Demethyleneberberine attenuates non-alcoholic fatty liver disease with activation of AMPK and inhibition of oxidative stress
Demethyleneberberine attenuates non-alcoholic fatty liver disease with activation of AMPK and inhibition of oxidative stress
复制标题
去亚甲基小檗碱通过激活 AMPK 和抑制氧化应激来减轻非酒精性脂肪肝
DOI：
10.1016/j.bbrc.2016.03.019
复制
发表时间：
2016-04-15
影响因子：
3.1
通讯作者：
Zhang, Yubin
中科院分区：
文献类型：
--
作者：
Qiang, Xiaoyan;Xu, Lulu;Zhang, Yubin
非酒精性脂肪性肝病（NAFLD）已在全球范围内达到流行水平，通过氧化应激和炎症的“二次打击”模型认识到其形成非酒精性脂肪性肝炎（NASH）。 AMP激活蛋白激酶（AMPK）长期以来被认为是能量代谢的关键调节因子，被认为是NAFLD治疗的关键靶点。在这里，我们介绍一种天然产物，去甲小檗碱 (DMB)，它可以通过激活 AMPK 途径来改善 NAFLD。我们的研究表明，腹腔注射 DMB（20 或 40 mg/kg 体重）可减少蛋氨酸和胆碱缺乏 (MCD) 高脂饮食喂养小鼠和 db/db 小鼠的肝脏脂质积累。进一步的研究表明，DMB 通过增加体外和体内的磷酸化来激活 AMPK。伴随着 AMPK 的激活，在 DMB 治疗的 NAFLD 小鼠中，脂肪生成基因的表达显着降低，而负责脂肪酸 β-氧化的基因则得以恢复。此外，DMB 治疗可减轻 NAFLD 引起的显着氧化损伤和炎症，具体表现为脂质氧化产物、丙二醛 (MDA) 和炎症因子、肿瘤坏死因子 α (TNF α) 和白细胞介素 1 β (IL-β) 的减少。综上所述，DMB可以作为一种新型AMPK激活剂，通过抑制氧化应激和炎症来治疗NAFLD并预防从NAFLD向NASH的病理进展。 (C) 2016 Elsevier Inc. 保留所有权利。
Non-alcoholic fatty liver disease (NAFLD) has reached an epidemic level globally, which is recognized to form non-alcoholic steatohepatitis (NASH) by the "two-hit" model, including oxidative stress and inflammation. AMP-activated protein kinase (AMPK) has long been regarded as a key regulator of energy metabolism, which is recognized as a critical target for NAFLD treatment. Here we introduce a natural product, demethyleneberberine (DMB), which potentially ameliorated NAFLD by activating AMPK pathways. Our study showed that the intraperitoneal injection of DMB (20 or 40 mg/kg body weight) decreased hepatic lipid accumulation in methionine and choline deficient (MCD) high-fat diet feeding mice and db/db mice. The further investigation demonstrated that DMB activated AMPK by increasing its phosphorylation in vitro and in vivo. Accompanied with AMPK activation, the expression of lipogenic genes were significantly reduced while genes responsible for the fatty acid beta-oxidation were restored in DMB-treated NAFLD mice. In addition, the remarkable oxidative damage and inflammation induced by NAFLD were both attenuated by DMB treatment, which is reflected by decreased lipid oxidative product, malonaldehyde (MDA) and inflammatory factors, tumor necrosis factor alpha (TNF alpha) and interleukin 1 beta (IL-beta). Based on all above, DMB could serve as a novel AMPK activator for treating NAFLD and preventing the pathologic progression from NAFLD to NASH by inhibiting the oxidative stress and inflammation. (C) 2016 Elsevier Inc. All rights reserved.