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Pregnane X Receptor Mediates Dyslipidemia Induced by the HIV Protease Inhibitor Amprenavir in Mice
Author(s) -
Helsley Robert Nathaniel,
Sui Yipeng,
Ai Ni,
Park SeHyung,
Welsh William J.,
Zhou Changcheng
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1169.20
Subject(s) - pregnane x receptor , amprenavir , protease , pharmacology , biology , cyp3a4 , nuclear receptor , hiv 1 protease , chemistry , cytochrome p450 , biochemistry , enzyme , transcription factor , gene
HIV protease inhibitors have been used successfully in extending the lifespan of people infected with HIV. However, the mechanisms responsible for the increased risk of dyslipidemia and cardiovascular diseases associated with the use of protease inhibitors remain elusive. Several protease inhibitors have been implicated to activate the nuclear receptor pregnane X receptor (PXR), which acts as a xenobiotic sensor to regulate xenobiotic metabolism. We recently revealed PXR's pro‐atherogenic effects in animal models and found that chronic activation of PXR induces hyperlipidemia in wild‐type mice. In the present study, we found that a widely used HIV protease inhibitor, amprenavir, is a potent agonist of PXR. Amprenavir can induce expression of PXR target genes in human hepatoma HepaRG cells and intestinal LS180 cells . In silico ligand‐PXR docking studies combined with site‐direct mutagenesis identified several key residues within PXR's ligand binding pocket that constitute points of interaction with amprenavir. Lastly, amprenvir‐induced PXR activation significantly increased atherogenic lipoprotein LDL cholesterol levels in wild‐type mice, but had no effect in PXR knockout mice. These findings provide critical mechanistic insight for understanding the impact of protease inhibitors on cardiovascular disease and demonstrate a potential role of PXR in mediating adverse effects of HIV protease inhibitors in humans. This work is supported by NIH grants T32HL072743, P30HL101300, P20GM103527 and AHA grant 09SDG2150176.