Activation of naturally occurring LCAT mutants by a novel activator compound

Lecithin:cholesterol acyltransferase (LCAT) is the unique plasma enzyme able to esterify cholesterol and plays an important role in HDL maturation and promotion of reverse cholesterol transport. Familial LCAT deficiency (FLD, OMIM #245900) is a rare recessive disease due to loss of function mutations in the LCAT gene, for which there is no cure. In this study, we assessed the in vitro efficacy of a novel small molecule LCAT activator. Cholesterol esterification rate (CER) and LCAT activity were tested in plasma from 6 controls and 5 FLD homozygous carriers of various LCAT mutations at different doses of the compound (0.1, 1 and 10 µg/mL). In control plasma, the compound significantly increased both CER (P<0.001) and LCAT activity (P=0.007) in a dose dependent manner. Both CER and LCAT activity increased by 4-5 fold, reaching maximum activation at the dose of 1 µg/mL. Interestingly, DS compound produced an increase in CER in 2 of the 5 tested LCAT mutants (Leu372---Arg and Val309---Met), while LCAT activity increased in 3 LCAT mutants (Arg147---Trp, Thr274---Ile and Leu372---Arg); mutant Pro254---Ser was not activated at any of the tested doses. The present findings pose the basis for personalized therapeutic interventions in FLD carriers and support the potential LCAT activation in secondary LCAT defects. Significance Statement We characterized the pharmacology of a novel small-molecule LCAT activator in vitro on a subset of naturally occurring LCAT mutants. Our findings pose the basis for personalized therapeutic intervention in FLD carriers, who can face severe complications and for whom no cure exists.