Cellular cholesterol transport and efflux in fibroblasts are abnormal in subjects with familial HDL deficiency

Familial high density lipoprotein (HDL) deficiency (FHD) is a genetic lipop rotein disorder characterized by a severe decrease in the plasma HDL choles terol (-C) level (less than the fifth percentile). Unlike Tangier disease, FHD is transmitted as an autosomal dominant trait. FHD subjects have none o f the clinical manifestations of Tangier disease (lymphoid tissue infiltrat ion with cholesteryl esters and/or neurological manifestations). Plasmas fr om FHD subjects contain pre-beta-migrating HDLs but are deficient in alpha- migrating HDLs. We hypothesized that a reduced HDL-C level in FHD is due to abnormal transport of cellular cholesterol to the plasma membrane, resulti ng in reduced cholesterol efflux onto nascent HDL particles, leading to lip id-depleted HDL particles that are rapidly catabolized. Cellular cholestero l metabolism was investigated in skin fibroblasts from FHD and control subj ects. HDL3- and apolipoprotein (apo) A-I-mediated cellular cholesterol and phosphatidylcholine efflux was examined by labeling cells with [H-3]cholest erol and [H-3]choline, respectively, during growth and cholesterol loading during growth arrest. FHD cells displayed an approximate to 25% reduction i n HDL3-mediated cellular cholesterol efflux and an approximate to 50% to 80 % reduction in apoA-I-mediated cholesterol and phosphatidylcholine efflux c ompared with normal cells. Cellular cholesterol ester levels were decreased when cholesterol-labeled cells were incubated with HDL, in normal cells, b ut cholesterol ester mobilization was significantly reduced in FHD cells. H DL, binding to fibroblasts and the possible role of the HDL binding protein /vigilin in FHD were also investigated. No differences were observed in I-1 25-HDL3 binding to LDL-loaded cells between FHD and control cells. HDL bind ing protein/vigilin mRNA levels and its protein expression were constitutiv ely expressed in FHD cells and could be modulated (approximate to 2-fold in crease) by elevated cellular cholesterol in normal cells. In conclusion, FH D is characterized by reduced HDL3- and apoA-I-mediated cellular cholestero l efflux. It is not associated with abnormal cellular HDL3 binding or a def ect in a putative HDL binding protein.