Abstract
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.
Highlights
This study examined the effect of human immunodeficiency virus (HIV) protease inhibitor therapy on lipoprotein production and catabolism in vivo
In agreement with results reported previously, treatment of chow-fed mice with ritonavir resulted in an average 30% increase in serum cholesterol and triglyceride levels compared with vehicle-treated controls, whereas there was an average 60% increase in serum cholesterol and triglyceride levels in ritonavir-treated mice when they were fed a high-fat and high-cholesterol diet
Serum was collected at hourly intervals for the measurement of triglyceride accumulation. The results of these studies showed that the amount of VLDL triglyceride produced within a 4 h period was 30% higher in the chow-fed ritonavir-treated mice compared with chowfed animals receiving only the vehicle control without the protease inhibitor (Fig. 1A)
Summary
This study examined the effect of human immunodeficiency virus (HIV) protease inhibitor therapy on lipoprotein production and catabolism in vivo. Active anti-retroviral therapy for human immunodeficiency virus (HIV)-infected patients has proven to be effective in reducing the morbidity and mortality of AIDS [1, 2] In HIV subjects, indinavir treatment causes only mild hypercholesterolemia, and hypertriglyceridemia is less common [10] Both serum cholesterol and triglyceride levels are dramatically elevated in ritonavir-treated seronegative and HIV-positive patients [10, 11]. These observations suggest that the various protease inhibitors may affect plasma lipid levels through different mechanisms.
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