduced in patients with poorly controlled diabetes, which can impair the metabolism of triglyceride-rich lipoproteins leading to hypertriglyceridemia.
- Hepatic lipase (16) – Hepatic lipase is localized to the sinusoidal surface of liver cells. It mediates the hydrolysis of triglycerides and phospholipids in IDL and LDL leading to smaller particles (IDL is converted to LDL; LDL is converted from large LDL to small LDL). It also mediates the hydrolysis of triglycerides and phospholipids in HDL resulting in smaller HDL particles.
- Endothelial lipase (17) – This lipase plays a major role in hydrolyzing the phospholipids in HDL.
- Lecithin – cholesterol acyltransferase (LCAT) (18) LCAT is made in the liver. In the plasma, it catalyzes the synthesis of cholesterol esters in HDL by facilitating the transfer of fatty acid from position 2 of lecithin to cholesterol. This allows for the transfer of the cholesterol from the surface of the HDL particle (free cholesterol) to the core of the HDL particle (cholesterol ester), which facilitates the continued uptake of free cholesterol by HDL particles by reducing the concentration of cholesterol on the surface of HDL.
- Cholesteryl ester transfer protein (CETP) (19) – This protein is synthesized in the liver and in the plasma mediates the transfer of cholesterol esters from HDL to VLDL, chylomicrons, and LDL and the transfer of triglycerides from VLDL and chylomicrons to HDL. Inhibition of CETP activity leads to an increase in HDL cholesterol and a decrease in LDL cholesterol.