Gubra, Hørsholm Kongevej 11B, DK-2970, Hørsholm, Denmark.
Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark.
Sci Rep. 2023 Dec 27;13(1):23056. doi: 10.1038/s41598-023-50328-5.
Non-alcoholic steatohepatitis (NASH) is emerging as a major cause of hepatocellular carcinoma (HCC), however, it is not resolved if compounds in late-stage clinical development for NASH may have additional therapeutic benefits in NASH-driven HCC (NASH-HCC). Here, we profiled monotherapy with semaglutide (glucagon-like-receptor-1 receptor agonist) and lanifibranor (pan-peroxisome proliferator-activated receptor agonist) in a diet-induced obese (DIO) mouse model of NASH-HCC. Disease progression was characterized in male C57BL/6 J mice fed the GAN (Gubra Amylin NASH) diet high in fat, fructose and cholesterol for 12-72 weeks (n = 15 per group). Other GAN DIO-NASH-HCC mice fed the GAN diet for 54 weeks and with biopsy-confirmed NASH (NAFLD Activity Score ≥ 5) and advanced fibrosis (stage F3) received vehicle (n = 16), semaglutide (30 nmol/kg, s.c., n = 15), or lanifibranor (30 mg/kg, p.o., n = 15) once daily for 14 weeks. GAN DIO-NASH-HCC mice demonstrated progressive NASH, fibrosis and HCC burden. Tumors presented with histological and molecular signatures of poor prognostic HCC. Consistent with clinical trial outcomes in NASH patients, both lanifibranor and semaglutide improved NASH while only lanifibranor reduced fibrosis in GAN DIO-NASH-HCC mice. Notably, only semaglutide reduced tumor burden in GAN DIO-NASH-HCC mice. In conclusion, the GAN DIO-NASH-HCC mouse is a clinical translational model of NASH-HCC. Semaglutide improves both NASH and tumor burden in GAN DIO-NASH-HCC mice, highlighting the suitability of this preclinical model for profiling novel drug therapies targeting NASH-HCC.
非酒精性脂肪性肝炎（NASH）正在成为肝细胞癌（HCC）的主要病因，但是否处于临床后期开发阶段的 NASH 化合物在 NASH 驱动的 HCC（NASH-HCC）中具有额外的治疗益处尚未确定。在这里，我们对 semaglutide（胰高血糖素样肽-1 受体激动剂）和 lanifibranor（全过氧化物酶体增殖物激活受体激动剂）单药治疗在 NASH-HCC 的饮食诱导肥胖（DIO）小鼠模型中的作用进行了分析。在 12-72 周内（每组 15 只），用高脂肪、果糖和胆固醇含量高的 GAN（Gubra Amylin NASH）饮食喂养雄性 C57BL/6J 小鼠，以研究疾病进展情况。喂养 GAN 饮食 54 周且活检证实存在 NASH（非酒精性脂肪性肝病活动评分≥5）和晚期纤维化（F3 期）的其他 GAN DIO-NASH-HCC 小鼠接受载体（n=16）、semaglutide（30 nmol/kg，皮下注射，n=15）或 lanifibranor（30 mg/kg，口服，n=15）治疗，每日 1 次，持续 14 周。GAN DIO-NASH-HCC 小鼠表现出进行性 NASH、纤维化和 HCC 负担增加。肿瘤具有不良预后 HCC 的组织学和分子特征。与 NASH 患者临床试验结果一致，lanifibranor 和 semaglutide 均改善了 NASH，而只有 lanifibranor 降低了 GAN DIO-NASH-HCC 小鼠的纤维化。值得注意的是，只有 semaglutide 降低了 GAN DIO-NASH-HCC 小鼠的肿瘤负担。总之，GAN DIO-NASH-HCC 小鼠是 NASH-HCC 的临床转化模型。Semaglutide 改善了 GAN DIO-NASH-HCC 小鼠的 NASH 和肿瘤负担，突出了该临床前模型在分析针对 NASH-HCC 的新型药物治疗方法方面的适用性。
