It may enter the brain via the choroid plexus with the potential to influence brain lipid homeostasis. Apo A2 is the second most abundant HDL apoprotein, and it exists as a homodimer with two polypeptide chains, each 77 amino acids in length and linked by a disulfide bond. Apo A4 is the largest member of the exchangeable apoprotein family and is a amino acid glycoprotein, which is synthesised in intestinal enterocytes and secreted as a constituent of chylomicrons.
It transfers to HDL in plasma, but a high proportion is lipid free. Apo A5 is expressed in liver mainly, where it can associate with hepatic lipid droplets. Although its concentration in plasma is relatively low, it is recognized as a potent regulator of plasma triacylglycerol levels through enhanced lipolysis and the clearance of lipoprotein remnants.
Apo C apoproteins are found in all lipoprotein classes. Apo C1 is the smallest exchangeable protein in this group and is synthesised in the liver, where like apo C3, the most abundant of the group, it tends to inhibit lipase activity.
In contrast, apo C2 is especially important as an activator of lipoprotein lipase see below. Apo D is atypical in that it is very different in structure from other apoproteins, and it is expressed widely in mammalian tissues most others are produced mainly in liver and intestine.
In plasma, it is present mainly in HDL and to a lesser extent in LDL, where it may function as a multi-ligand binding protein capable of transporting small hydrophobic molecules such as arachidonic acid, steroid hormones, and cholesterol for metabolism or signalling. Apo E is an O -linked glycoprotein in three isoforms and is synthesised by many tissues, including liver, brain, adipose tissue, and arterial wall, but most is present in plasma lipoproteins derived primarily from the liver.
It is involved in many aspects of lipid and lipoprotein homeostasis, both for the triacylglycerol-rich lipoproteins and HDL, and it is believed to have some non-lipid related functions, for example on immune response and inflammation. That produced in adipose tissue may have a metabolic role in obesity. In addition, as most lipoproteins cannot cross the blood-brain barrier, apo E is synthesised in the brain where it is the main apoprotein and is of particular importance for cholesterol metabolism.
The physical properties of apoproteins enable them to bind readily at the interface between water and phospholipids, and specifically they bind to the phospholipids on the surface of the lipoproteins. In effect, this outer shell of amphipathic lipids and proteins solubilizes the hydrophobic lipid core in the aqueous environment.
Each apoprotein, other than apo B, tends to have a helical shape with a hydrophobic domain on one side that binds to the lipid core and a hydrophilic face that orientates to the aqueous phase.
As the lipid compositions of the lipoproteins change during circulation throughout the body, the apoproteins are able to adapt to the altering affinities at the surface by changing conformation. For example, some have very little tertiary structure so are flexible, while apo A1 has a mobile or hinge domain. The polar nature of the surface monolayer prevents the lipoprotein particles from aggregating to form larger units. In addition, apoproteins have many different functions, some of which are listed in Table 3 and are discussed further below.
For example, some are ligands for receptors on cell surfaces and specify the tissues to which the lipid components are delivered, while others are cofactors for lipases or regulate lipid metabolism in the plasma in various ways.
LDL particles, for example, average 22 nm in diameter with roughly lipid molecules in total, and they contain a hydrophobic core of approximately triacylglycerol, cholesterol ester and unesterified cholesterol molecules.
The amphipathic surface monolayer has a single copy of apo B together with about phospholipid and free cholesterol molecules. Phosphatidylcholine, about molecules, and sphingomyelin, about molecules, are the main phospholipids, together with smaller numbers of lysophosphatidylcholine, phosphatidylethanolamine and other lipid molecules. The structure and physical functions of LDLs depend mainly on the core—lipid composition and the conformation of the apoB, which is able to interact with extracellular membranes such as blood vessel intima where the LDL lipids are susceptible to modification, e.
In contrast, HDL are highly heterogeneous in terms of their size, lipid and protein contents, and their functional properties, and they can be separated by various means, including ultracentrifugation and gel filtration, into subclasses, that reflect the differences in composition. These have been designated in various ways, e. Discoidal nascent HDL particles are believed to consist of a small unilamellar bilayer, containing approximately molecules of phospholipid, which is surrounded by four apoprotein molecules, including at least two apo A1 monomers.
