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

Abstract

Background & Aims:The most prescribed non-nucleoside reverse transcriptase inhibitor efavirenz has been associated with elevated risk for dyslipidemia and hepatic steatosis in HIVinfected 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

The atypical antipsychotic quetiapine induces hyperlipidemia by activating intestinal PXR signaling

“…PXR is expressed at high levels in both liver and intestine, which are essential for whole-body lipid homeostasis. To define the tissue-specific role of PXR in xenobiotic and lipid metabolism, we have recently successfully generated hepatocyte-specific PXR-deficient mice (termed as PXR ΔHep ) by crossing mice carrying PXR flox alleles (PXR fl/fl ) with Albumin-Cre transgenic mice (29). For the current study, PXR fl/fl mice were also crossed with Villin-Cre transgenic mice to generate intestinal epithelial cell-specific (IEC-specific) PXR-deficient mice (PXR ΔIEC ) (Supplemental Figure 1A; supplemental material available online with this article; https://doi.org/10.1172/jci.insight.125657DS1).…”

“…Animals. Mice carrying PXR flox alleles (PXR fl/fl ) on C57BL/6 background were generated by using mouse embryonic stem cell clones containing conditional PXR flox allele from International Knockout Mouse Consortium (EUMMCR, EPD0141_1_G04) (29). PXR fl/fl mice were further crossed with Villin-Cre (The Jackson Laboratory; catalog 004586) or Albumin-Cre transgenic mice (The Jackson Laboratory; catalog 003574) to generate PXR ΔIEC or PXR ΔHep .…”

Gene Expression Profiling Reveals that PXR Activation Inhibits Hepatic PPARα Activity and Decreases FGF21 Secretion in Male C57Bl6/J Mice

“…However, its role in the regulation of cholesterol homeostasis is more controversial. The anti-HIV drug Efavirenz has been recently shown to induce steatosis and hypercholesterolemia, an effect that was absent in a model of hepatic deletion of PXR [12]. These perturbations were mediated through increased fatty acid transport and cholesterol synthesis, via the PXR-dependent regulation of Cd36 and Sqle .…”

“…However, the mechanisms by which PXR activation induces perturbations of lipid metabolism are not fully elucidated. Recently, it was shown that the activation of intestinal PXR signaling induced dyslipidemia and intestinal cholesterol accumulation [11], while activation of hepatic PXR signaling was sufficient to promote hypercholesterolemia and hepatic lipid accumulation [12].…”

New Drugs for NASH and HIV Infection: Great Expectations for a Great Need

“…A recent preclinical model has shown a putative mechanism linking efavirenz to the development of steatosis through pregnane X receptor activation and the disruption of fatty acid transport and cholesterol biosynthesis. ( 24 )…”