Regulation of ATP-binding cassette transporter A1 in cholesteryl ester storage disease

Previous studies from the Francis laboratory have determined that regulation of ABCA1 expression is impaired in the lysosomal cholesterol storage disorder Niemann-Pick type C (NPC) disease, the presumed reason for the low plasma HDL-cholesterol (HDL-C) levels found in the majority of NPC disease patients. Cholesteryl ester storage disease (CESD) is another lysosomal cholesterol storage disorder, resulting from deficiency in lysosomal acid lipase (LAL). CESD patients develop premature atherosclerosis, possibly related to their known low plasma HDL-C levels. We hypothesized that in CESD the reduced activity of LAL also leads to impaired ABCA1 regulation and HDL formation due to the decrease in release of unesterified cholesterol from lysosomes. Our results show that human CESD fibroblasts exhibit a blunted increase in ABCA1 mRNA and protein in response to addition of low density lipoprotein (LDL) to the medium when compared to normal human fibroblasts. Efflux of LDL-derived cholesterol radiolabel and mass to apolipoprotein A-I-containing medium was markedly reduced in CESD fibroblasts compared to normal fibroblasts. Cellular radiolabeled cholesteryl ester derived from LDL and total cell cholesteryl ester mass was increased in CESD compared to normal cells. Delivery of an adenovirus expressing full length human lysosomal acid lipase (Ad-hLAL) results in correction of LAL activity and an increase ABCA1 protein expression, as well as correction of cholesterol and phospholipid release to apoA-I and normalization of cholesteryl ester levels in the CESD fibroblasts. These accumulated results suggest ABCA1 expression is dependent on lysosomal acid lipase activity, and provide additional support for a major role of the lysosomal pool of unesterified cholesterol as a regulator of ABCA1 expression and HDL formation in humans.Medicine, Faculty ofMedicine, Department ofExperimental Medicine, Division ofGraduat