School of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui, 230011, People's Republic of China.
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang, 550014, People's Republic of China.
Int J Nanomedicine. 2024 Oct 25;19:10839-10856. doi: 10.2147/IJN.S485084. eCollection 2024.
Metabolic dysfunction-associated steatotic liver disease (MASLD), the most prevalent chronic liver disorder, has garnered increasing attention globally owing to its associated health complications. However, the lack of available therapeutic medications and inadequate management of complications in metabolic dysfunction-associated steatohepatitis (MASH) present significant challenges. There are little studies evaluating the effectiveness of POM in treating MASLD. In this study, we synthesized polyoxometalates (POM) for potential treatment of MASLD.
We induced liver disease in mice using two approaches: feeding a high-fat diet (HFD) to establish MASLD or feeding a methionine-choline deficient (MCD) diet to induce hepatic lipotoxicity and MASH. Various metabolic parameters were detected, and biochemical and histological evaluations were conducted on MASLD. Western blotting, qRT-PCR and immunofluorescence assays were used to elucidate the molecular mechanism of POM in the treatment of MASLD.
POM therapy resulted in significant improvements in weight gain, dyslipidemia, liver injury, and hepatic steatosis in mice fed a HFD. Notably, in a more severe dietary-induced MASH model with MCD diet, POM significantly attenuated hepatic lipid accumulation, inflammation, and fibrosis. POM treatment effectively attenuated palmitic acid and oleic acid-induced lipid accumulation in HepG2 and Huh7 cells by targeting the AMPK pathway to regulate lipid metabolism, which was confirmed by AMPK inhibitor. Additionally, the activation of AMPK signaling by POM suppressed the expression of lipid synthesis genes, including sterol regulatory element-binding protein 1c (SREBP1c) and SREBP2, while concurrently upregulating the expression of sirtuin 1 (SIRT1) to promote fatty acid oxidation.
These findings suggest that POM is a promising therapeutic strategy with high efficacy in multiple MASLD models.
代谢相关脂肪性肝病（MASLD）是最常见的慢性肝脏疾病，由于其相关的健康并发症，在全球范围内受到越来越多的关注。然而，代谢相关性脂肪性肝炎（MASH）缺乏可用的治疗药物和并发症管理不足，这是目前面临的重大挑战。目前评估磷钼杂多酸盐（POM）治疗 MASLD 效果的研究较少。在本研究中，我们合成了磷钼杂多酸盐（POM），以探索其治疗 MASLD 的潜力。
我们通过两种方法诱导小鼠发生肝病：高脂饮食（HFD）喂养以建立 MASLD 或甲硫氨酸-胆碱缺乏（MCD）饮食诱导肝毒性和 MASH。检测各种代谢参数，并对 MASLD 进行生化和组织学评估。Western blot、qRT-PCR 和免疫荧光检测用于阐明 POM 治疗 MASLD 的分子机制。
POM 治疗可显著改善 HFD 喂养小鼠的体重增加、血脂异常、肝损伤和肝脂肪变性。值得注意的是，在更严重的 MCD 饮食诱导的 MASH 模型中，POM 显著减轻了肝脂肪堆积、炎症和纤维化。POM 治疗通过靶向 AMPK 通路调节脂质代谢，有效抑制棕榈酸和油酸诱导的 HepG2 和 Huh7 细胞内脂质堆积，这一作用可被 AMPK 抑制剂所阻断。此外，POM 通过激活 AMPK 信号通路，抑制固醇调节元件结合蛋白 1c（SREBP1c）和 SREBP2 等脂质合成基因的表达，同时上调 SIRT1 的表达，促进脂肪酸氧化，从而抑制脂质合成。
这些发现表明，POM 是一种很有前途的治疗策略，在多种 MASLD 模型中具有高效性。
