Dong Lile, Han Xu, Tao Xufeng, Xu Lina, Xu Youwei, Fang Linlin, Yin Lianhong, Qi Yan, Li Hua, Peng Jinyong
College of Pharmacy, Dalian Medical University, Western 9 Lvshunnan Road, Dalian 116044, China.
Foods. 2018 Jun 8;7(6):88. doi: 10.3390/foods7060088.
We previously reported the effects of the total flavonoids (TFs) from Michx fruit against carbon tetrachloride-induced liver damage, non-alcoholic fatty liver disease, and liver ischemia-reperfusion injury. However, there have been no papers reporting the role of TFs against lipopolysaccharide (LPS)-induced liver injury. In this paper, liver injury in mice was induced by LPS, and extract was intragastrically administered to the mice for 7 days. Biochemical parameters in serum and liver tissue were examined, and pathological changes were observed by transmission electron microscopy, hematoxylin and eosin (H&E) and Oil Red O staining. The results showed that the TFs markedly reduced serum ALT (alanine transferase), AST (aspartate transaminase), TG (total triglyceride), and TC (total cholesterol) levels and relative liver weights and improved liver pathological changes. In addition, the TFs markedly decreased tissue MDA (malondialdehyde) level and increased the levels of SOD (superoxide dismutase) and GSH-Px (glutathione peroxidase). A mechanistic study showed that the TFs significantly increased the expression levels of Nrf2 (nuclear erythroid factor2-related factor 2), HO-1 (heme oxygenase-1), NQO1 (NAD(P)H dehydrogenase (quinone 1), GCLC (glutamate-cysteine ligase catalytic subunit), and GCLM (glutamate-cysteine ligase regulatory subunit) and decreased Keap1 (Kelch-like ECH-associated protein 1) level by activating FXR (farnesoid X receptor) against oxidative stress. Furthermore, the TFs markedly suppressed the nuclear translocation of NF-κB (nuclear factor-kappa B) and subsequently decreased the expression levels of IL (interleukin)-1β, IL-6, HMGB-1 (high -mobility group box 1), and COX-2 (cyclooxygenase-2) by activating FXR and FOXO3a (forkhead box O3) against inflammation. Besides, the TFs obviously reduced the expression levels of SREBP-1c (sterol regulatory element-binding proteins-1c), ACC1 (acetyl-CoA carboxylase-1), FASN (fatty acid synthase), and SCD1 (stearoyl-coenzyme A desaturase 1), and improved CPT1 (carnitine palmitoyltransferase 1) level by activating FXR to regulate lipid metabolism. Our results suggest that TFs exhibited protective effect against LPS-induced liver injury by altering FXR-mediated oxidative stress, inflammation, and lipid metabolism, and should be developed as an effective food and healthcare product for the therapy of liver injury in the future.
我们之前报道了来自Michx果实的总黄酮（TFs）对四氯化碳诱导的肝损伤、非酒精性脂肪性肝病和肝缺血再灌注损伤的影响。然而，尚无文献报道TFs在脂多糖（LPS）诱导的肝损伤中的作用。在本文中，通过LPS诱导小鼠肝损伤，并对小鼠进行为期7天的提取物灌胃给药。检测血清和肝组织中的生化参数，并通过透射电子显微镜、苏木精-伊红（H&E）染色和油红O染色观察病理变化。结果表明，TFs显著降低血清谷丙转氨酶（ALT）、谷草转氨酶（AST）、总甘油三酯（TG）和总胆固醇（TC）水平以及相对肝脏重量，并改善肝脏病理变化。此外，TFs显著降低组织丙二醛（MDA）水平，提高超氧化物歧化酶（SOD）和谷胱甘肽过氧化物酶（GSH-Px）水平。机制研究表明，TFs通过激活法尼醇X受体（FXR）对抗氧化应激，显著提高核红细胞因子2相关因子2（Nrf2）、血红素加氧酶-1（HO-1）、醌氧化还原酶1（NQO1）、谷氨酸-半胱氨酸连接酶催化亚基（GCLC）和谷氨酸-半胱氨酸连接酶调节亚基（GCLM）的表达水平，并降低 Kelch样ECH相关蛋白1（Keap1）水平。此外，TFs通过激活FXR和叉头框O3（FOXO3a）对抗炎症，显著抑制核因子κB（NF-κB）的核转位，随后降低白细胞介素-1β（IL-1β）、白细胞介素-6、高迁移率族蛋白B1（HMGB-1）和环氧化酶-2（COX-2）的表达水平。此外，TFs通过激活FXR调节脂质代谢，明显降低固醇调节元件结合蛋白-1c（SREBP-1c）、乙酰辅酶A羧化酶-1（ACC1）、脂肪酸合酶（FASN）和硬脂酰辅酶A去饱和酶1（SCD1）的表达水平，并提高肉碱棕榈酰转移酶1（CPT1）水平。我们的结果表明，TFs通过改变FXR介导的氧化应激、炎症和脂质代谢，对LPS诱导的肝损伤具有保护作用，未来应开发成为治疗肝损伤的有效食品和保健品。
