PROBUCOL AND ALPHA-TOCOPHEROL STIMULATE BILE-ACID SYNTHESIS IN CULTURED RABBIT HEPATOCYTES

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.