基于SERCA对内质网稳态的调控探讨维生素D缓解非典型抗精神病药致脂质代谢紊乱的机制研究

Atypical antipsychotics（AAPs）have serious metabolic side effects, which greatly limit its long-term use. Vitamin D (VD) deficiency is widely prevalent in patients with schizophrenia (SCZ), VD not only regulate the calcium and phosphorus homeostasis, but also involve in the glucose and lipid metabolism. In our previous work, we found that the genetic polymorphisms of VDR are associated with the metabolic changes caused by risperidone treatment. Subsequently, we further demonstrated that VD deficiency exacerbates AAPs-induced metabolic side effects in rats. Intriguingly, recent research indicates that the AAPs-induced lipogenesis is tightly linked to the hepatic intracellular Ca2+ imbalance and endoplasmic reticulum (ER) stress, whereas VD can enhance SERCA expression and mitigate AAPs-induced ER stress. Based on these findings, it is tempting to hypothesize that the beneficial effect of VD on AAPs-induced lipogenesis is through its modulating effect on SERCA and ER stress. To test this hypothesis, we plan to use the VD deficient rats, which were subsequently administrated with AAPs, and explore the effects of VD on AAPs-induced lipogenesis and ER stress. Finally, we will confirm the role of SERCA in the alleviating action of VD on AAPs-induced metabolic side effects. This project will shed novel insight into the pathological mechanisms and preventive strategies for the AAPs-induced dysregulation of lipid metabolism.

非典型抗精神病药（AAPs）严重的代谢不良反应是限制其长期使用的主要原因。精神分裂症（SCZ）患者普遍伴随维生素D（VD）的缺乏, 而VD不仅影响着钙磷稳态，也参与调控糖脂代谢。前期我们发现VDR基因多态性与AAPs引起的脂代谢紊乱有关，随后进一步证实VD缺乏加剧了AAPs引起的代谢异常。研究表明AAPs诱导的脂质生成与肝细胞Ca2+失衡及由此导致的内质网应激有关，而VD能够调节内质网Ca2+-ATP酶（SERCA），缓解内质网应激。据此我们推测VD可能通过SERCA缓解内质网应激，进而影响AAPs引起的脂质代谢异常。为验证该假说，我们拟建立VD缺乏及补充的大鼠模型，随后长期给予AAPs干预，分析VD水平对脂代谢、内质网应激的影响，并在整体和细胞水平确证SERCA在VD调节AAPs引起的内质网应激及代谢紊乱中的作用，以期为进一步阐明AAPs致脂质代谢异常的机制及防治策略提供新的思路。

非典型抗精神病药（AAPs）严重的代谢不良反应是限制其长期使用的主要原因。精神分裂症（SCZ）患者普遍伴随维生素D（VD）的缺乏。我们前期的研究证实VD缺乏加剧了AAPs引起的代谢异常，而补充VD能够改善AAPs引起的代谢不良反应，提示VD可能是防治AAPs引起的代谢不良反应的新策略。本课题研究发现AAPs显著抑制了SERCA表达并诱导了内质网应激，而补充VD则抑制了AAPs诱导的内质网应激。体外应用SERCA激活剂CDN1163同样能够缓解AAPs诱导的内质网应激并下调脂质合成基因表达。这些结果提示VD很可能通过缓解内质网应激改善AAPs引起的脂质代谢异常。我们进一步利用体内、外模型验证了1,25(OH)2D3对于改善奥氮平（OLZ）引起的代谢不良反应的有效性。体外应用siRNA抑制VDR表达发现，抑制VDR表达后1,25(OH)2D3对OLZ诱导的SREBP及下游脂质合成靶基因蛋白的抑制作用显著降低。此外，1,25(OH)2D3能够在体内、外均抑制OLZ诱导的肝细胞内质网应激，而抑制VDR表达后，1,25(OH)2D3缓解内质网应激的作用明显降低。这些结果表明，1,25(OH)2D3通过VDR调节肝细胞内质网应激，进而缓解OLZ引起脂质代谢紊乱。以上研究结果对于阐明AAPs致脂质代谢异常的机制及防治靶点提供新的思路和理论依据。