Depletion in LpA-I:A-II particles enhances HDL-mediated endothelial protection in familial LCAT deficiency

Abstract

A-II high density lipoprotein lecithin:cholesterol acyltransferase LCAT deficiency is a rare disorder of lipoprotein metabolism due to loss-of-function mutations in the human LCAT gene. LCAT deficiency is inherited in an autosomal codominant fashion with respect to the obligate biochemical phenotypes characterized by reduced plasma cholesterol esterification, LCAT activity, HDL-cholesterol (HDL-C) and apoA-I levels, and enhanced unesterified/total cholesterol ratio (1, 2). LCAT deficiency leads to the development of two biochemically and clinically distinct syndromes, classical familial LCAT deficiency (FLD) and fish-eye disease (FED). In FLD cases, the lack of LCAT activity is complete, and the enzyme loses its ability to esterify cholesterol in both HDL and LDL particles with severe clinical manifestations that include corneal opacity, anemia, and renal disease (3). In FED cases, the enzyme loses its capacity to esterify cholesterol in HDL, but retains the activity in LDL, thus leading to less severe clinical manifestations, normally limited to corneal opacity (3). The severe deficiency of atheroprotective HDL in carriers of LCAT deficiency should increase their risk of developing coronary heart disease; however, imaging studies evaluating carotid intima-media thickness, a validated surrogate marker for atherosclerotic