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Resources Find an Expert. What is cholesterol? Different types of lipoproteins have different purposes: HDL stands for high-density lipoprotein. It is sometimes called "good" cholesterol because it carries cholesterol from other parts of your body back to your liver.
Your liver then removes the cholesterol from your body. LDL stands for low-density lipoprotein. It is sometimes called "bad" cholesterol because a high LDL level leads to the buildup of plaque in your arteries. VLDL stands for very low-density lipoprotein. Some people also call VLDL a "bad" cholesterol because it too contributes to the buildup of plaque in your arteries. What causes high cholesterol?
The most common cause of high cholesterol is an unhealthy lifestyle. This can include Unhealthy eating habits, such as eating lots of bad fats. One type, saturated fat, is found in some meats, dairy products, chocolate, baked goods, and deep-fried and processed foods.
Another type, trans fat, is in some fried and processed foods. Eating these fats can raise your LDL bad cholesterol. Lack of physical activity, with lots of sitting and little exercise. This lowers your HDL good cholesterol. Smoking, which lowers HDL cholesterol, especially in women. It also raises your LDL cholesterol. What can raise my risk of high cholesterol? A variety of things can raise your risk for high cholesterol: Age.
Your cholesterol levels tend to rise as you get older. Even though it is less common, younger people, including children and teens , can also have high cholesterol. High blood cholesterol can run in families. Being overweight or having obesity raises your cholesterol level. Certain races may have an increased risk of high cholesterol. Therefore, further mechanisms such as that involving the HDL discussed next are required to return the excess LDL cholesterol to liver.
In macrophages, scavenger receptors mediate the uptake of LDL that has been damaged by oxidation or other means such that its affinity to the LDL receptor is reduced. This has the unfortunate effect that cholesterol can accumulate in macrophages in an unregulated manner, a possible first step in the development of atherosclerosis. Mature HDL undergo constant dynamic remodelling over their 4 to 5 day life cycle. In addition, HDL have an important function in triacylglycerol transport by facilitating the activation of lipoprotein lipase, in the transfer of triacylglycerols between lipoprotein classes, and in the removal of chylomicron remnants and VLDL enriched in triacylglycerols.
The latter mediates a net transfer of phospholipids from apoB-containing triacylglycerol-rich lipoproteins into HDL, and also exchanges phospholipids between lipoproteins; it is believed to be a factor in the enlargement of HDL.
As many of the lipid and protein constituents of HDL are exchangeable with other lipoproteins, many different types subclasses of HDL particle are generated with differing metabolic roles. The nascent HDL are synthesised in the extracellular space of the liver and small intestine as protein-rich disc-shaped particles, but their compositions change and evolve as the HDL circulate in the plasma.
Apo A1 synthesised in the liver together with that released spontaneously from chylomicrons is a key molecule that binds to phospholipids with a little cholesterol of cellular origin. It has been described as the scaffold for HDL assembly and is secreted as pro-apo A1, which is rapidly cleaved by a circulating metalloproteinase to generate the mature polypeptide. The further development of mature HDL is dependent on the enzyme lecithin:cholesterol acyltransferase LCAT , which requires apo A1 for activation and is present mainly in the plasma compartment of the circulation lecithin is an early trivial name for phosphatidylcholine.
Our web page on cholesterol esters contains a description of the mechanism of action of this enzyme, but in brief it transfers a fatty acid from position sn -2 of phosphatidylcholine to the hydroxyl group of cholesterol, resulting in the formation of cholesterol esters and lysophosphatidylcholine. The cholesterol esters are highly hydrophobic and accumulate in the core of the HDL, while the lysophosphatidylcholine is removed from the HDL and eventually from the plasma by binding to albumin.
Early in the formation of HDL, apo A2 is secreted from the liver and added to the surface, and those HDL particles enriched with apo A2 are able to stimulate the activities of various enzymes, including platelet-activating factor acetylhydrolase and lipoprotein-associated phospholipase A 2 , as well as exerting antioxidant effects.
Cholesterol but not cholesterol esters or phospholipids is also obtained by extraction from cell surface membranes to the spherical HDL using the ABCA-1 and ABCG-1 transporters; the latter protein is related to but distinct from the former, which is utilized by the nascent HDL both are members of the same protein family.
Two processes are involved, one involving simple diffusion and the other facilitated diffusion the SR-BI-mediated pathway , with the result that the levels of intracellular cholesterol are reduced as cholesterol stored in cells in the form of cholesterol esters is mobilized to replace that removed from the plasma membrane. The removal of excess cholesterol from macrophage-derived foam cells in atherosclerotic plaques has been considered to be of particular importance, but the magnitude of this effect is now believed to be small.
