high-density lipoprotein high-density lipoprotein high-density lipoprotein (hdl) is one of the five major groups of lipoproteins. lipoproteins are complex particles composed of multiple proteins which transport all fat molecules (lipids) around the body within the water outside cells. they are typically composed of 80–100 proteins per particle (organized by one, two or three apoa. hdl particles enlarge while circulating in the blood, aggregating more fat molecules) and transporting up to hundreds of fat molecules per particle. overview lipoproteins are divided into five subgroups, by density/size (an inverse relationship), which also correlates with function and incidence of cardiovascular events. unlike the larger lipoprotein particles, which deliver fat molecules to cells, hdl particles remove fat molecules from cells. the lipids carried include cholesterol, phospholipids, and triglycerides, amounts of each are variable. increasing concentrations of hdl particles are associated with decreasing accumulation of atherosclerosis within the walls of arteries, reducing the risk of sudden plaque ruptures, cardiovascular disease, stroke and other vascular diseases. hdl particles are commonly referred to as "good cholesterol", because they transport fat molecules out of artery walls, reduce macrophage accumulation, and thus help prevent or even regress atherosclerosis. however, recent investigations have shown that very high concentrations of hdl particles can be associated with an increased mortality risk and an increased cardiovascular risk, especially in hypertensive patients. testing because of the high cost of directly measuring hdl and ldl (low-density lipoprotein) protein particles, blood tests are commonly performed for the surrogate value, hdl-c, i.e. the cholesterol associated with apoa-1/hdl particles. in healthy individuals, about 30% of blood cholesterol, along with other fats, is carried by hdl. this is often contrasted with the amount of cholesterol estimated to be carried within low-density lipoprotein particles, ldl, and called ldl-c. hdl particles remove fats and cholesterol from cells, including within artery wall atheroma, and transport it back to the liver for excretion or re-utilization; thus the cholesterol carried within hdl particles (hdl-c) is sometimes called "good cholesterol" (despite being the same as cholesterol in ldl particles). those with higher levels of hdl-c tend to have fewer problems with cardiovascular diseases, while those with low hdl-c cholesterol levels (especially less than 40 mg/dl or about 1 mmol/l) have increased rates for heart disease. higher native hdl levels are correlated with lowered risk of cardiovascular disease in healthy people. the remainder of the serum cholesterol after subtracting the hdl is the non-hdl cholesterol. the concentration of these other components, which may cause atheroma, is known as the non-hdl-c. this is now preferred to ldl-c as a secondary marker as it has been shown to be a better predictor and it is more easily calculated. structure and function with a size ranging from 5 to 17 nm, hdl is the smallest of the lipoprotein particles. it is the densest because it contains the highest proportion of protein to lipids. its most abundant apolipoproteins are apo a-i and apo a-ii. a rare genetic variant, apoa-1 milano, has been documented to be far more effective in both protecting against and regressing arterial disease, atherosclerosis. the liver synthesizes these lipoproteins as complexes of apolipoproteins and phospholipid, which resemble cholesterol-free flattened spherical lipoprotein particles, whose nmr structure was recently published; the complexes are capable of picking up cholesterol, carried internally, from cells by interaction with the atp-binding cassette transporter a1 (abca1). a plasma enzyme called lecithin-cholesterol acyltransferase (lcat) converts the free cholesterol into cholesteryl ester (a more hydrophobic form of cholesterol), which is then sequestered into the core of the lipoprotein particle, eventually causing the newly synthesized hdl to assume a spherical shape. hdl particles increase in size as they circulate through the blood and incorporate more cholesterol and phospholipid molecules from cells and other lipoproteins, such as by interaction with the abcg1 transporter and the phospholipid transport protein (pltp). hdl transports cholesterol mostly to the liver or steroidogenic organs such as adrenals, ovary, and testes by both direct and indirect pathways. hdl is removed by hdl receptors such as scavenger receptor bi (sr-bi), which mediate the selective uptake of cholesterol from hdl. in humans, probably the most relevant pathway is the indirect one, which is mediated by cholesteryl ester transfer protein (cetp).this protein exchanges triglycerides of vldl against cholesteryl esters of hdl. as the result, vldls are processed to ldl, which are removed from the circulation by the ldl receptor pathway. the triglycerides are not stable in hdl, but are degraded by hepatic lipase so that, finally, small hdl particles are left, which restart the uptake of cholesterol from cells. the cholesterol delivered to the liver is excreted into the bile and, hence, intestine either directly or indirectly after conversion into bile acids. delivery of hdl cholesterol to adrenals, ovaries, and testes is important for the synthesis of steroid hormones. several steps in the metabolism of hdl can participate in the transport of cholesterol from lipid-laden macrophages of atherosclerotic arteries, termed foam cells, to the liver for secretion into the bile. this pathway has been termed reverse cholesterol transport and is considered as the classical protective function of hdl toward atherosclerosis. hdl carries many lipid and protein species, several of which have very low concentrations but are biologically very active. for example, hdl and its protein and lipid constituents help to inhibit oxidation, inflammation, activation of the endothelium, coagulation, and platelet aggregation. all these properties may contribute to the ability of hdl to protect from atherosclerosis, and it is not yet known which are the most important. in addition, a small subfraction of hdl lends protection against the protozoan parasite trypanosoma brucei brucei. this hdl subfraction, termed trypanosome lytic factor (tlf), contains specialized proteins that, while very active, are unique to the tlf molecule. in the stress response, serum amyloid a, which is one of the acute-phase proteins and an apolipoprotein, is under the stimulation of cytokines (interleukin 1, interleukin 6), and cortisol produced in the adrenal cortex and carried to the damaged tissue incorporated into hdl particles. at the inflammation site, it attracts and activates leukocytes. in chronic inflammations, its deposition in the tissues manifests itself as amyloidosis. it has been postulated that the concentration of large hdl particles more accurately reflects protective action, as opposed to the concentration of total hdl particles. this ratio of large hdl to total hdl particles varies widely and is measured only by more sophisticated lipoprotein assays using either electrophoresis (the original method developed in the 1970s) or newer nmr spectroscopy methods (