Although most HDL particles in human plasma are spherical, the structures are poorly characterized in comparison to discoidal HDL. It is believed that the apo A1 molecule changes conformation from the discoidal state and adopts a helical structure with the C-terminal domain binding to the phospholipids.
They include lipases, acyltransferases, transport proteins, some with anti-oxidative or anti-inflammatory properties, and some concerned with metabolic processes that do not involve lipids. Lipoproteins are often categorized simplistically according to their main metabolic functions. While these functions are considered separately for ease of discussion in the account that follows, it should be recognized that the processes are highly complex and inter-related, and they involve transfer of apoproteins, enzymes and lipid constituents among the heterogeneous mix of all the lipoprotein fractions.
As birds, amphibians, fishes and even round worms have lipoprotein systems comparable to those in mammals, it is evident that these must have developed early in evolution. The equivalent protein in these species is vitellogin, which is closely related to mammalian apo B. Lipoprotein a Lp a is structurally and metabolically distinct from the other lipoproteins, and it consists of an LDL-like particle containing a specific highly polymorphic glycoprotein named apolipoprotein a apo a , which is covalently bound via a disulfide bond to the apo B of the LDL-like particle.
While its physiological function is uncertain, Lp a is of particular interest because clinical evidence strongly supports a causal relationship between high plasma concentrations and the increased risk of cardiovascular diseases, including myocardial infarctions and stroke see below.
Apo a should not be confused with apo A. Triacylglycerols are the most energy-dense molecules available to the body as a source of fuel but are highly hydrophobic. For efficient transport from the intestine and the liver to other organs of the body, it is essential that they be packaged in a form compatible with the aqueous environment in plasma, i. Chylomicrons and VLDL are mainly involved, although some proteins that are shared with HDL are essential for the process to function normally.
For example, exchangeable apoproteins protect triacylglycerol-rich particles from non-specific interactions in plasma and ensure that they have the correct configuration to be acted upon by lipases. Chylomicron formation: Dietary fatty acids and monoacylglycerols are absorbed by the enterocytes in the intestines, where they must cross the cytoplasm to the endoplasmic reticulum with the aid of fatty acid binding proteins. These are immediately utilized to form new triacylglycerols, and are thus detoxified see our web page on triacylglycerol biosynthesis , mainly by the monoacylglycerol pathway.
The triacylglycerols are incorporated together with dietary cholesterol, much of which is in cholesterol ester form, into spherical chylomicron particles.
These have a surface layer of phospholipids to which is attached a single molecule of the truncated form of apo B, apo B48, which is diagnostic for triacylglycerol-rich lipoproteins of intestinal origin. The synthesis of apo B and its truncated form, and the accumulation of lipids to form chylomicrons or VLDL in intestinal cells and liver, respectively, are complex processes that are still only partly understood.
Simplistically, secretory proteins such as apo B are synthesised on ribosomes on the surface of the endoplasmic reticulum and translocated through the membrane to the lumen of the endoplasmic reticulum.
VLDL are then assembled by accretion of lipids, for example with the aid of a microsomal triacylglycerol transfer protein MTTP , an essential protein that transfers phospholipids and triacylglycerols to nascent apo B for the assembly of lipoproteins. This occurs in three stages - pre-VLDL pre-chylomicrons - nascent lipoproteins , VLDL2, a triacylglycerol-poor form of VLDL that is assembled in the Golgi and is transported to the basolateral membrane, where the final triacylglycerol-rich VLDL1 or chylomicrons with the assistance of apo B48 and apo A4, are secreted by a process of reverse exocytosis into the intestinal lamina propria.
Apo A1 is generated separately in the endoplasmic reticulum of enterocytes, and it is transported to the Golgi and added to the chylomicrons just before the mature particle is secreted into the lymph. The chylomicrons are transported via the intestinal lymphatic system and enter the blood stream at the left subclavian vein. During circulation throughout the body, triacylglycerols are removed by the peripheral tissues by endothelial-bound lipoprotein lipase with entry of fatty acids into muscle for energy production and adipocytes for storage.
