Department of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon, Republic of Korea.
Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Br J Pharmacol. 2024 Oct;181(19):3717-3742. doi: 10.1111/bph.16438. Epub 2024 Jun 9.
Only limited therapeutic agents have been developed for non-alcoholic steatohepatitis (NASH). Glabridin, a promising anti-obesity candidate, has only limited druggability due to its low in vivo chemical stability and bioavailability. Therefore, we developed vutiglabridin (VUTI), which is based on a glabridin backbone, and investigated its mechanism of action in treating NASH in animal models.
Anti-NASH effects of VUTI were determined in in vitro fatty liver models, spheroids of primary human hepatocytes and L02 normal liver cell lines. To identify VUTI possible cellular target/s, biotin-labelled VUTI was synthesized and underwent chemical proteomic analysis. Further, the evaluation of VUTI therapeutic efficacy was carried out using an amylin-NASH and high-fat (HF) diet-induced obese (DIO) mouse models. This was carried out using transcriptomic, lipidomic and proteomic analyses of the livers from the amylin-NASH mouse model.
VUTI treatment markedly reduces hepatic steatosis, fibrosis and inflammation by promoting lipid catabolism, activating autophagy and improving mitochondrial dysfunction, all of which are hallmarks of effective NASH treatment. The cellular target of VUTI was identified as paraoxonase 2 (PON2), a newly proposed protein target for the treatment of NASH, VUTI enhanced PON2 activity. The results using PON2 knockdown cells demonstrated that PON2 is important for VUTI- activation of autophagy, promoting mitochondrial function, decreasing oxidative stress and alleviating lipid accumulation under lipotoxic condition.
Our data demonstrated that VUTI is a promising therapeutic for NASH. Targeting PON2 may be important for improving liver function in various immune-metabolic diseases including NASH.
目前仅有有限的治疗药物被开发用于治疗非酒精性脂肪性肝炎（NASH）。由于其体内化学稳定性和生物利用度低，作为一种有前途的抗肥胖候选药物，甘草素的成药性有限。因此，我们开发了基于甘草素骨架的 vutiglabridin（VUTI），并在动物模型中研究了其治疗 NASH 的作用机制。
在体外脂肪肝模型、原代人肝细胞球体和 L02 正常肝细胞系中确定了 VUTI 的抗 NASH 作用。为了确定 VUTI 可能的细胞靶标，合成了生物素标记的 VUTI 并进行了化学蛋白质组学分析。此外，还使用淀粉样肽-NASH 和高脂肪（HF）饮食诱导肥胖（DIO）小鼠模型评估了 VUTI 的治疗效果。这是通过对淀粉样肽-NASH 小鼠模型的肝脏进行转录组、脂质组和蛋白质组分析来完成的。
VUTI 通过促进脂质分解、激活自噬和改善线粒体功能来显著减轻肝脂肪变性、纤维化和炎症，所有这些都是有效 NASH 治疗的标志。VUTI 的细胞靶标被鉴定为对氧磷酶 2（PON2），这是一种新提出的 NASH 治疗蛋白靶标，VUTI 增强了 PON2 的活性。使用 PON2 敲低细胞的结果表明，PON2 对于 VUTI 激活自噬、促进线粒体功能、减少氧化应激和缓解脂毒性条件下的脂质积累非常重要。
我们的数据表明，VUTI 是治疗 NASH 的一种有前途的药物。针对 PON2 可能对改善包括 NASH 在内的各种免疫代谢疾病的肝功能很重要。
