한빛사 논문
Taesik Gwag,1,a Zhaojie Meng,1,a Yipeng Sui,1 Robert N. Helsley,1,b Se-Hyung Park,1 Shuxia Wang,1 Richard N.Greenberg,2 and Changcheng Zhou1,*
1Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, USA
2Department of Medicine, University of Kentucky, Lexington, Kentucky, USA
aThese authors contributed equally to this work.
bR.N.H.’s present address is: Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
*Corresponding author: Changcheng Zhou, Ph.D., Department of Pharmacology and Nutritional Sciences, University of Kentucky, 900 South Limestone, 517 Wethington Building, Lexington, KY 40536, USA.
Abstract
Background & Aims
The most prescribed non-nucleoside reverse transcriptase inhibitor efavirenz has been associated with elevated risk for dyslipidemia and hepatic steatosis in HIV-infected patients but the underlying mechanisms remain elusive. Here 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 pharmacology differences across species, we also confirmed these findings in PXR-humanized mice and human primary hepatocytes.
Conclusions
The widely prescribed anti-retroviral 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 anti-retroviral drugs.
Keywords : HIV, anti-retroviral drugs, dyslipidemia, hepatic steatosis, pregnane X receptor, squalene epoxidase
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