Non-nucleoside reverse transcriptase inhibitor efavirenz activates PXR to induce hypercholesterolemia and hepatic steatosis.

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.

Methods: 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.

Results: 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.

Conclusions: 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.

Lay Summary: 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.