In general, the density of the lipoprotein increases as the proportion of apolipoprotein increases. Small amounts of cholesterol may be transported as part of chylomicrons, but cholesterol is usually carried within lipoproteins, including low density lipoprotein LDL , which carries cholesterol from the liver to muscle and other tissues, and high density lipoprotein HDL , which carries cholesterol to the liver for conversion to bile acids.
Physicians are especially concerned when patients have high levels of LDL the so-called bad cholesterol in blood; moderate exercise and low-cholesterol diets help to increase HDL the so-called good cholesterol.
Either high fat intake or problems with transport of cholesterol can lead to atherosclerosis, which in turn can contribute to heart attack myocardial infarction or stroke. Boyer, Rodney F. Concepts in Biochemistry, 2nd edition. Devlin, Thomas M. Textbook of Biochemistry: With Clinical Correlations, 5th edition. Shipped with Ice Packs Add to Cart.
Back to Top. LDL is a low-density lipoprotein that transports cholesterol and triglycerides from the liver to peripheral tissues. LDL like all lipoproteins facilitates the movement of fats and cholesterol within the water based solution of the blood stream. Because it contains less lipid and more protein in comparison to VLDL, its density is greater.
LDL is responsible for carrying cholesterol to cells that need it. Elevated LDL levels are associated with an increased risk of cardiovascular disease. HDL is made in the liver and in the intestines. It is responsible for carrying cholesterol from cells back to the liver.
There are also other lipoproteins that also function in transporting fats to cells, but are not commonly measured in a routine lipid panel. These include:. Chylomicrons are the least dense out of all of the lipoproteins.
These molecules are primarily made up of triglycerides and a small amount of protein. Chylomicrons are responsible for transporting lipids from the intestinal tract to cells in the body. As the triglycerides on VLDL are broken down by the cells that need it, the particle becomes denser due to the change in the lipid to protein ratio.
Looking to start a diet to better manage your cholesterol? Changing lifelong eating habits can be scary at first, but our guide will make it easier. Feingold KR. Introduction to lipids and lipoproteins. Endotext [Internet]. Centers for Disease Control and Prevention. Lipoprotein lipase , the key enzyme in the peripheral tissues that is responsible for the hydrolysis of triacylglycerols from the chylomicrons and VLDL, is bound to the vascular surface of the endothelial cells of the capillaries of adipose tissue, heart and skeletal muscle, and lactating mammary gland primarily.
The enzyme is synthesised in the endoplasmic reticulum where it is activated by lipase maturation factor 1 LMF1 , before the complex is stabilized with other chaperones so that it attains a proper tertiary fold for transport to the luminal surface of endothelial cells and into the interstitial space in the form of a monomer not as a homodimer as was once believed.
A small glycosylphosphatidylinositol-anchored protein designated GPIHBP1 facilitates the transfer of lipoprotein lipase across the cell, and in concert with heparin sulfate-proteoglycans HSPG on the capillary wall anchors the enzyme to the endothelial cell surface. There, GPIHBP1 binds the enzyme in an appropriate conformation in a complex mediated via the carboxyl-terminal domain to enable hydrolysis of the triacylglycerols of chylomicrons and LDL; it also stabilizes the structure and catalytic activity of the enzyme.
Apo C2 is an absolute requirement for activation of the enzyme, and there is evidence that this opens a lid-like region of the enzyme to enable the active site to hydrolyse the fatty acid ester bonds of the triacylglycerols; apo A5 is also stimulatory. However, monoacylglycerols can be taken up directly by cells and are not found in the remnant lipoproteins or bound to circulating albumin.
As the transport of VLDL particles progresses, the core of triacylglycerols is reduced and the proteins, including apo C2, and phospholipids on the surface are transferred away to the HDL.
However, sufficient apo C2 remains to ensure that most of the triacylglycerols are removed. As partially delipidated lipoproteins are detected in the circulation, it is believed that there is a process of dissociation and rebinding to the enzyme, during each step of which triacylglycerols are hydrolysed and apo C2 is gradually released with formation of remnant particles.
