Lecithin:Cholesterol Acyltransferase, High-Density Lipoproteins, and Atheroprotection in Humans

The lecithin:cholesterol acyltransferase (LCAT) enzyme is responsible for the synthesis of cholesteryl esters in human plasma. Lecithin:cholesterol acyltransferase is a critical enzyme in high-density lipoprotein (HDL) metabolism, and deficiency of LCAT-mediated cholesterol esterification leads to defective HDL maturation with accumulation of nascent pre-β HDL. In addition to its function in HDL metabolism, LCAT has also long been believed to play a critical role in macrophage reverse cholesterol transport (RCT). However, recent findings have shown that human LCAT overexpression in mice does not enhance macrophage RCT in vivo, and conversely, LCAT-deficient mice display a preserved macrophage RCT despite the severe plasma HDL reduction. In agreement with this observation, defective LCAT activity does not result in enhanced atherosclerosis, despite the reduced HDL cholesterol levels. These findings challenge the notion that LCAT is required for effective atheroprotection and suggest that elevating LCAT expression and/or activity is not a promising therapeutic strategy to reduce cardiovascular risk.