Department of Endocrinology, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong Province, China.
Guangdong Provincial Key Laboratory of Biomedical Imaging and Guangdong Provincial Engineering Research Center of Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-Sen University, Zhuhai, Guangdong Province, China.
Mol Imaging Biol. 2022 Dec;24(6):909-919. doi: 10.1007/s11307-022-01740-2. Epub 2022 Jun 15.
Sigma-1 receptor (Sig-1R), a chaperone that resides at the mitochondrion-associated endoplasmic reticulum (ER) membrane, is an ER stress biomarker. It is thought that ER stress plays a critical role in the progression of metabolic-associated fatty liver disease (MAFLD). The aim of this study was to evaluate a positron emission tomography (PET) tracer [F]F-TZ3108 targeting Sig-1R for MAFLD.
The mouse model of MAFLD was established by feeding high-fat diet (HFD) for 12 weeks. Dynamic (0-60 min) PET/CT scans were performed after intravenous injection of 2-deoxy-2[F]fluoro-D-glucose ([F]-FDG) and [F]F-TZ3108. Tracer kinetic modeling was performed for quantification of the PET/CT imaging of the liver. Post-PET biodistribution, the liver tissue western blotting (WB), and immunofluorescence (IF) were performed to compare the expression of Sig-1R levels in the organs harvested from both MAFLD and age-matched control mice.
The micro PET/CT imaging revealed a significantly decreased uptake of [F]F-TZ3108 in the livers of the MAFLD group compared to the healthy controls, while the uptake of [F]-FDG in the livers was not significantly different between the two groups. Based on the tracer kinetic modeling, the binding disassociate rate (k) for [F]F-TZ3108 was significantly increased in MAFLD group compared to healthy controls. The volume distribution (V), and the non-displacement binding potential (BP) revealed significantly decrease in MAFLD compared to healthy controls respectively. The post-PET biodistribution (%ID/g) of [F]F-TZ3108 in the livers of MAFLD mice was significantly reduced nearly twofold than that in the livers of control mice. WB and IF experiments further confirmed the reduction of Sig-1R expression in the MAFLD group.
The expression of Sig-1R in the liver, measured by the PET tracer, [F]F-TZ3108, was significantly decreased in mouse model of MAFLD. The [F]F-TZ3108 PET/CT imaging may provide a novel means of visualization for ER stress in MAFLD or other diseases in vivo.
西格玛-1 受体（Sig-1R）是一种驻留在线粒体相关内质网（ER）膜上的伴侣蛋白，是 ER 应激的生物标志物。人们认为 ER 应激在代谢相关脂肪性肝病（MAFLD）的进展中起着关键作用。本研究旨在评估一种针对 MAFLD 的正电子发射断层扫描（PET）示踪剂 [F]F-TZ3108。
通过喂养高脂肪饮食（HFD）12 周建立 MAFLD 小鼠模型。在静脉注射 2-脱氧-2[F]氟-D-葡萄糖（[F]-FDG）和 [F]F-TZ3108 后进行动态（0-60 分钟）PET/CT 扫描。对肝脏的 PET/CT 成像进行示踪动力学建模，以定量分析。在 PET 后进行生物分布，对从 MAFLD 和年龄匹配的对照组小鼠中采集的器官进行肝脏组织的 Western blot（WB）和免疫荧光（IF），以比较 Sig-1R 水平的表达。
微 PET/CT 成像显示，与健康对照组相比，MAFLD 组肝脏对 [F]F-TZ3108 的摄取明显减少，而两组肝脏对 [F]-FDG 的摄取无明显差异。基于示踪动力学建模，与健康对照组相比，MAFLD 组 [F]F-TZ3108 的结合解离率（k）显著增加。与健康对照组相比，MAFLD 组的容积分布（V）和非置换结合潜能（BP）分别显著降低。MAFLD 小鼠肝脏的 [F]F-TZ3108 后 PET 生物分布（%ID/g）比对照组小鼠肝脏减少近两倍。WB 和 IF 实验进一步证实了 MAFLD 组 Sig-1R 表达减少。
通过 PET 示踪剂 [F]F-TZ3108 测量的 MAFLD 小鼠肝脏中 Sig-1R 的表达明显降低。[F]F-TZ3108 PET/CT 成像可能为 MAFLD 或其他疾病的体内 ER 应激提供一种新的可视化方法。
