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

• Published in: Journal of lipid research 2022-07, Vol.63 (7), p.100232-100232, Article 100232
• Main Authors: Pavanello, Chiara, Ossoli, Alice, Strazzella, Arianna, Risè, Patrizia, Veglia, Fabrizio, Lhomme, Marie, Parini, Paolo, Calabresi, Laura
• Format: Article
• Language: English
• Subjects: apoB-containing lipoproteins; Apolipoproteins B; CEFA; Cholesterol - metabolism; Cholesterol Esters; cholesteryl ester FAs; cholesteryl esters; familial LCAT deficiency; fat loading; Humans; Lecithin Cholesterol Acyltransferase Deficiency - genetics; Lipoproteins; Medicin och hälsovetenskap; Phosphatidylcholine-Sterol O-Acyltransferase - genetics; Phosphatidylcholine-Sterol O-Acyltransferase - metabolism; SOAT2; Sterol O-Acyltransferase - metabolism; Sterol O-Acyltransferase 2; VLDL
• ISSN: 0022-2275; 1539-7262; 1539-7262
• DOI: 10.1016/j.jlr.2022.100232

Mutations in the LCAT gene cause familial LCAT deficiency (Online Mendelian Inheritance in Man ID: #245900), a very rare metabolic disorder. LCAT is the only enzyme able to esterify cholesterol in plasma, whereas sterol O-acyltransferases 1 and 2 are the enzymes esterifying cellular cholesterol in cells. Despite the complete lack of LCAT activity, patients with familial LCAT deficiency exhibit circulating cholesteryl esters (CEs) in apoB-containing lipoproteins. To analyze the origin of these CEs, we investigated 24 carriers of LCAT deficiency in this observational study. We found that 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). FA distribution in CE (CEFA) was evaluated in whole plasma and 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 sterol O-acyltransferase 2.