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A more recent version of this article appeared on October 1, 2003

Papers In Press, published online ahead of print July 1, 2003
J. Lipid Res., doi:10.1194/jlr.M200487-JLR200
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Submitted on December 26, 2002
Revised on June 9, 2003
Accepted on June 27, 2003

Modulation of the LDL receptor and LRP levels by HIV protease inhibitors

Huan Tran, Susan Robinson, Irina Mikhailenko, and Dudley K. Strickland

Department of Vascular Biology, J. Holland Laboratory, American Red Cross, Rockville, MD 20855

Corresponding Author: strickla{at}usa.redcross.org

Inhibitors of the HIV-1 protease have proven to be effective anti-retroviral drugs. However, patients receiving HIV protease inhibitors develop serious metabolic abnormalities characterized by a peripheral lipodystrophy syndrome, insulin resistance, hypertriglyceridemia, and hypercholesterolemia resulting from elevated LDL levels. The objective of the present study was to identify mechanisms by which HIV protease inhibitors increase plasma cholesterol levels. Plasma LDL levels are regulated by a balance between biosynthetic and clearance pathways which involves removal of LDL from the plasma mediated by the hepatic LDL receptor. We hypothesized that HIV protease inhibitors may effect gene regulation of certain LDL receptor family members. 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 the LDL receptor and other LDL receptor family members. Our results demonstrate that one of these drugs, Nelfinavir significantly decreases LDL receptor and the LDL receptor-related protein (LRP) mRNA and protein levels, resulting in reduced functional activity of these two receptors. Nelfinavir exerts its effect by reducing levels of active SREBP1 in the nucleus. The findings that Nelfinavir reduces the levels of two key receptors (LRP and LDL receptor) involved in lipoprotein catabolism and maintenance of vessel wall integrity identifies a mechanism causing hypercholesterolemia complications present in HIV patients treated with this drug and raises concerns about the atherogenic nature of Nelfinavir.


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