HDL Cholesterol

HDL cholesterol (HDL-C) measures the cholesterol cargo of high-density lipoproteins and is an indirect marker of HDL, whose functions are exerted by entire HDL particles or by distinct proteins or lipids they carry rather than by their cholesterol. ^[1] HDL is the smallest circulating lipoprotein, and spherical HDL particles with a hydrophobic neutral lipid core measure approximately 8 to 11 nm in diameter. ^[1] ApoA-I, the most abundant apolipoprotein on HDL, maintains HDL structure and contributes to the removal of excess cellular cholesterol through the ATP-binding cassette transporter ABCA1. ^[1] An inverse relationship between HDL-C and the risk of coronary heart disease was first observed in the 1950s and reinforced by many studies since the 1970s, earning HDL-C the label of 'good cholesterol' as opposed to LDL cholesterol. ^[1] HDL is not a single entity but a family of particles differing in size, density, shape, charge and composition that are continuously remodelled in the circulation. ^[1]

Plasma lipoproteins are the main means of cholesterol transport among tissues: apoB-containing lipoproteins (VLDL, IDL and LDL) deliver cholesterol from the liver to peripheral tissues, while HDL appears to mediate the reverse movement of cholesterol back to the liver. ^[2] In reverse cholesterol transport, HDL acts as the acceptor of excess cholesterol from peripheral tissues and delivers it to the liver, where it is excreted into the bile directly or after conversion to bile acids. ^[3] Cholesterol efflux from plaque foam cells to HDL particles, which depends on the transporters ABCA1 and ABCG1, is the first step of reverse cholesterol transport and has been considered a promising antiatherogenic target. ^[3] Cholesterol taken up by small HDL is esterified in the circulation by lecithin-cholesterol acyltransferase (LCAT), forming larger HDL particles that deliver cholesteryl ester to the liver by direct and indirect routes. ^[2] Cholesteryl ester transfer protein (CETP) moves cholesteryl esters among lipoproteins, and genetic CETP deficiency is associated with low LDL-C and a profoundly elevated HDL-C. ^[4] Beyond cholesterol transport, HDL suppresses inflammatory signalling in macrophages, and HDL and its proteins apoA-I and paraoxonase 1 protect against cellular

HDL-C quantifies only the cholesterol carried by HDL and does not reflect the efficiency of reverse cholesterol transport. ^[1] Non-HDL cholesterol encompasses all plasma lipoproteins except HDL (LDL, triglyceride-rich lipoproteins and their remnants, and Lp(a)), and its popularity reflects its ease of estimation and independence from fasting status. ^[6] In a meta-analysis of 61 prospective studies, the ratio of total to HDL cholesterol was the strongest simple predictor of ischaemic heart disease mortality, 40% more informative than non-HDL cholesterol and more than twice as informative as total cholesterol. ^[7] The ratio of triglycerides to HDL-C (TG/HDL-C) has been proposed as a biomarker for predicting both metabolic syndrome and cardiovascular disease. ^[8] HDL was historically subdivided by density into lighter, larger HDL2 and heavier, smaller HDL3, and nuclear magnetic resonance spectroscopy can now separate HDL size fractions in clinical laboratories.