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The atypical antipsychotic quetiapine induces hyperlipidemia by activating intestinal PXR signaling
Zhaojie Meng, … , Xiangping Zhou, Changcheng Zhou
Zhaojie Meng, … , Xiangping Zhou, Changcheng Zhou
Published February 7, 2019
Citation Information: JCI Insight. 2019;4(3):e125657. https://doi.org/10.1172/jci.insight.125657.
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Research Article Endocrinology Metabolism

The atypical antipsychotic quetiapine induces hyperlipidemia by activating intestinal PXR signaling

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Abstract

Quetiapine, one of the most prescribed atypical antipsychotics, has been associated with hyperlipidemia and an increased risk for cardiovascular disease in patients, but the underlying mechanisms remain unknown. Here, we identified quetiapine as a potent and selective agonist for pregnane X receptor (PXR), a key nuclear receptor that regulates xenobiotic metabolism in the liver and intestine. Recent studies have indicated that PXR also plays an important role in lipid homeostasis. We generated potentially novel tissue-specific PXR-KO mice and demonstrated that quetiapine induced hyperlipidemia by activating intestinal PXR signaling. Quetiapine-mediated PXR activation stimulated the intestinal expression of cholesterol transporter Niemann-Pick C1-Like 1 (NPC1L1) and microsomal triglyceride transfer protein (MTP), leading to increased intestinal lipid absorption. While NPC1L1 is a known PXR target gene, we identified a DR-1–type PXR-response element in the MTP promoter and established MTP as a potentially novel transcriptional target of PXR. Quetiapine’s effects on PXR-mediated gene expression and cholesterol uptake were also confirmed in cultured murine enteroids and human intestinal cells. Our findings suggest a potential role of PXR in mediating adverse effects of quetiapine in humans and provide mechanistic insights for certain atypical antipsychotic-associated dyslipidemia.

Authors

Zhaojie Meng, Taesik Gwag, Yipeng Sui, Se-Hyung Park, Xiangping Zhou, Changcheng Zhou

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Figure 6

MTP is a transcriptional target of PXR.

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MTP is a transcriptional target of PXR.
(A) Putative MTP DR-1 promoter s...
(A) Putative MTP DR-1 promoter sequences in different species. (B and C) In vitro translated human PXR and RXR proteins were incubated with [32P]-labeled MTP/DR-1 probes for EMSA analysis. (B) PXR/RXR proteins were incubated with [32P]-labeled WT MTP/DR-1 probes for EMSA analysis. (C) PXR/RXR proteins were incubated with [32P]-labeled WT or mutated MTP/DR-1 probes for EMSA analysis (left panel). PXR/RXR proteins were incubated with 2 different anti-PXR antibodies, goat anti-PXR, or rabbit anti-PXR antibodies for 1 hour prior to the addition of the WT [32P]-labeled MTP/DR-1 probes for EMSA analysis (right panel). (D and E) ChIP analysis was performed to determine the recruitment of PXR onto the MTP promoter. Intestine samples were collected from PXRfl/fl and PXRΔIEC mice after 1-week treatment of 10 mg/kg/day quetiapine (D) (n = 3). Control and PXR siRNA-treated human intestinal LS180 cells were treated with DMSO control or 10 μM quetiapine for 24 hours before ChIP analysis (E) (n = 3).

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