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Nelfinavir and Ritonavir Stimulate Triglyceride Production in Hepatic Cells D. WINEGAR, B. KOSZALKA, and J. LENHARD*.
Glaxo Wellcome Inc., Res. Triangle Park, NC Objective: To determine the effects of HIV protease inhibitors on the synthesis and secretion of lipids in the human hepatoma cell line HepG2.
Methods: HepG2 cells were treated for 24 hrs with varying doses (0.1-10 uM) of amprenavir, indinavir, nelfinavir, saquinavir and ritonavir. Cells were then labeled with [14C]acetate and the incorporation of radiolabel into cellular and secreted fatty acids, triglycerides, cholesterol and cholesteryl esters was determined by HPLC analysis.
Results: Nelfinavir produced a concentration-dependent increase in the synthesis and secretion of triglycerides derived from [14C]acetate (maximal 2.5-fold increase in cellular triglycerides at 10 uM nelfinavir). Synthesis of fatty acids, cholesterol and cholesteryl esters remained unchanged. Ritonavir showed a similar, but somewhat weaker effect, increasing triglyceride synthesis 38% at 10 uM. Amprenavir, indinavir and saquinavir had no effect on lipid synthesis.
Conclusion: Treatment with certain HIV protease inhibitors is often accompanied by elevations in serum triglycerides and cholesterol. Among the drugs used, ritonavir, the combination ritonavir/saquinavir and nelfinavir are often associated with increases in both triglyceride and cholesterol levels. In HepG2 cells, ritonavir and nelfinavir significantly increased the synthesis and secretion of triglycerides. Stimulation of triglyceride synthesis and secretion in hepatic cells may, in part, explain the elevation in serum triglycerides observed with protease inhibitor therapy.
Key Words: liver, protease inhibitors, triglycerides
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