Functional LCAT is not required for macrophage cholesterol efflux to human serum

• Published in: Atherosclerosis 2009-05, Vol.204 (1), p.141-146
• Main Authors: Calabresi, Laura, Favari, Elda, Moleri, Elsa, Adorni, Maria Pia, Pedrelli, Matteo, Costa, Sara, Jessup, Wendy, Gelissen, Ingrid C, Kovanen, Petri T, Bernini, Franco, Franceschini, Guido
• Format: Article
• Language: English
• Subjects: ABCA1; Adult; Animals; Atherosclerosis (general aspects, experimental research); ATP Binding Cassette Transporter 1; ATP Binding Cassette Transporter, Subfamily G, Member 1; ATP-Binding Cassette Transporters - metabolism; Biological and medical sciences; Blood and lymphatic vessels; Blood coagulation; Cardiology. Vascular system; Cardiovascular; Case-Control Studies; CHO Cells; Cholesterol - blood; Cholesterol efflux; Chymases - metabolism; Cricetinae; Cricetulus; Cyclic AMP - metabolism; Familial LCAT deficiency; Female; Foam Cells - metabolism; High density lipoproteins; Humans; Investigative techniques, diagnostic techniques (general aspects); Lecithin Cholesterol Acyltransferase Deficiency - blood; Lecithin Cholesterol Acyltransferase Deficiency - enzymology; Lecithin Cholesterol Acyltransferase Deficiency - genetics; Lipoproteins, HDL - blood; Macrophages; Male; Medical sciences; Mice; Middle Aged; Mutation; Phosphatidylcholine-Sterol O-Acyltransferase - blood; Phosphatidylcholine-Sterol O-Acyltransferase - genetics; Rats; Scavenger Receptors, Class B - metabolism; Transfection
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2008.08.038

Abstract Objectives To evaluate the capacity of serum from carriers of LCAT gene mutations to promote cell cholesterol efflux through the ABCA1, ABCG1, and SR-BI pathways. Methods Serum was obtained from 41 carriers of mutant LCAT alleles (14 carriers of two mutant LCAT alleles and 27 heterozygotes) and 10 non-carrier relatives (controls). The capacity of serum to promote cholesterol efflux was tested in pathway-specific cell models. Results LCAT deficient sera were significantly more efficient than control sera in promoting cell cholesterol efflux via ABCA1 (3.1 ± 0.3% for carriers of two mutant LCAT alleles and 2.6 ± 0.2% for heterozygotes vs. 1.5 ± 0.4% for controls), and less efficient in promoting ABCG1- and SR-BI-mediated cholesterol efflux. The enhanced capacity of LCAT deficient serum for ABCA1 efflux is explained by the increased content of preβ-HDL, as indicated by the significant positive correlation between ABCA1 efflux and serum preβ-HDL content ( R = 0.468, P < 0.001). Moreover, chymase treatment of LCAT deficient serum selectively degraded preβ-HDL and completely abolished ABCA1 efflux. Despite the remarkable reductions in serum HDL levels, LCAT deficient sera were as effective as control sera in removing mass cholesterol from cholesterol-loaded macrophages. Conclusions Serum from carriers of LCAT gene mutations has the same capacity of control serum to decrease the cholesterol content of cholesterol-loaded macrophages due to a greater cholesterol efflux capacity via ABCA1.