Vitamin D Receptor Activation Attenuates Olanzapine‐Induced Dyslipidemia in Mice Through Alleviating Hepatic Endoplasmic Reticulum Stress

Abstract

The involvement of vitamin D (VD) signaling in atypical antipsychotics (AAPs)‐induced metabolic disturbances has been previously established. This study aims to elucidate the role of VD in maintaining endoplasmic reticulum (ER) homeostasis and its impact on AAPs‐induced metabolic adverse effects. Female C57BL/6 mice receive either calcitriol or vehicle one week prior to co‐treatment with olanzapine (OLZ) for an additional four weeks. Metabolic parameters, hepatic ER homeostasis, and the SREBPs pathway are assessed through biochemical assays and protein expression profiling. HepG2 cells are transfected with vitamin D receptor (VDR) siRNA for VDR knockdown. OLZ‐treated HepG2 cells are exposed to calcitriol to examine its effects on SREBPs and the unfolded protein response (UPR) pathways. VDR activation by calcitriol reduces OLZ‐induced hepatic ER stress, leading to decreased SREBPs activity and lipid accumulation. Conversely, the knockdown of VDR in HepG2 cells diminishes the protective effects of calcitriol against OLZ‐induced ER stress and SREBPs activation. This resulted in sustained UPR activation, elevated cleaved SREBPs levels, and increased lipid accumulation. These findings highlight an essential role of VDR signaling in the beneficial effects of VD on OLZ‐induced metabolic side effects. Targeting VDR to resolve ER stress is likely an applicable therapeutic strategy for AAPs‐induced metabolic disturbances.