Sulforaphane Attenuates Antipsychotic-Elicited Hypercholesterolemia Through Inhibition of Pregnane X Receptor
- 1Division of Biomedical Sciences, School of Medicine, University of California, 900 University Avenue, Riverside, CA 92521, USA
- 2Vascular Biology Program, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA
- 3Department of Pharmacology and Nutritional Science, University of Kentucky, Lexington, KY 40536, USA
Abstract
Olanzapine is a widely prescribed antipsychotic that has been associated with increased risk of cardiometabolic disorders including hyperlipidemia. However, the underlying mechanisms of olanzapine’s dyslipidemic properties are poorly understood. We previously identified several clinically used drugs with dyslipidemic properties as ligands for the nuclear receptor pregnane X receptor (PXR), a key regulator of xenobiotic metabolism. Recent studies have revealed the important functions of PXR in lipid homeostasis. Here, we report that olanzapine is a potent PXR agonist that elicits hyperlipidemia through PXR signaling. Olanzapine activated PXR to stimulate key intestinal lipogenic gene expression in primary cells and in vivo. Exposure to olanzapine caused higher plasma total cholesterol and atherogenic very low-density lipoprotein (VLDL), as well as low-density lipoprotein (LDL) cholesterol levels, in mice in a PXR-dependent manner. We then explored the therapeutic potential of a previously identified human PXR antagonist, sulforaphane, and found that sulforaphane can efficiently block olanzapine-elicited PXR activation and attenuate olanzapine-elicited hypercholesterolemia in PXR-humanized mice. Our studies provide mechanistic insights for understanding the cardiovascular disease risk associated with antipsychotic olanzapine treatment in patients and demonstrate the therapeutic potential of PXR antagonists in mitigating the adverse effects of PXR agonistic drugs on cardiovascular health.
Related
- Inhibition of Panx1/P2X7R/NLRP3 Signaling Attenuates Bone Cancer Pain and Spinal Microglial Activation
- Dexmedetomidine Inhibition of GABA Neurons in the Ventral Tegmental Area Attenuates the Depth of Sedation in Mice
- Small-molecule ACOD1 inhibition attenuates colitis and tumor growth through a shared myeloid mechanism, diverging from genetic deletion
- Inhibition of spinal astrocytic GPR177 attenuates neuropathic pain by modulating C3/C3aR signaling in male rats
- Enhancer of Zeste Homolog 2 Inhibition Attenuates Atrial Fibrillation Post-Myocardial Infarction Through Reduced Atrial Fibrosis
BibTeX
@article{pan2026sulforaphane,
title = {{Sulforaphane Attenuates Antipsychotic-Elicited Hypercholesterolemia Through Inhibition of Pregnane X Receptor}},
author = {Jianfei Pan and Zhaojie Meng and Seung Hyun Park and Hong Chen and Shuxia Wang and Changcheng Zhou},
journal = {Biomolecules},
year = {2026},
month = oct,
doi = {10.3390/biom16101455},
url = {https://www.mdpi.com/2218-273X/16/10/1455},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Sulforaphane Attenuates Antipsychotic-Elicited Hypercholesterolemia Through Inhibition of Pregnane X Receptor
AU - Jianfei Pan
AU - Zhaojie Meng
AU - Seung Hyun Park
AU - Hong Chen
AU - Shuxia Wang
AU - Changcheng Zhou
PY - 2026
DA - 2026/10/01
JO - Biomolecules
DO - 10.3390/biom16101455
UR - https://www.mdpi.com/2218-273X/16/10/1455
AB - Olanzapine is a widely prescribed antipsychotic that has been associated with increased risk of cardiometabolic disorders including hyperlipidemia. However, the underlying mechanisms of olanzapine’s dyslipidemic properties are poorly understood. We previously identified several clinically used drugs with dyslipidemic properties as ligands for the nuclear receptor pregnane X receptor (PXR), a key regulator of xenobiotic metabolism. Recent studies have revealed the important functions of PXR in lipid homeostasis. Here, we report that olanzapine is a potent PXR agonist that elicits hyperlipidemia through PXR signaling. Olanzapine activated PXR to stimulate key intestinal lipogenic gene expression in primary cells and in vivo. Exposure to olanzapine caused higher plasma total cholesterol and atherogenic very low-density lipoprotein (VLDL), as well as low-density lipoprotein (LDL) cholesterol levels, in mice in a PXR-dependent manner. We then explored the therapeutic potential of a previously identified human PXR antagonist, sulforaphane, and found that sulforaphane can efficiently block olanzapine-elicited PXR activation and attenuate olanzapine-elicited hypercholesterolemia in PXR-humanized mice. Our studies provide mechanistic insights for understanding the cardiovascular disease risk associated with antipsychotic olanzapine treatment in patients and demonstrate the therapeutic potential of PXR antagonists in mitigating the adverse effects of PXR agonistic drugs on cardiovascular health.
SN - 2218-273X
ER -