The liver is the major organ responsible for HDL clearance, and the entire HDL particle can enter the hepatocytes through an apo A1-receptor interaction, where it undergoes a facilitated transfer of cholesterol and cholesterol esters to distinct pools within the cell. The modified HDL are secreted back into the circulation where they can acquire further cholesterol before returning to the liver. In a second less-efficient pathway, the added apo E in the HDL aids their uptake and catabolism by a process of endocytosis via a specific receptor similar to that described above for LDL, which results in the degradation of all the HDL constituents.
Some of this cholesterol is converted to bile acids and exported into the intestines to aid digestion. As a proportion of these are eventually excreted, it is a means of reducing total amount of cholesterol in the body. The apo A1 recycles extracellularly between lipid-poor pre-beta and lipid-rich spheroidal lipoproteins, though de-lipidated apo A1-particles are cleared by the kidneys preferentially.
In many animal species, there is an alternative process in which cholesterol is obtained from plasma HDL by a mechanism whereby the lipoproteins bind to the surface of cells and part specifically with their cholesteryl esters by a process known as the selective cholesterol uptake pathway , without the uptake and lysosomal degradation of the particle itself.
This is a high capacity and highly regulated bulk delivery system for cholesterol that operates primarily but not exclusively in steroidogenic tissues to selectively internalize cholesterol esters and thence their cholesterol to produce steroid hormones, for example in adrenal, ovarian and testicular tissues.
In this pathway, scavenger receptor B type 1 SR-B1 is the cell surface receptor responsible for selective uptake of HDL cholesterol esters. Unesterified cholesterol may be taken up from HDL by a related process in the liver for bile acid production. This means that excess cellular cholesterol can be returned to the liver by the LDL-receptor pathway as well as by the HDL-receptor pathway.
Once in the HDL, triacylglycerols are rapidly broken down by various lipolytic enzymes, though the physiological significance of this in health terms at least is a matter of debate. There is also a phospholipid transfer protein that mediates a net transfer of phospholipids from apoB-containing, triacylglycerol-rich lipoproteins into HDL, and also exchanges phospholipids between lipoproteins; it appears to be essential for maintaining normal HDL levels in plasma.
There are reports from experiments with animals and humans that some cholesterol is secreted directly into the intestines by a process known as trans-intestinal cholesterol efflux. However, much of this may be re-absorbed under normal physiological conditions. Phosphatidylcholine in HDL is also taken up by the liver, and in mice it has been demonstrated that half of the hepatic phosphatidylcholine is derived from the circulation, and perhaps surprisingly a high proportion of this is converted to triacylglycerols.
Following assembly, HDL particles undergo continual remodelling both of the lipids and proteins, through interactions with enzymes such as lipases, acyltransferases, lipid transfer proteins and scavenger receptors for proteins. Rearrangements probably occur within HDL particles through protein-protein, lipid-protein, and lipid-lipid interactions.
In addition to the main lipid and protein components, HDL transports small RNAs, hormones, carotenoids, vitamins and bioactive lipids. As it has the ability to interact with most cells and to deliver lipid-soluble cargo, HDL has the capacity to affect innumerable biological processes other than those concerned with cholesterol metabolism. While the importance of HDL in the metabolism of cholesterol is undeniable, it may now be too simplistic an approach to consider only total HDL cholesterol as of clinical relevance, and there are suggestions that in consequence too little weight has been given to other functions of HDL.
For example, some of these are reported to have anti-oxidative, anti-inflammatory, anti-apoptotic, anti-thrombotic, anti-infective, and vasoprotective effects. Rather, individual subclasses of HDL with distinct lipid and protein complements may need to be considered separately. For example, lipoproteins from the protein-rich HDL 3 sub-fraction have a protective role against cardiovascular disease by acting as anti-inflammatory regulators to limit the activity of pro-inflammatory cytokines.
Other HDL subclasses carry an enzyme that hydrolyses platelet activating factor PAF-acetyl hydrolase , which is a potent phospholipid mediator with pro-inflammatory properties. HDL prevents the oxidation of LDL and limits the concentrations of oxidized components, which might otherwise render them atherogenic. Thus, human serum paraoxonase is a calcium-dependent enzyme associated with HDL, which catalyses the hydrolysis of oxidized fatty acids from phospholipids and prevents the accumulation of oxidized lipids in lipoproteins, especially LDL.
On the other hand, apo A1 can itself be oxidized and then become pro-inflammatory with a reduced capacity for reverse cholesterol transport. While only a few persons carry inherited defects in lipoprotein metabolism, such as hyper- or hypolipoproteinemias, abnormal lipoprotein metabolism is often observed as a secondary effect of diabetes, hypothyroidism and kidney disease.
