The effects of probucol and alpha-tocopherol on cholesterol and bile a
cid metabolism was studied in primary rabbit hepatocyte culture. Prein
cubation of hepatocytes with 100 muM probucol or alpha-tocopherol for
24 h stimulated the synthesis of bile acids in medium containing 10% f
etal calf serum and [C-14] cholesterol. This effect is probably associ
ated with the enhanced uptake of exogenous cholesterol by high density
lipoproteins (HDL2). Probucol, unlike alpha-tocopherol, stimulated in
tracellular accumulation of [C-14]cholesterol from HDL2. Probucol favo
red secretion of bile acids in the presence of 250 mug/ml of HDL2 by 3
0-45%. Incubation of hepatocytes in serum-free medium with 100 muM pro
bucol stimulated apoprotein E (apo E) synthesis 1.5- to 3-fold, the HD
L2 preincubated with cells in the presence of probucol contain 2- to 3
-fold more apo E than that preincubated in cells without probucol HDL2
preincubated with hepatocytes in the presence of 100 muM probucol are
more effectively (1.5-3-fold) incorporated into cultured human fibrob
lasts. This uptake was inhibited 30-50% by addition of anti-LDL recept
or monoclonal antibodies. These findings suggest an involvement of the
secreted apo E and HDL2-associated apo E in probucol-stimulated, rece
ptor-mediated HDL2 uptake resulting in subsequent stimulation of bile
acid synthesis and secretion. alpha-Tocopherol, unlike probucol stimul
ates bile acid synthesis by increasing the pool of de novo synthesized
cholesterol.