EFFECTS OF TOCOTRIENOL ON THE INTRACELLULAR TRANSLOCATION AND DEGRADATION OF APOLIPOPROTEIN-B - POSSIBLE INVOLVEMENT OF A PROTEASOME INDEPENDENT PATHWAY

gamma-Tocotrienol (gamma-T3), a HMG CoA reductase inhibitor, was previ ously shown to stimulate the intracellular degradation of apolipoprote in B (apoB) in HepG2 cells. The aim of this study was to explore the e ffects of gamma-T3 on the proteasome dependent cotranslational degrada tion and the proteasome independent post-translational degradation of apoB. Previous studies have shown that apoB translocation across the e ndoplasmic reticulum (ER) membrane governs the co-translational degrad ative pathway of apoB. Therefore, we first examined the effects of gam ma-T3 on this pathway using a specific translocation assay derived fro m HepG2 cells. Our results indicated that gamma-T3 reduced the efficie ncy of apoB translocation across the ER membrane, suggesting that co-t ranslational degradation may be partially involved. Evidence of an ER associated post-translational degradation was also provided upon pre-t reating digitonin-permeabilized HepG2 cells with a proteasome inhibito r, lactacystin. When chased for 2h, ER degradation of apoB was observe d and was further enhanced in the presence of gamma-T3 versus untreate d control, in spite of proteasome inhibition. Combined with the abilit y of ALLN, a proteasome and cysteine protease inhibitor, to block the post-translational degradation of apoB, the data suggest that gamma-T3 diverted more apoB to a cytosolic proteasomal dependent and possibly an ER-associated proteasomal independent degradation pathways. (C) 199 8 Academic Press.