Department of Life Sciences, College of Arts and Sciences, New York Institute of Technology, Old Westbury, NY 11568, USA.
Department of Biomedical Sciences, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY 11568, USA.
Nutrients. 2018 Apr 25;10(5):531. doi: 10.3390/nu10050531.
Non-alcoholic fatty liver disease (NAFLD) affects more than 70% of patients with type 2 diabetes mellitus (T2DM) and has become one of the most common metabolic liver diseases worldwide. To date, treatments specifically targeting NAFLD do not exist. Oxidative stress and insulin resistance have been implicated in the pathogenesis of NAFLD in diabetes. Accordingly, the goal of this present study was to determine whether Ellagic acid (EA), a natural antioxidant polyphenol found in berries and nuts, mitigates hepatic oxidative stress and insulin resistance in T2DM rats, and thus alleviates NAFLD. Using adult female Goto Kakizaki (GK) rats, a non-obese and spontaneous model of T2DM, we found that EA treatment significantly lowered fasting blood glucose and reduced insulin resistance, as shown by a 21.8% reduction in the homeostasis model assessment index of insulin resistance (HOMA-IR), while triglyceride and total cholesterol levels remained unchanged. Increased hepatic lipid accumulation and oxidative stress present in diabetic GK rats was markedly reduced with EA treatment. This effect was associated with a downregulation of the NADPH oxidase subunit, p47-phox, and overexpression of NF-E2-related factor-2 (NRF2). Moreover, EA was able to decrease the hepatic expression of hypoxia-inducible factor (HIF-α), a transcription factor linked to hypoxia and hepatic steatosis. We further showed that EA treatment activated an insulin signaling pathway in the liver, as evidenced by increased levels of phosphorylated Akt (Ser 473). In conclusion, our results demonstrate that EA diminishes blood glucose levels and potently suppress NAFLD in diabetic rats via mechanisms that involve reductions in p47-phox and HIF-α, upregulation of NRF2 and enhancement of the Akt signaling pathway in the liver. Together, these results reveal that EA improves hepatic insulin sensitivity and lipid metabolism as a result of its antioxidant effects. This implies an anti-diabetic effect of EA with beneficial effects for the treatment of hepatic complications in T2DM.
非酒精性脂肪性肝病（NAFLD）影响超过 70%的 2 型糖尿病（T2DM）患者，已成为全球最常见的代谢性肝病之一。迄今为止，尚无专门针对 NAFLD 的治疗方法。氧化应激和胰岛素抵抗与糖尿病 NAFLD 的发病机制有关。因此，本研究旨在确定是否鞣花酸（EA），一种存在于浆果和坚果中的天然抗氧化多酚，可以减轻 T2DM 大鼠的肝氧化应激和胰岛素抵抗，从而缓解 NAFLD。使用成年雌性 Goto Kakizaki（GK）大鼠，一种非肥胖和自发性 T2DM 模型，我们发现 EA 治疗可显著降低空腹血糖并降低胰岛素抵抗，表现为胰岛素抵抗的稳态模型评估指数（HOMA-IR）降低 21.8%，而甘油三酯和总胆固醇水平保持不变。GK 糖尿病大鼠肝内脂质堆积和氧化应激增加明显减少，与 EA 治疗有关。这种作用与 NADPH 氧化酶亚基 p47-phox 的下调和核因子 E2 相关因子 2（NRF2）的过表达有关。此外，EA 能够降低与缺氧和肝脂肪变性相关的转录因子缺氧诱导因子（HIF-α）在肝脏中的表达。我们进一步表明，EA 治疗通过增加磷酸化 Akt（Ser 473）的水平，激活了肝脏中的胰岛素信号通路。总之，我们的结果表明，EA 通过降低 p47-phox 和 HIF-α、上调 NRF2 和增强 Akt 信号通路，降低血糖水平并有效抑制糖尿病大鼠的 NAFLD。这些结果表明，EA 通过其抗氧化作用改善肝脏胰岛素敏感性和脂质代谢，从而具有抗糖尿病作用，对治疗 T2DM 肝并发症有益。
