Higashikawa Kei, Uehara Riho, Horiguchi Sawako, Shibata Yuki, Okubo Naoto, Mizuno Yuki, Yasui Hironobu, Ohnishi Shunsuke, Takeda Hiroshi, Kuge Yuji
Central Institute of Isotope Science, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, 060-0815, Japan.
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, 060-0812, Japan.
Mol Imaging Biol. 2024 Dec;26(6):1036-1045. doi: 10.1007/s11307-024-01964-4. Epub 2024 Nov 13.
Metabolic dysfunction-associated steatotic liver disease (MASLD) comprises simple steatosis (SS), which has a low risk of mortality, and metabolic dysfunction-associated steatohepatitis (MASH), which can progress to liver cirrhosis and hepatocellular carcinoma. Because differentiation between MASH and SS is the most important issue in the diagnosis of MASLD, the establishment of noninvasive diagnostic methods is urgently needed. In this study, we evaluated the potential of [I]IIMU, a thymidine phosphorylase (TYMP) targeted SPECT imaging probe, for differential diagnosis of MASLD in a preclinical animal model.
SS and MASH mice were prepared by feeding db/db mice with a standard diet and a methionine/choline-deficient diet, respectively. Control mice were prepared by feeding m/m mice with a standard diet. TYMP expression in the liver was evaluated by RT-PCR, western blotting, and immunohistochemistry. The biodistribution of [I]IIMU in the three model mice was evaluated at 30 min post-injection. SPECT/CT imaging studies of the three model mice were performed 30 min after injection of [I]IIMU.
Hepatic TYMP expression level was the highest in the SS mice and the lowest in the MASH mice at both mRNA and protein levels. The immunohistochemistry experiment showed a patchy distribution of TYMP only in the liver of MASH mice. In the biodistribution study, the hepatic accumulation of [I]IIMU was the highest in the SS mice and the lowest in the MASH mice. The SPECT/CT imaging study showed similar results to the biodistribution experiment.
Hepatic TYMP expression level may serve as a promising imaging biomarker for differential diagnosis of SS and MASH. SPECT imaging using [I]IIMU potentially provides a novel noninvasive diagnostic method to differentiate MASH and SS.
代谢功能障碍相关脂肪性肝病（MASLD）包括死亡率较低的单纯性脂肪肝（SS）和可进展为肝硬化及肝细胞癌的代谢功能障碍相关脂肪性肝炎（MASH）。由于MASH与SS的鉴别是MASLD诊断中最重要的问题，因此迫切需要建立非侵入性诊断方法。在本研究中，我们在临床前动物模型中评估了胸苷磷酸化酶（TYMP）靶向SPECT成像探针[I]IIMU对MASLD进行鉴别诊断的潜力。
分别通过给db/db小鼠喂食标准饮食和蛋氨酸/胆碱缺乏饮食来制备SS和MASH小鼠。通过给m/m小鼠喂食标准饮食来制备对照小鼠。通过RT-PCR、蛋白质印迹和免疫组织化学评估肝脏中TYMP的表达。在注射后30分钟评估[I]IIMU在三种模型小鼠中的生物分布。在注射[I]IIMU后30分钟对三种模型小鼠进行SPECT/CT成像研究。
在mRNA和蛋白质水平上，肝脏TYMP表达水平在SS小鼠中最高，在MASH小鼠中最低。免疫组织化学实验显示TYMP仅在MASH小鼠肝脏中呈斑片状分布。在生物分布研究中，[I]IIMU在肝脏中的蓄积在SS小鼠中最高，在MASH小鼠中最低。SPECT/CT成像研究显示出与生物分布实验相似的结果。
肝脏TYMP表达水平可能是鉴别SS和MASH的一种有前景的成像生物标志物。使用[I]IIMU进行SPECT成像可能提供一种区分MASH和SS的新型非侵入性诊断方法。
