Is Low-Density Lipoprotein Cholesterol the Key to Interpret the Role of Lecithin:Cholesterol Acyltransferase in Atherosclerosis?
Authors: Cecilia Vitali, Alan T. Remaley, Marina Cuchel
Journal: Circulation (2018)

ecithin:cholesterol acyltransferase (LCAT) is the only enzyme able to esterify cholesterol on plasma lipoproteins. 1LCAT catalyzes the transfer of fatty acids from phosphatidylcholine to unesterified cholesterol, thus generating lysophosphatidylcholine and cholesterol esters. 1 Although LCAT displays both α and β activity (toward high-density lipoprotein [HDL] and apolipoprotein B-containing lipoproteins, respectively), it is widely believed that its preferred substrates are nascent discoidal HDL, which mainly consists of unesterified cholesterol, phospholipids, and apolipoprotein A-I, the main activator of LCAT. 1 The result of LCAT activity on nascent HDL particles has profound metabolic consequences.First, the conversion of unesterified cholesterol into the more hydrophobic esterified cholesterol promotes the migration of cholesterol esters to the core of spherical HDL particles, thus generating a gradient of unesterified cholesterol between the lipoprotein surface and the peripheral cell membrane. 1Furthermore, the maturation of HDL into cholesterol ester-enriched particles facilitates their further remodeling and catabolism by promoting the interaction with circulating proteins, such as cholesteryl ester transfer protein and others, and liver cell receptors such as scavenger receptor class B type I. 1 Given these findings, LCAT has been proposed to play a crucial role in raising high-density lipoprotein cholesterol (HDL-C) levels in vivo and in promoting reverse cholesterol transport; however, its role in the pathogenesis of atherosclerosis remains controversial. 1 Reverse cholesterol transport is believed to be one of the main mechanisms through which HDL exerts a cardio-protective effect. 2LCAT activity, therefore, would be expected to be associated with protection from atherosclerosis and cardiovascular risk; however, data from human and animal studies have provided conflicting results. 1 LCAT overexpression in different mouse models has been associated with either increased or decreased atherosclerosis, whereas LCAT deficiency, in general, has been associated with atheroprotection. 1 In rabbits and monkeys, which, like humans, express cholesteryl ester transfer protein, increased LCAT expression improves the lipoprotein profile and may reduce atherosclerosis. 1 Genome-wide association studies and mendelian randomization studies in humans confirmed the link between LCAT variants and HDL-C levels, but it did not appear to alter cardiovascular risk. 3Data from carriers of LCAT loss-of-function mutations are similarly contradictory. 1,3CAT deficiency is a rare condition associated with 2 clinically distinct syndromes: familial LCAT deficiency (FLD) and fish-eye disease (FED). 1 From a biochemical point of view, FLD-causing mutations induce a complete loss of both α and β LCAT enzymatic function, whereas FED-causing mutations decrease esterification on HDL but not on apolipoprotein B-containing lipoproteins. 1 Both syndromes are char-