However, the apo B48 remains with the residual particle. The chylomicrons also contain some apo A1, which is synthesised in the intestines and liver, but this is transferred spontaneously to the HDL as soon as the chylomicrons reach the circulation, while transfer of apo E and apo C in the reverse direction from the HDL to the surface of the chylomicrons, displacing apo A4, occurs at the same time. The main LDL receptor in liver is a polypeptide of amino acids to which complex carbohydrate moieties are linked that spans the plasma membrane and has an extracellular domain, which is responsible for binding to apo B and apo E.
After binding of the LDL and some of the VLDL remnants to the receptor, the LDL-receptor complexes are internalized by endocytosis of the coated pit and then dissociated by means of an ATP-dependent proton pump, which lowers the pH in the endosomes, enabling the receptors to be recycled to the plasma membrane. The LDL-containing endosomes fuse with lysosomes, and lipolytic enzymes, especially a lysosomal acid lipase LAL , release free fatty acids and cholesterol from triacylglycerols and cholesterol esters, while acid hydrolases degrade the apoproteins.
However, much of the apo E is believed to escape this process and is returned to the circulation and the HDL. An additional receptor, the LDL-receptor-related-protein, assists in the removal of chylomicron remnants. After their release from lysosomes, the fatty acids and other lipid components serve as precursors for the synthesis of new lipid species and may also function in the regulation of many metabolic processes.
Secretion from the liver: The triacylglycerols of the remnant chylomicrons, together with cholesterol and cholesterol esters, are secreted by the liver into the circulation in the form of VLDL, which contain one molecule of the full-length form of apo B, apo B In addition, an appreciable amount of triacylglycerol in VLDL is synthesised in the liver from free fatty acids reaching it from adipose tissue via the plasma in the post-absorptive and fasted states, and stored in triacylglycerol form in lipid droplets for mobilization upon demand.
In effect, liver lipid droplets and VLDL serve to buffer the plasma free fatty acids released following lipolysis in adipose tissue in excess of the requirements of muscle and liver. Within the liver, the nascent VLDLs are assembled from apo B and lipids, which consist largely of triacylglycerol droplets with some phospholipid, in the endoplasmic reticulum with the aid of chaperone, namely, microsomal triglyceride transfer protein MTTP , before they are transported to the Golgi in a complex multistep process, involving a specific VLDL transport vesicle.
In the lumen of the cis -Golgi, VLDLs undergo a number of essential modifications before they are transported to the plasma membrane and secreted into the circulatory system. The surface layer of the newly synthesised VLDL is enriched in phosphatidylethanolamine, which rapidly exchanges with the phosphatidylcholine of other lipoproteins.
The newly synthesised VLDL contain a little apo C3, apo E and apo A5, which may have a role in the assembly process, but they rapidly take up apo C2 molecules and apo E from HDL after a few minutes in the circulation while the small amount of apo A1 of intestinal origin is transferred to HDL. 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.
This process is called atherosclerosis. Skip directly to site content Skip directly to page options Skip directly to A-Z link. Section Navigation. Facebook Twitter LinkedIn Syndicate. Minus Related Pages. Get Email Updates.
A blood test can measure your cholesterol levels, including HDL. When and how often you should get this test depends on your age, risk factors, and family history. The general recommendations are:. With HDL cholesterol, higher numbers are better, because a high HDL level can lower your risk for coronary artery disease and stroke.
How high your HDL should be depends on your age and sex:. If your HDL level is too low, lifestyle changes may help. These changes may also help prevent other diseases, and make you feel better overall:.
Some cholesterol medicines , including certain statins , can raise your HDL level, in addition to lowering your LDL level. Health care providers don't usually prescribe medicines only to raise HDL.
If you are taking one of these and you have a very low HDL level, ask your provider if you should continue to take them. Diabetes can also lower your HDL level, so that gives you another reason to manage your diabetes. The information on this site should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health. What is cholesterol? It is sometimes called the "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.
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