LAUSR

To explain the atherogenicity and the antiatherogenicity of LDLs (low-density lipoproteins) and HDLs (high-density lipoproteins), respectively, many students and patients are taught that LDLs deliver cholesterol from liver to peripheral cells, whereas HDLs return excess cholesterol from peripheral cells back to liver for biliary excretion by reverse cholesterol transport (RCT). This keep-it-simple scheme is misleading. First, the vast majority of LDL cholesterol is taken up by the liver rather than by nonhepatic peripheral cells. Most of the latter can synthesize enough cholesterol for their need and limit the uptake of cholesterol with LDL by downregulation of LDLR (LDL receptor) expression. Only cells expressing nonsterol regulated scavenger receptors, notably macrophages, for example, in the atherosclerotic plaque, can take up excessive amounts of cholesterol via modified LDL.1 Second, a large proportion of cholesterol carried by LDL is derived from HDL. The exchange of triglycerides carried by VLDLs (very-low-density lipoproteins) and their remnants against cholesteryl esters carried by HDL through the action of CETP (cholesteryl ester transfer protein) is an important source of LDL cholesterol. By CETP-mediated receipt of cholesteryl esters from HDL for subsequent LDLR-mediated uptake into the liver, LDL contributes to RCT. The blockage of this pathway may be one reason for the futility of CETP inhibitors toward prevention of major cardiovascular events, especially when combined with statins that upregulate LDLR and thereby enhance hepatic removal of LDL cholesterol.2