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
G. Rogler et al., 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, Nieren- und Hochdruckkrankheiten, 24(2), 1995, pp. 81-83
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.