title: Modulation of the LDL receptor and LRP levels by HIV protease inhibitors.
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.
authors.affiliation: Department of Vascular Biology, Jerome H. Holland Laboratories, American Red Cross, Rockville, MD 20855, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Tran
authors.forename: Susan
authors.initials: S
authors.lastname: Robinson
authors.forename: Irina
authors.initials: I
authors.lastname: Mikhailenko
authors.forename: Dudley K
authors.initials: DK
authors.lastname: Strickland
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D008074:Lipoproteins / Q000097:blood / Q000378:metabolism; D019888:Nelfinavir / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D017320:HIV Protease Inhibitors; D008074:Lipoproteins; D012333:RNA, Messenger; D011973:Receptors, LDL; C497387:SREBF1 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D002784:Cholesterol; D019888:Nelfinavir