Pregnane X Receptor Mediates Dyslipidemia Induced by the HIV Protease Inhibitor Amprenavir in Mices
Pregnane X Receptor Mediates Dyslipidemia Induced by the HIV Protease Inhibitor Amprenavir in Mices
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DOI：
10.1124/mol.113.085753
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发表时间：
2013-06-01
影响因子：
3.6
通讯作者：
Zhou, Changcheng
中科院分区：
文献类型：
--
作者：
Helsley, Robert N.;Sui, Yipeng;Zhou, Changcheng
人类免疫缺陷病毒（HIV）蛋白酶抑制剂（PI）已成功用于延长HIV感染者的寿命。PI的使用也与血脂异常和心血管疾病风险增加有关，但潜在的机制仍然难以捉摸。几种PI涉及激活核受体异戊烷X受体（PXR），其作为外源性生物质传感器调节肝脏和肠道中的外源性生物质代谢。最近的研究表明，PXR也可能在调节脂质稳态中发挥重要作用。在本研究中，我们确定安普那韦，一种广泛使用的HIV PI，作为一种有效的PXR选择性激动剂。结合定点诱变的计算对接研究确定了PXR配体结合口袋内的几个关键残基，这些残基构成了与安普那韦的相互作用点。安普那韦在体外和体内有效激活PXR并诱导PXR靶基因表达。短期暴露于安普那韦显著增加野生型小鼠的血浆总胆固醇和致动脉粥样硬化低密度脂蛋白胆固醇水平，但在PXR缺陷小鼠中没有。安普那韦介导的PXR激活刺激了几个关键的肠道基因参与脂质稳态的表达。这些发现为理解PI对心血管疾病的影响提供了重要的机制见解，并证明了PXR在介导人类HIV PI的不良反应中的潜在作用。
Human immunodeficiency virus (HIV) protease inhibitors (PIs) have been used successfully in extending the life span of people infected with HIV. The use of PIs has also been associated with dyslipidemia and an increased risk of cardiovascular disease, but the underlying mechanisms remain elusive. Several PIs have been implicated in activating the nuclear receptor pregnane X receptor (PXR), which acts as a xenobiotic sensor to regulate xenobiotic metabolism in the liver and intestine. Recent studies indicate that PXR may also play an important role in the regulation of lipid homeostasis. In the present study, we identified amprenavir, a widely used HIV PI, as a potent PXR-selective agonist. Computational docking studies combined with site-direct mutagenesis identified several key residues within the ligand-binding pocket of PXR that constitute points of interaction with amprenavir. Amprenavir efficiently activated PXR and induced PXR target gene expression in vitro and in vivo. Short-term exposure to amprenavir significantly increased plasma total cholesterol and atherogenic low-density lipoprotein cholesterol levels in wild-type mice, but not in PXR-deficient mice. Amprenavir-mediated PXR activation stimulated the expression of several key intestinal genes involved in lipid homeostasis. These findings provide critical mechanistic insight for understanding the impact of PIs on cardiovascular disease and demonstrate a potential role of PXR in mediating the adverse effects of HIV PIs in humans.