Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact

Issue highlight: February 7, 2019

Mechanisms of quetiapine-induced hyperlipidemia

Published February 7, 2019, by Journal staff

Issue highlight

Related articles

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.
View: Text | PDF
Research Article Endocrinology Metabolism

The atypical antipsychotic quetiapine induces hyperlipidemia by activating intestinal PXR signaling

  • Text
  • PDF
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

×
Advertisement

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts