# Role of PXR in drug-elicited cardiovascular disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2024 · $697,761

## Abstract

Project Summary
Antipsychotic therapy is widely used in the treatment of psychiatric conditions including bipolar disorder,
schizophrenia, and major depressive disorder. These conditions, which together affect more than 20% of the
population, usually require lifelong medication. Atypical antipsychotics have superior therapeutic action and
reduced adverse effects as compared with typical antipsychotics, but the use of atypical antipsychotics is also
associated with dyslipidemia and an increased risk of cardiovascular disease (CVD) in patients. The underlying
mechanisms responsible for these adverse effects remain largely unknown, which poses serious health
challenges to patients undergoing long-term antipsychotic treatment. To this end, we recently identified several
atypical antipsychotics including quetiapine that promote dyslipidemia, as potent agonists for the nuclear
receptor pregnane X receptor (PXR). Our previous work revealed novel and unsuspected roles of PXR in lipid
homeostasis and atherogenesis, and showed that PXR ligands increase dyslipidemia and atherosclerosis in
atherogenic mouse models including PXR-humanized mice. Given intestine and lymphatic systems are
essential for dietary lipid absorption and transport, our latest preliminary study using novel tissue-specific PXR
knockout mouse models demonstrated that exposure to quetiapine fails to cause hyperlipidemia in intestine-
specific PXR knockout mice. How PXR signaling in enterocytes regulates the intestinal lipid metabolism is an
open and highly clinically relevant question. Furthermore, our pilot study revealed that ablation of PXR blunts
VEGF receptor 3 signaling in lymphatic endothelial cells and reduces lymphatic button junction formation in
lacteals of PXR-deficient mice. It is completely unknow how lymphatic PXR regulates lipid absorption and
transport by gut lymphatic vessels. To unveil the aforementioned central mystery and to study the action mode
of PXR in mediating antipsychotic-elicited adverse effects on lipid homeostasis and atherosclerosis, we
propose the following specific aims to determine the molecular mechanisms of the atherogenic effects of
atypical antipsychotics: 1) Define the enterocyte signaling through which PXR-activating antipsychotics
regulate lipid homeostasis and atherosclerosis; 2) Determine the molecular mechanisms underlying PXR-
regulated lymphatic lipid absorption and transport in atherosclerosis; and 3) Investigate the therapeutic
potential of a naturally occurring PXR antagonist in preventing antipsychotic-induced dyslipidemia and
atherosclerosis. Successful completion of the proposed work will fill in the void in uncovering novel molecular
mechanisms underlying antipsychotic therapy-associated CVD risk. Our findings may also inaugurate new
class of therapeutic strategies to treat dyslipidemia in patients undergoing long-term antipsychotic therapy.

## Key facts

- **NIH application ID:** 10754955
- **Project number:** 5R01HL167206-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA RIVERSIDE
- **Principal Investigator:** Hong Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $697,761
- **Award type:** 5
- **Project period:** 2022-12-15 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10754955

## Citation

> US National Institutes of Health, RePORTER application 10754955, Role of PXR in drug-elicited cardiovascular disease (5R01HL167206-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10754955. Licensed CC0.

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