THE FENOFIBRATE-MEDIATED DECREASE IN APO-B SECRETION FROM HEP G2 CELLS OCCURS BY A POSTTRANSLATIONAL MECHANISM

We recently demonstrated that hypolipidemic fibrate drugs directly modulate lipoprotein production by fiver cells. Fenofibrate caused a 30% decrease in apo B secretion from Hep G2 cells after 4 days of treatment, which was not due to inhibition of apo B synthesis. The mechanism of this fenofibrate-mediated decrease in apo B secretion has now been further investigated The effects of fenofibrate on apo B mRNA concentrations apo B degradation and neutral lipid synthesis were examined in Hep G2 cells. Studies with [C-14] fenofibrate were carried out to determine the relationship between fenofibrate metabolism and its effects on apo B. Fenofibrate had no effect on apo B mRNA levels, while intracellular degradation of apo B was increased within 4 h of fenofibrate addition. The 4-day lag period before apo B secretion was not due to intracellular accumulation of the drug or its metabolites. Cells treated with fenofibrate for I day followed by withdrawal for 3 days exhibited decreased secretion of apo B after 4 days, even though cell-associated fenofibrate was negligible at this time. We investigated the possibility that neutral lipid synthesis may be the initial target of fenofibrate action. Triglyceride synthesis was not reduced until 4 days after the onset of treatment, but a significant decrease in cholesteryl ester synthesis occurred earlier and preceded any effect on apo B secretion. Fenofibrate-induced inhibition of apo B secretion therefore occurs by a post-translational mechanism which can be set in motion by a brief exposure to fenofibrate, and is related to neutral lipid synthesis.