CETP deficiency due to a novel mutation in the CETP gene promoter and its effect on cholesterol efflux and selective uptake into hepatocytes

Abstract

ObjectivesTo identify the genetic variant in the CETP gene of the proband with high HDL-C and low CETP activity and to investigate whether HDL from the CETP-deficient subject was dysfunctional in the reverse cholesterol transport (RCT) pathway. MethodsWe sequenced the CETP gene and assessed its promoter activity. Cholesterol efflux and hepatic cholesteryl ester delivery studies were also performed using the proband's HDL. ResultsA proband was a compound heterozygote for a known D459G variant and a novel 18-bp deletion mutation in the CETP promoter. This promoter mutation markedly reduced the transcriptional activity in HepG2 cells. HDL2 from this subject increased SR-BI-mediated cholesterol efflux, whereas cholesteryl ester delivery into hepatocytes was maintained. ConclusionA novel deletion mutation in the CETP promoter is associated with high HDL-C and decreased promoter activity. HDL from this CETP-deficient subject was not dysfunctional in mediating two main steps of RCT assessed in vitro.