Interdisciplinary Research Program of Bioinformatics and Longevity Science, Pusan National University, Busan 46241, Republic of Korea.
Department of Pharmacy, College of Pharmacy, Research Institute for Drug Development, Pusan National University, Busan 46241, Republic of Korea.
Int J Mol Sci. 2024 Sep 8;25(17):9730. doi: 10.3390/ijms25179730.
8-Prenylgenistein (8PG), a genistein derivative, is present in fermented soybeans (Glycine max), including cheonggukjang (CGJ), and exhibits osteoprotective, osteogenic, and antiadipogenic properties. However, the hepatoprotective effects of 8PG and its underlying molecular mechanisms remain largely unexplored. Here, we identified the high binding affinity of 8PG with AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), which acts as a potent AMPK activator that counteracts hepatic steatosis. Notably, 8PG exhibited better pharmacokinetics with greater absorption and higher plasma binding than the positive controls for the target proteins. Moreover, 8PG exerted non-carcinogenic activity in rats and significantly increased AMPK phosphorylation. Compound C, an AMPK inhibitor, did not antagonize 8PG-activated AMPK in HepG2 cells. 8PG significantly attenuated palmitate-induced lipid accumulation and enhanced phosphorylated AMPK and its downstream target, acetyl-CoA carboxylase. Further, 8PG activated nuclear SIRT1 at the protein level, which promoted fatty acid oxidation in palmitate-treated HepG2 cells. Overall, 8PG acts as a potent AMPK activator, further attenuating hepatic steatosis via the SIRT1-mediated pathway and providing new avenues for dietary interventions to treat metabolic dysfunction-associated steatotic liver disease (MASLD).
8- 异戊烯基染料木黄酮（8PG）是一种染料木黄酮衍生物，存在于发酵大豆（Glycine max）中，包括红曲（CGJ），具有护骨、成骨和抗脂肪生成特性。然而，8PG 的保肝作用及其潜在的分子机制在很大程度上仍未得到探索。在这里，我们确定了 8PG 与 AMP 激活的蛋白激酶（AMPK）和沉默调节蛋白 1（SIRT1）的高结合亲和力，后者作为一种有效的 AMPK 激活剂，可对抗肝脂肪变性。值得注意的是，8PG 表现出更好的药代动力学特性，具有更高的吸收率和更高的靶蛋白血浆结合率。此外，8PG 在大鼠中表现出非致癌活性，并显著增加 AMPK 磷酸化。AMPK 抑制剂 Compound C 不能拮抗 HepG2 细胞中 8PG 激活的 AMPK。8PG 显著减轻棕榈酸诱导的脂质积累，并增强磷酸化 AMPK 及其下游靶标乙酰辅酶 A 羧化酶。此外，8PG 在蛋白水平上激活核 SIRT1，促进棕榈酸处理的 HepG2 细胞中的脂肪酸氧化。总体而言，8PG 作为一种有效的 AMPK 激活剂，通过 SIRT1 介导的途径进一步减轻肝脂肪变性，为治疗与代谢功能障碍相关的脂肪性肝病（MASLD）的饮食干预提供了新途径。
