西北工业大学段佳林等研究人员合作发现，竹节参皂苷IVa作为一种新型赖氨酸特异性去甲基化酶1抑制剂可改善小鼠高脂饮食诱导的MASLD。2024年11月20日，《中国药理学报》杂志在线发表了这项成果。

研究人员表示，饮食诱导的代谢功能障碍性脂肪肝疾病（MASLD），也称为非酒精性脂肪肝病（NAFLD），目前治疗策略有限。研究人员之前已经展示了来自南美草本植物的饮食皂苷竹节参皂苷IVa（CHS），其对代谢具有益处，并能减轻饮食诱导的糖尿病。

研究人员探讨了CHS对MASLD的益处及其潜在机制。研究人员通过高脂饮食（HFD）建立了MAFLD小鼠模型，持续6周后，使用CHS（50 mg/kg每天，口服）治疗另8周。通过在棕榈酸处理的HepG2细胞和原代肝细胞中进行转录组分析，以及在肝脏组织中进行脂质组分析，研究人员证明HFD激活了肠道法尼醇X受体（FXR）通路，导致FGF15/19的释放。进而促进肝脏FXR-SHP与cAMP反应元件结合蛋白H（CREBH）的结合，从而抑制CREBH介导的脂肪酸氧化（FAO）和酮体生成。

值得注意的是，研究人员发现CHS通过抑制FXR-SHP肠肝交叉作用，改善了高脂饮食小鼠的脂质代谢，增强了CREBH的转激活作用。在这些过程中，赖氨酸特异性去甲基化酶1（LSD1）介导的组蛋白去甲基化在脂质代谢重编程中起着关键作用。此外，研究人员发现LSD1是CHS的一个重要细胞靶点，CHS通过直接与LSD1的Lys661和Tyr761结合，抑制其组蛋白去甲基化活性。

这些研究结果表明，使用CHS靶向肠道LSD1可能是治疗MAFLD的有前景策略，并为天然产物的生物利用度和疗效提供了新的见解。

附：英文原文

Title: Identification of chikusetsusaponin IVa as a novel lysine-specific demethylase 1 inhibitor that ameliorates high fat diet-induced MASLD in mice

Author: Liu, Yu-wen, Luo, Ru-yue, Liu, An-qi, Wang, Jia-wei, Hu, Na-ping, Li, Wang-ting, Li, Jian-kang, Wang, Jing-wen, Duan, Jia-lin

Issue&Volume: 2024-11-20

Abstract: Diet-induced metabolic dysfunction steatotic liver disease (MASLD) is also called as non-alcoholic fatty liver disease (NAFLD) with limited effective strategies available. We previously have shown that chikusetsusaponin IVa (CHS), a dietary saponin from herbs in South American known for their metabolic benefits, mitigates diet-induced diabetes. In this study we investigated the beneficial effects of CHS on MASLD and the underlying mechanisms. MAFLD mouse model was established by the high-fat diet (HFD) for 6 weeks and then were treated with CHS (50mg·kg1·d1, i.g.) for another 8 weeks. By conducting transcriptomic analysis in palmitic acid-treated HepG2 cells and primary hepatocytes as well as lipidomic analysis in liver tissues, we demonstrated that HFD activated the intestinal farnesoid X receptor (FXR) pathway, leading to the release of FGF15/19, which in turn promoted hepatic FXR-SHP binding with cAMP-responsive element-binding protein H (CREBH), thereby inhibiting CREBH-mediated fatty acid oxidation (FAO) and ketogenesis. Intriguingly, we found that CHS improved lipid metabolism in HFD mice by suppressing the enterohepatic crosstalk of FXR-SHP to enhance CREBH transactivation. Among these, lysine-specific demethylase 1 (LSD1)-mediated histone demethylation played a crucial role in lipid metabolic reprogramming. Moreover, we identified LSD1 as a critical cellular target of CHS, directly binding to Lys661 and Tyr761 of LSD1 to inhibit its histone demethylation activity. Our results suggest that targeting intestinal LSD1 with CHS could be a promising strategy for MAFLD treatment, offering new insights into the bioavailability and efficacy of natural products.

DOI: 10.1038/s41401-024-01412-7

Source: https://www.nature.com/articles/s41401-024-01412-7