Lipoprotein lipase is also involved in the non-hydrolytic uptake of esters of cholesterol and retinol, possibly by facilitating transport. Some of the unesterified fatty acids resulting from the action of lipoprotein lipase on VLDL triacylglycerols are taken up immediately by the cells by both receptor-mediated CD36 and receptor-independent pathways, where they can be used for energy purposes or for the synthesis of other lipids.
The remainder is bound to circulating albumin from which it is released slowly to meet the cellular requirements of peripheral tissues. The glycerol produced is transported back to the liver and kidneys, where it can be converted to the glycolytic intermediate dihydroxyacetone phosphate.
In muscle tissue, much of the fatty acids taken up are oxidized to two-carbon units, but in adipose tissue triacylglycerols are formed for storage purposes while in lactating mammary gland they are used for milk fat synthesis.
During fasting, hormone-sensitive lipase releases fatty acids from the triacylglycerols stores and they are transported back into the circulation. Apo C1 and apo C3 inhibit lipoprotein lipase by competing for binding to lipoproteins rather than by deactivating the enzyme. Apo C3 inhibits the hepatic uptake of VLDL remnants also and so has a controlling influence on the turnover of triacylglycerols; high levels have been correlated with elevated levels of blood lipids hypertriglyceridemia.
In addition, angiopoietin-like proteins are key regulators of plasma lipid metabolism by serving as potent inhibitors of lipoprotein lipase. Improper regulation of the enzyme has been associated with the pathologies of atherosclerosis, coronary heart disease, cerebrovascular accidents, Alzheimer disease and chronic lymphocytic leukemia.
Cholesterol has a vital role in life and is essential for the normal functioning of cells both as a cell membrane constituent and as a precursor of steroid hormones and other key metabolites. In the lumen of the small intestine, free cholesterol from the diet and from biliary secretion is solubilized in mixed micelles containing bile acids and phospholipids before it is absorbed by the enterocytes by a mechanism for which the apical protein Niemann-Pick C1-like 1 NPC1L1 is crucial.
Within the enterocyte, the metabolic fate of the absorbed cholesterol involves an integrated network of many different proteins. Most of it is transported to the endoplasmic reticulum where it is converted to cholesterol esters by the enzyme acyl-CoA:cholesterol acyltransferase 2 ACAT2 and is selectively packaged into chylomicron particles, a process that requires a specific microsomal transfer protein and apoprotein B48, for transport out of the enterocyte into the lymphatic system and subsequently to the liver for uptake at the basolateral side of the hepatocytes as described above for triacylglycerols.
LDL are the main carriers of cholesterol from the liver to the adrenals and adipose tissue, where there are receptors requiring apo B, and they are able to take in the LDL by a similar process to that occurring in liver. Within these tissues, the cholesterol esters are hydrolysed to yield free cholesterol, which is incorporated into the plasma membranes as required. Any excess cholesterol is re-esterified by an acyl-CoA:cholesterol acyltransferase for intracellular storage.
Other peripheral tissues have much lower requirements for cholesterol, but that delivered by the LDL may be helpful in suppressing synthesis of cholesterol de novo within cells.
It may also inhibit the expression of lipoprotein receptors. The cholesterol at the particle surface is essential to enable VLDL to carry triacylglycerols efficiently in the aqueous environment of plasma. However, once this has been accomplished, the cholesterol-rich, triacylglycerol-depleted remnant LDL by-products are potentially toxic and must be removed from the circulation.
Some have argued that a significant part of the complexity of lipoprotein metabolism is concerned with the disposal of this LDL cholesterol before it can cause damage to the cardiovascular system. The liver is able to scavenge chylomicron remnants much more rapidly than LDL particles, and it seems likely that this specificity has evolved because the former are especially atherogenic. 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.
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