College of Pharmacy, Hubei University of Chinese Medicine, Wuhan, People's Republic of China.
Food Funct. 2019 Jun 19;10(6):3410-3420. doi: 10.1039/c9fo00284g.
Previous studies in humans have indicated that de novo lipogenesis contributes considerably to redundant lipid storage and steatosis in the liver of patients with nonalcoholic fatty liver disease (NAFLD), and then more severe complications occur. Recently, ellagic acid (EA) has drawn attention mainly due to its biological functionalities and a series of molecular targets. However, the molecular mechanism by which EA attenuates hepatic steatosis in individuals with undesirable hepatic genetic alterations remains rarely studied. Here, we evaluate the therapeutic efficacy of EA in a hepatic steatosis mouse model featuring elevated expression of sterol regulatory element-binding protein-1 (SREBP-1) and its downstream modulators of lipogenesis by hydrodynamic injection of v-akt murine thymoma viral oncogene homolog (AKT). Hematoxylin and eosin staining, oil red O staining, immunohistochemistry, immunoblotting, and quantitative polymerase chain reaction (qPCR) were performed for mechanistic investigations. Human hepatoma cell lines were used for mechanical validation in vitro. The results suggest that EA lightens the accumulation of lipids in hepatocytes of AKT-injected mice and an oleic acid-induced in vitro hepatic steatosis model. Mechanistically, EA administration decreases the expression of phospho-AKT (Thr308) and suppresses two effectors lying downstream of the AKT/mTORC1 pathway, ribosomal protein S6 (RPS6) and SREBP-1, in the AKT-injected mice. The consequence of the EA-mediated decrease of SREBP-1 is found to be a transcriptional and translational inhibition of fatty acid synthase (FASN), accompanied by the downregulation of acetyl-CoA carboxylase (ACC). Consistent with in vivo findings, EA efficiently represses the SREBP-1/FASN axis in vitro. Collectively, our study provides a novel mechanism whereby EA alleviates AKT-triggered hepatic de novo lipogenesis, indicating that EA might serve as a potential agent in the therapy of hepatic steatosis in patients with NAFLD and/or steatosis-associated complications, especially in that characterized by activation of AKT/mTORC1 signaling in the liver.
先前的人体研究表明，从头合成脂肪会导致非酒精性脂肪性肝病 (NAFLD) 患者肝脏中多余的脂质储存和脂肪变性，进而导致更严重的并发症。最近，由于其生物学功能和一系列分子靶点，鞣花酸 (EA) 引起了人们的关注。然而，EA 减轻具有不良肝遗传改变个体肝脂肪变性的分子机制仍很少研究。在这里，我们通过水动力注射 v-akt 鼠胸腺瘤病毒癌基因同源物 (AKT) 评估了 EA 在肝脂肪变性小鼠模型中的治疗效果，该模型表现出固醇调节元件结合蛋白-1 (SREBP-1) 及其下游脂肪生成调节剂的表达升高。进行了苏木精和曙红染色、油红 O 染色、免疫组织化学、免疫印迹和定量聚合酶链反应 (qPCR) 以进行机制研究。体外使用人肝癌细胞系进行机械验证。结果表明，EA 减轻了 AKT 注射小鼠肝细胞中脂质的积累和油酸诱导的体外肝脂肪变性模型。从机制上讲，EA 给药可降低 AKT 注射小鼠磷酸化 AKT (Thr308) 的表达，并抑制 AKT/mTORC1 途径下游的两个效应物核糖体蛋白 S6 (RPS6) 和 SREBP-1。发现 EA 介导的 SREBP-1 减少的结果是脂肪酸合酶 (FASN) 的转录和翻译抑制，伴随着乙酰辅酶 A 羧化酶 (ACC) 的下调。与体内发现一致，EA 有效地抑制了体外的 SREBP-1/FASN 轴。总之，我们的研究提供了一种新的机制，即 EA 缓解 AKT 触发的肝从头脂肪生成，表明 EA 可能作为 NAFLD 患者和/或与脂肪变性相关的并发症，尤其是在肝 AKT/mTORC1 信号激活的患者的肝脂肪变性治疗中的潜在药物。
