Sulforaphane Attenuates Antipsychotic-Elicited Hypercholesterolemia Through Inhibition of Pregnane X Receptor

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.