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 mod ulate lipoprotein production by fiver cells. Fenofibrate caused a 30% decrease in apo B secretion from Hep G2 cells after 4 days of treatmen t, which was not due to inhibition of apo B synthesis. The mechanism o f this fenofibrate-mediated decrease in apo B secretion has now been f urther investigated The effects of fenofibrate on apo B mRNA concentra tions apo B degradation and neutral lipid synthesis were examined in H ep G2 cells. Studies with [C-14] fenofibrate were carried out to deter mine the relationship between fenofibrate metabolism and its effects o n apo B. Fenofibrate had no effect on apo B mRNA levels, while intrace llular degradation of apo B was increased within 4 h of fenofibrate ad dition. The 4-day lag period before apo B secretion was not due to int racellular 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-associate d fenofibrate was negligible at this time. We investigated the possibi lity that neutral lipid synthesis may be the initial target of fenofib rate action. Triglyceride synthesis was not reduced until 4 days after the onset of treatment, but a significant decrease in cholesteryl est er synthesis occurred earlier and preceded any effect on apo B secreti on. Fenofibrate-induced inhibition of apo B secretion therefore occurs by a post-translational mechanism which can be set in motion by a bri ef exposure to fenofibrate, and is related to neutral lipid synthesis.