In Tangier disease, patients have mutations in both copies of the genes that code for the ABCA1 transporter protein see previous section , so they have very little circulating HDL. Similarly, defects in any of the enzymes involved in triacylglycerol transport and metabolism can lead to hypertriglyceridaemia with a severe impact upon health.
Oxidative stress can damage lipids carried by lipoproteins and indeed the protein components in plasma or when retained in the artery wall, leading to conversion of LDL into oxidized LDL oxLDL especially, increased levels of which are strongly correlated to various diseases, including atherosclerosis, cancer and non-alcoholic steatohepatitis.
Both HDL and LDL can carry phospholipids and other lipids in which the polyunsaturated fatty acid components are oxidized in various ways, and some of these oxidation products carry reactive electronegative aldehyde moieties that can form adducts with the amino acid residues of apolipoproteins see our web page on oxidized phospholipids , for example.
Under conditions of oxidative stress the peptide chains of apoproteins can also be subjected to oxidative modifications with consequences for plaque formation.
All of these reactions occur mainly within the subendothelial space of the arterial wall, although other deleterious reactions, such as glycation or homocysteinylation, occur in plasma. Circulating oxLDL may signal to cells at more distant sites and possibly trigger a systemic antioxidant defence, and they are recognized as biomarkers of atherosclerosis and metabolic disorders such as diabetes and obesity.
Under normal physiological conditions, there is a response by phagocytes of the reticulo-endothelial system to remove oxLDL from circulation, assisted by Kupffer cells of the liver, sinusoidal endothelial cells, and macrophages. However, under conditions of high oxidative stress, these cells can be overwhelmed by oxLDL such that the excessive accumulation of lipids transforms them into foam cells, characteristic of the progression of atherosclerosis.
The result is to reduce the affinity of oxLDL for LDL receptors, while increasing their recognition by scavenger receptors. For example, the lectin-like oxidized LDL receptor-1 LOX-1 is a scavenger receptor that promotes endothelial dysfunction by inducing pro-atherogenic signalling and plaque formation through the endothelial uptake of oxLDL.
This contributes to the initiation, progression, and destabilization of atheromatous plaques, and leads eventually to the development of myocardial infarction and certain forms of stroke.
In addition, LOX-1 is expressed in macrophages, cardiomyocytes, neutrophils and many other cell types, further implicating this receptor in numerous aspects of atherosclerotic plaque formation. HDL are not immune to oxidative modification, such as cross-linking of HDL apoproteins apo-A1 by oxidized phospholipids, especially those that are oxidatively truncated and contain alkenyl aldehyde moieties.
This can contribute to the loss of the atheroprotective function of HDL in vivo , and indeed in some pathological conditions oxidized HDL can be proinflammatory. In addition, HDL is the major carrier of F 2 -isoprostanes in plasma. The role of lipoproteins in the metabolism of triacylglycerol and cholesterol in relation to cardiovascular disease is highly complex and contentious. The problem is manifested first when LDL and other apo B-containing particles become oxidized, aggregated, or enzymatically-modified within the arterial wall and are no longer recognized by the LDL receptor.
Instead, they are taken up by scavenger receptors expressed on macrophages and smooth muscle cells in the vascular wall, a process that is not regulated by a feedback mechanism. Cholesterol esters are hydrolysed by the lysosomal acid lipase and a massive accumulation of cholesterol can occur in these cells. The result is an increased transformation of macrophages into foam cells, which are the basis of atherosclerotic plaques, and an increased risk of coronary artery disease.
Apo E is involved in cholesterol efflux from cholesterol-loaded macrophage foam cells and other atherosclerosis-relevant cells, and in reverse cholesterol transport, so it may have a role in the attenuation of atherosclerosis.
While further discussion is best left to clinical specialists, suffice it to say that there are a number of epidemiological studies that have demonstrated that low concentrations of HDL cholesterol are associated with a higher risk of atherosclerosis; conversely, high concentrations of HDL cholesterol are associated with a lower risk. It is believed that HDL may protect against atherosclerosis via the promotion of reverse cholesterol transport.
Unfortunately, drug treatments that have focused on raising HDL-cholesterol levels have failed to reduce morbidity and mortality in coronary heart disease, and it seems probable that concentration on this factor alone may not be an effective strategy for the prevention and treatment of this condition. Indeed, some consider that the triacylglycerol concentration of HDL may be a better practical marker for metabolic and cardiovascular risk. The apoproteins and associated enzymes of HDL are believed to be important for the maintenance of health in many further ways, including antioxidant, anti-inflammatory and anti-thrombotic effects.
