The HIV protease inhibitor ritonavir increases lipoprotein production and has no effect on lipoprotein clearance in mice

This study examined the effect of human im- munodeficiency virus (HIV) protease inhibitor therapy on lipoprotein production and catabolism in vivo. The HIV protease inhibitor ritonavir was given to C57BL/6 mice fed either a basal low-fat diet or a Western type high-fat diet. Fasted mice were injected with Triton WR1339 fol- lowed by hourly blood collection to monitor lipoprotein production. Results showed that ritonavir increased VLDL triglyceride production by 30% over a 4 h period when mice were fed the low-fat basal diet. The ritonavir effect was more pronounced under high-fat feeding conditions, with a 2-fold increase in VLDL triglyceride production rate. Ritonavir did not alter hepatic expression levels of diacylglycerol acyltransferase or microsomal triglyceride transfer protein, but increased hepatic apolipoprotein B (apoB) secretion rates under both low- and high-fat di- etary conditions. In contrast to its effect on lipoprotein production, ritonavir did not alter triglyceride-rich lipo- protein clearance from circulation under either dietary condition. Taken together, these results indicate that the hyperlipidemic effect of HIV protease inhibitors is a direct result of increased hepatic lipoprotein production. The mechanism appears to be related to their role in pre- venting proteasome-mediated degradation of apoB and activated sterol regulatory element binding proteins in the liver. —Riddle, T. M., N. M. Schildmeyer, C. Phan, C. J. Fichtenbaum, and D. Y. Hui. The HIV protease inhibitor ritonavir increases lipoprotein production and has no ef- fect on lipoprotein clearance in mice. J. Lipid Res. 2002. 43: 1458-1463.