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Journal of Lipid Research, Vol. 43, 1458-1463, September 2002
Copyright © 2002 by Lipid Research, Inc.

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

Tara M. Riddle, Nicholas M. Schildmeyer, Cam Phan, Carl J. Fichtenbaum and David Y. Hui¹

Center for Lipid and Arteriosclerosis Studies, Departments of Pathology and Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH

¹ To whom correspondence should be addressed. e-mail: huidy{at}email.uc.edu

This study examined the effect of human immunodeficiency 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 followed 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 dietary conditions. In contrast to its effect on lipoprotein production, ritonavir did not alter triglyceride-rich lipoprotein 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 preventing proteasome-mediated degradation of apoB and activated sterol regulatory element binding proteins in the liver.

Abbreviations: HIV, human immunodeficiency virus; MTP, microsomal triglyceride transfer protein; SREBP, sterol regulatory element binding protein

Supplementary key words anti-retroviral therapy • very low density lipoprotein synthesis • apolipoprotein B • high-fat diet

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