It has also been argued that the levels of apo B and of apo C3 in plasma may be good predictors of the risk of coronary heart disease. For example, apo B may mediate the interaction between LDL and the arterial wall, and this may initiate the development of atherosclerosis. Indeed, virtually all of the apo B-containing lipoproteins can pass through the endothelial layer of arteries and initiate atherogenesis, but the smaller LDL are especially atherogenic because they enter the plaques with relative ease and have a high content of cholesterol.
Thus, they provide substrates that trigger plaque initiation and growth. Apo A4 has anti-oxidative and anti-inflammatory properties, and by its role in reverse-cholesterol transport, it may be protective against cardiovascular disease. It also affects other metabolic functions related to food intake, obesity and diabetes by acting as an acute satiation factor and by modulating glucose homeostasis. Lipoproteins are not able to cross the blood-brain barrier, but various brain cells are able to express lipoprotein receptors, lipid transporters and apoproteins, which are required for cholesterol turnover and HDL biogenesis.
Apo E is especially important for cholesterol metabolism in the brain, but excess of one specific form apo E4 is associated with late onset Alzheimer's disease where it is believe to influence the accumulation of the extracellular amyloid plaques composed of amyloid beta peptides that are the hallmark of the disease. While apo E does not appear to affect overall levels of cholesterol and phospholipids in the central nervous system, it may modulate cholesterol and phospholipid homeostasis in particular subcellular membrane compartments.
In addition, apo E mediates sulfatide trafficking and metabolism in the brain, and it is seen as a target for therapeutic intervention in diseases of the central nervous system. Apo E is also believed to influence susceptibility to parasitic, bacterial and viral infections, and in HIV-positive patients apo E4 may hasten the progression to AIDS. Lipoproteins and HDL especially play an important role in host defense as part of the innate immune system. Infection and inflammation induce the acute-phase response, which leads to many changes in lipid and lipoprotein metabolism and initially protects the host from the harmful effects of bacteria, viruses, and parasites, provided that the infections are not prolonged.
For example, an important defensive function is the ability of HDL and other lipoproteins to bind the endotoxin lipopolysaccharides , which are primary constituents of the outer surface membrane of Gram-negative bacteria, and so neutralize their toxic effects. High concentrations of lipoprotein a Lp a in plasma have long been recognized to be a risk factor for cardiovascular disorders such as coronary heart disease and the development of aortic stenosis. One possible explanation for the atherogenicity of Lp a is that it is especially susceptible to oxidation and carries proinflammatory oxidized phospholipids, which are bound covalently to the apo a component.
While the homology between apolipoprotein a and plasminogen suggests another link between the processes of atherosclerosis and thrombosis, it appears that it has yet to be demonstrated that this similarity has pathophysiological relevance in humans. It is evident that much of the metabolic fate of Lp a remains uncertain, and studies are hampered by the lack of a model experimental animal; it is almost certainly synthesised at the surface of the liver, or in an extra-hepatic space separated from the plasma, but how it is cleared from the circulation does not appear to be known.
Insects have a distinctive but relatively simple lipoprotein metabolism that serves as a useful model system for comparative studies e. The hemolymph, the circulatory fluid in insects, contains a single multifunctional lipoprotein termed lipophorin that transports lipids to wherever they are required for energy and other purposes. Rather than triacylglycerols, the main lipid components are 1,2-diacyl- sn -glycerols , together with hydrocarbons, phospholipids and sterols.
Phosphatidylethanolamine rather than phosphatidylcholine is the main phospholipid constituent. High-density lipophorin HDLp is the main lipoprotein class and it is composed of two integral and non-exchangeable apoproteins, apolipophorin I kDa and apolipophorin II 80 kDa , which are apolipoprotein B homologues and produced from a common precursor by proteolytic cleavage.
In contrast, the exchangeable apolipophorin-III is a lipid-free hemolymph protein that associates with lipophorin during hormone-induced lipid mobilization and has functions beyond lipid transport. Lipophorin transports dietary lipids from the insect gut to the fat body, the main metabolic organ that simplistically can be considered to combine the roles of the mammalian liver and adipose tissue, and thence to the peripheral tissues. Rather than being immediately internalized and the constituents recycled as with the mammalian lipoproteins, lipophorin functions as a reusable lipid shuttle that delivers lipids to storage or peripheral tissues before returning for another cycle of loading and unloading.
When there is a demand for energy, for example during hibernation or especially for flight muscle activity, triacylglycerols in the fat bodies are mobilized by conversion to 1,2-diacyl- sn -glycerols rather than to free acids as in vertebrates , which are loaded onto the HDLp particles, decreasing their density and producing low-density lipophorin LDLp.
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