Plasma FA composition in familial LCAT deficiency indicates SOAT2-derived cholesteryl ester formation in humans

Mutations in the LCAT gene cause familial LCAT deficiency (FLD, OMIM#245900), a very rare metabolic disorder. LCAT is the only enzyme able to esterify cholesterol in plasma, while sterol O-acyltransferase 1 and 2 (SOAT1 and SOAT2) are the enzymes esterifying cellular cholesterol in cells. Despite the complete lack of LCAT activity, FLD patients exhibit circulating cholesteryl esters (CEs) in apoB-containing lipoproteins. To analyze the origin of these CEs, we investigated twenty-four carriers of LCAT deficiency in this observational study. We found CE plasma levels were significantly reduced and highly variable among carriers of two mutant LCAT alleles [22.5(4.0-37.8) mg/dL], and slightly reduced in heterozygotes [218(153-234) mg/dL]. Fatty acid (FA) distribution in cholesteryl esters (CEFA) was evaluated in whole plasma and in VLDL in a subgroup of the enrolled subjects. We found enrichment of C16:0, C18:0, and C18:1 species, and a depletion in C18:2 and C20:4 species in the plasma of carriers of two mutant LCAT alleles. No changes were observed in heterozygotes. Furthermore, plasma triglyceride-FA distribution was remarkably similar between carriers of LCAT deficiency and controls. CEFA distribution in VLDL essentially recapitulated that of plasma, being mainly enriched in C16:0 and C18:1, while depleted in C18:2 and C20:4. Finally, after fat loading, chylomicrons of carriers of two mutant LCAT alleles showed CEs containing mainly saturated FAs. This study of CEFA composition in a large cohort of carriers of LCAT deficiency shows that in the absence of LCAT-derived CEs, CEs present in apoB-containing lipoproteins are derived from hepatic and intestinal SOAT2.