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.
Zhaojie Meng, Taesik Gwag, Yipeng Sui, Se-Hyung Park, Xiangping Zhou, Changcheng Zhou
Usage data is cumulative from March 2023 through March 2024.
Usage information is collected from two different sources: this site (JCI) and Pubmed Central (PMC). JCI information (compiled daily) shows human readership based on methods we employ to screen out robotic usage. PMC information (aggregated monthly) is also similarly screened of robotic usage.
Various methods are used to distinguish robotic usage. For example, Google automatically scans articles to add to its search index and identifies itself as robotic; other services might not clearly identify themselves as robotic, or they are new or unknown as robotic. Because this activity can be misinterpreted as human readership, data may be re-processed periodically to reflect an improved understanding of robotic activity. Because of these factors, readers should consider usage information illustrative but subject to change.