THE HIGH-DENSITY LIPOPROTEIN-INDUCED AND APOLIPOPROTEIN A-I-INDUCED MOBILIZATION OF CELLULAR CHOLESTEROL IS IMPAIRED IN FIBROBLASTS FROM TANGIER DISEASE SUBJECTS

Tangier disease (also known as familial HDL-deficiency) is characterized by very low high density lipoprotein (HDL) plasma levels, splenomegaly, and massive cholesteryl ester accumulation in the cytoplasm of various cell types. Since this phenotype may in part be caused by a defect in the pathway mediating cholesterol efflux from peripheral cells, we investigated the HDL(3)-mediated mobilization of cholesterol synthesized de novo from [C-14]-mevalonolactone in cultivated fibroblasts from two patients with Tangier disease. Our results indicate that the KDL(3)-induced translocation of [C-14]-cholesterol from intracellular pools to the plasma membrane and its subsequent secretion into the extracellular medium was approximately 50 % less in the cells from the patients than in controls. The same result was also obtained with artificial apolipoprotein A-I-containing phospholipid vesicles. By contrast, no significant difference in HDL(3)-induced cholesterol efflux was observed when plasma membrane was labeled with exogenous [C-14]-cholesterol. We conclude that inefficient cholesterol efflux in Tangier disease is primarily caused by impaired HDL(3)-induced activation of cholesterol translocation from intracellular pools to the plasma membrane. (C) 1994 Academic Press, Inc.