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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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Categories: 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 3

Quetiapine elicits hypercholesterolemia in PXRfl/fl mice but not in PXRΔIEC mice.

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Quetiapine elicits hypercholesterolemia in PXRfl/fl mice but not in PXRΔ...
(A) qPCR analysis of PXR mRNA levels in major tissues of PXRfl/fl and PXRΔIEC mice (n = 4–5, Student’s t test, *P < 0.05, ***P < 0.001). (B) Western blot analysis of PXR proteins in intestine and liver of PXRfl/fl and PXRΔIEC mice. (C–F) Eight-week-old male PXRfl/fl and PXRΔIEC littermates were treated with vehicle control or 10 mg/kg/day of quetiapine by oral gavage for 1 week. Body weight (C), fasting plasma total cholesterol (D), and triglyceride (E) levels were measured. Lipoprotein fractions (VLDL, LDL, and HDL) were isolated, and the cholesterol levels of each fraction were measured (F) (n = 6–8, 2-way ANOVA, *P < 0.05, **P < 0.01, and ***P < 0.001).
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