Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA.
Department of Medicine, University of Kentucky, Lexington, KY, USA.
J Hepatol. 2019 May;70(5):930-940. doi: 10.1016/j.jhep.2018.12.038. Epub 2019 Jan 21.
BACKGROUND & AIMS: The most prescribed non-nucleoside reverse transcriptase inhibitor, efavirenz, has been associated with elevated risk of dyslipidemia and hepatic steatosis in HIV-infected patients but the underlying mechanisms remain elusive. Herein, we investigated the role of pregnane X receptor (PXR) in mediating the adverse effects of efavirenz on lipid homeostasis.
Cell-based reporter assays, primary cell culture, and multiple mouse models including conditional knockout and humanized mice were combined to study the impact of efavirenz on PXR activities and lipid homeostasis in vitro and in vivo. A novel liver-specific Pxr knockout mouse model was also generated to determine the contribution of hepatic PXR signaling to efavirenz-elicited dyslipidemia and hepatic steatosis.
We found that efavirenz is a potent PXR-selective agonist that can efficiently activate PXR and induce its target gene expression in vitro and in vivo. Treatment with efavirenz-induced hypercholesterolemia and hepatic steatosis in mice but deficiency of hepatic PXR abolished these adverse effects. Interestingly, efavirenz-mediated PXR activation regulated the expression of several key hepatic lipogenic genes including fatty acid transporter CD36 and cholesterol biosynthesis enzyme squalene epoxidase (SQLE), leading to increased lipid uptake and cholesterol biosynthesis in hepatic cells. While CD36 is a known PXR target gene, we identified a DR-2-type of PXR-response element in the SQLE promoter and established SQLE as a direct transcriptional target of PXR. Since PXR exhibits considerable differences in its pharmacology across species, we also confirmed these findings in PXR-humanized mice and human primary hepatocytes.
The widely prescribed antiretroviral drug efavirenz induces hypercholesterolemia and hepatic steatosis by activating PXR signaling. Activation of PXR should be taken into consideration for patients undergoing long-term treatment with PXR agonistic antiretroviral drugs.
Efavirenz is widely prescribed for HIV-infected patients but has some side effects. It can increase lipid levels in patients' blood and liver. Here we show that efavirenz can activate a unique liver protein called PXR which mediates the adverse effects of efavirenz on lipid levels in mouse models.
最常被开具的非核苷类逆转录酶抑制剂依非韦伦与 HIV 感染患者的血脂异常和肝脂肪变性风险升高相关，但潜在机制仍不清楚。在此，我们研究了孕烷 X 受体（PXR）在介导依非韦伦对脂质稳态的不良影响中的作用。
采用基于细胞的报告基因检测、原代细胞培养以及包括条件性敲除和人源化小鼠在内的多种小鼠模型，研究依非韦伦对 PXR 活性和体内外脂质稳态的影响。还生成了一种新型肝特异性 Pxr 敲除小鼠模型，以确定肝 PXR 信号对依非韦伦引起的血脂异常和肝脂肪变性的贡献。
我们发现依非韦伦是一种强效的 PXR 选择性激动剂，可在体外和体内有效激活 PXR 并诱导其靶基因表达。依非韦伦治疗可诱导小鼠出现高胆固醇血症和肝脂肪变性，但肝 PXR 缺失则消除了这些不良影响。有趣的是，依非韦伦介导的 PXR 激活调节了几种关键的肝内源性脂质生成基因的表达，包括脂肪酸转运蛋白 CD36 和胆固醇生物合成酶鲨烯环氧化酶（SQLE），导致肝细胞内脂质摄取和胆固醇生物合成增加。虽然 CD36 是已知的 PXR 靶基因，但我们在 SQLE 启动子中鉴定出了一种 DR-2 型 PXR 反应元件，并将 SQLE 确立为 PXR 的直接转录靶标。由于 PXR 在不同物种中的药理学存在显著差异，我们还在 PXR 人源化小鼠和人原代肝细胞中证实了这些发现。
广泛应用于 HIV 感染患者的抗逆转录病毒药物依非韦伦通过激活 PXR 信号诱导高胆固醇血症和肝脂肪变性。对于长期接受 PXR 激动性抗逆转录病毒药物治疗的患者，应考虑 PXR 激活的作用。
依非韦伦常用于治疗感染 HIV 的患者，但有一些副作用。它会增加患者血液和肝脏中的脂质水平。在这里，我们发现依非韦伦可以激活一种名为 PXR 的独特肝脏蛋白，这种蛋白介导了依非韦伦对脂质水平的不良影响。
