HIGH-DENSITY LIPOPROTEIN-MEDIATED EFFLUX OF NEWLY SYNTHESIZED CHOLESTEROL AND PHOSPHOLIPIDS IS IMPAIRED IN FIBROBLASTS FROM TANGIER PATIENTS WHILE MEMBRANE DESORPTION AND EFFLUX OF LYSOSOMAL CHOLESTEROL ARE NORMAL

Mononuclear phagocytes (MNPs) from Tangier patients have been shown pr eviously by our laboratory to have a defect in the interaction with hi gh density lipoproteins (HDL) and abnormalities in the intracellular t raffic of lipoproteins and lipids. Similar to Tangier MNPs, fibroblast s show marphologic abnormalities of the Golgi apparatus and abnormal r ate of synthesis and catabolism for cellular lipids, indicating that t he cellular defect of the disease is expressed in both cell types. The refore, transport of cellular lipids from their site of synthesis or s torage to the cell membrane and release into the medium was studied in cultured skin fibroblasts from Tangier patients. Different from MNPs, fibroblasts do not internalize appreciable amounts of HDL(3), indicat ing that uptake and retroendocytosis of HDL(3) is not a relevant metab olic pathway in fibroblasts. When HDL(3)-mediated efflux of newly synt hesized cholesterol was determined by incorporation of the radioactive pre cursor (C-14)-mevalonolactone, this was reduced by approximately 80% in Tangier fibroblasts. Similarly, HDL(3)-mediated efflux of phosp hatidylcholine and sphingomyelin labelled with (H-3)-choline was reduc ed by approximately 80% and 30%, respectively. On the other hand, effl ux of cholesterol taken up by the LDL-receptor pathway was similar in control and Tangier cells. Desorption of cholesterol and phospholipids , incorporated into the cell membrane by diffusion, was also not diffe rent between control and Tangier fibroblasts. These data indicate a sp ecific disturbance in the translocation of newly synthesized cholester ol and phospholipids from their site of synthesis to the cell membrane . This may be due either to a defect in the transport of endogenous ch olesterol and phospholipids or to a defect in HDL(3)-mediated transloc ation of endogenous cholesterol and phospholipids.