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2nd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV13-15 September 2000, Toronto, Canada |
HIV PROTEASE INHIBITORS INCREASE SECRETION OF APOLIPOPROTEIN B-LIPOPROTEINS FROM HEPATOMA CELLS BY PREVENTING PROTEASOMAL DEGRADATION
Antiviral Therapy 2000; 5(Suppl. 5):12 (abstract no. O18)
J-S Liang1, O Distler1, DA Cooper2, SL Sturley1 and HN Ginsberg1
1Columbia University, N.Y., USA; 2National Center in HIV Epidemiology and Clinical Research, Sydney, Australia
BACKGROUND: HIV protease inhibitor (PI) treatment of HIV infection is commonly associated with hypertriglyceridemia and increased levels of very low density lipoproteins (VLDL). The secretion of apolipoprotein B (apoB), the major protein of VLDL, is regulated significantly at the co- and post-translational level by degradation of newly synthesized apoB. This degradation is regulated by lipid availability and is carried out by the proteasome. PIs were recently shown to inhibit the proteasome.
OBJECTIVES: Effects of PIs on secretion of apoB lipoproteins from HepG2 and McArdle RH7777 hepatoma cells.
DESIGN AND RESULTS: Incubation of either of these cells with saquinavir or ritonavir (10-100 µM) for 2 h, resulted in significant protection of intracellular apoB from degradation. The protected apoB was ubiquitinated, indicating that proteasomal degradation had been inhibited. Surprisingly, PI-treatment was associated with decreased secretion of apoB. However, when HepG2 cells were incubated simultaneously with PI and 0.4 µM oleic acid (OA), secretion of apoB lipoproteins was increased 65% versus cells treated with only OA. Additionally, when cells were treated with ritonavir for 90 min, and then the medium was changed to one with 0.4 µM OA, apoB secretion increased 45% during the next 120 min compared to cells not treated with PIs but with only OA. The apoB lipoproteins secreted during PI/OA treatment had the same density distribution as apoB-lipoproteins secreted after OA alone. There was no significant effect of PI treatment on either MTP binding to apoB, or on the secretion of apoprotein AI or albumin.
CONCLUSIONS: PI treatment can increase the assembly and secretion of apoB-lipoproteins. These results provide a potential molecular basis for PI-associated hypertriglyceridemia.
000913
O18
Copyright © 2000 - International Medical Press Ltd. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Medical Editor, International Medical Press, 36 St Mary-at-Hill, London EC3R 8DU, United Kingdom.
