Abstract
Inhibitors of the human immunodeficiency virus (HIV)-1 protease have proven to be effective antiretroviral drugs. However, patients receiving these drugs develop serious metabolic abnormalities, including hypercholesterolemia. The objective of the present study was to identify mechanisms by which HIV protease inhibitors increase plasma cholesterol levels. We hypothesized that HIV protease inhibitors may affect gene regulation of certain LDL receptor (LDLR) family members, thereby altering the catabolism of cholesterol-containing lipoproteins. In this present study we investigated the effect of several HIV protease inhibitors (ABT-378, Amprenavir, Indinavir, Nelfinavir, Ritonavir, and Saquinavir) on mRNA, protein, and functional levels of LDLR family members. Our results demonstrate that one of these drugs, Nelfinavir, significantly decreases LDLR and LDLR-related protein (LRP) mRNA and protein levels, resulting in the reduced functional activity of these two receptors. Nelfinavir exerts its effect by reducing levels of active SREBP1 in the nucleus. The finding that Nelfinavir reduces the levels of two key receptors (LRP and LDLR) involved in lipoprotein catabolism and maintenance of vessel wall integrity identifies a mechanism that causes hypercholesterolemia complications in HIV patients treated with this drug and raises concerns about the atherogenic nature of Nelfinavir.
Highlights
Inhibitors of the human immunodeficiency virus (HIV)-1 protease have proven to be effective antiretroviral drugs
These results reveal that various HIV protease inhibitors differentially regulate sterol-regulatory element binding protein (SREBP) activation, consistent with recent reports showing accumulation of activated SREBP-1 in the liver of mice given Ritonavir [15], and decreased levels of cleaved SREBP-1 in Nelfinavir-treated 3T3-L1 cells induced to differentiate, when compared with untreated cells [18]
These protease inhibitors do not appear to be precise in their cellular targets, and therapy is associated with a variety of metabolic disorders, which include hypercholesterolemia, hypertriglyceridemia, insulin resistance, and a peripheral lipodystrophy syndrome [2, 5, 7, 52,53,54]
Summary
Inhibitors of the human immunodeficiency virus (HIV)-1 protease have proven to be effective antiretroviral drugs. We hypothesized that HIV protease inhibitors may affect gene regulation of certain LDL receptor (LDLR) family members, thereby altering the catabolism of cholesterol-containing lipoproteins In this present study we investigated the effect of several HIV protease inhibitors (ABT-378, Amprenavir, Indinavir, Nelfinavir, Ritonavir, and Saquinavir) on mRNA, protein, and functional levels of LDLR family members. Liang et al [13] found that high levels of Ritonavir and Saquinavir protect apolipoprotein B (apoB) from proteosomal-mediated degradation resulting in increased apoB secretion, while Lenhard et al [14] noted that HIV protease inhibitors stimulated triglyceride synthesis [14] In support of these cell-based studies, Riddle et al [15] found that mice treated with Ritonavir showed an increase in fatty acid and sterol biosynthesis. Individuals with defects in the LDLR have excessively high plasma cholesterol levels that result in the development of atherosclerotic lesions and coronary artery disease [12, 25]
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