Acanthoic acid modulates lipogenesis in nonalcoholic fatty liver disease via FXR/LXRs-dependent manner
Acanthoic acid modulates lipogenesis in nonalcoholic fatty liver disease via FXR/LXRs-dependent manner
复制标题
棘皮酸通过 FXR/LXR 依赖性方式调节非酒精性脂肪肝疾病的脂肪生成
DOI：
10.1016/j.cbi.2019.108794
复制
发表时间：
2019-09-25
影响因子：
5.1
通讯作者：
Wu, Yan-Ling
中科院分区：
文献类型：
--
作者：
Han, Xin;Cui, Zhen-Yu;Wu, Yan-Ling
胡萝卜酸（AA）是从五加科植物朝鲜五加中分离得到的一种海松二烯类二萜，具有抗炎和保肝作用。本研究拟通过激活法尼醇X受体（FXR）和肝X受体（LXRs）信号通路，揭示AA对脂质蓄积相关的非酒精性脂肪性肝病（NAFLD）的作用及其机制。C57 BL/6小鼠接受含有71%高脂肪（L-D）的改良Lieber-DeCarli饮食，并用AA（20和40 mg/kg）或等体积的盐水处理12周。在用棕榈酸（PA）促脂肪变性刺激的AML 12细胞中也检测到AA对脂质积累的调节。当用AA处理L-D饮食喂养的小鼠时，观察到体重、肝脏指数和肝脏脂滴的减轻以及甘油三酯（TG）和血清转氨酶的降低。此外，AA还能降低固醇调节元件结合蛋白1（SREBP-1）及其靶基因的表达，调节PPAR α和PPAR γ的表达，改善肝纤维化指标，增强肝脏FXR和LXR，调节AMPK-LKB1和SIRT1信号通路。此外，AA通过FXR和LXR活化在脂肪变性AML-12细胞中减弱脂质蓄积，这通过guggulsterones（FXR拮抗剂）或GW3965（LXR激动剂）证实。AA激活FXR和LXR信号通路可能通过增加AMPK-SIRT1信号通路参与调节脂质蓄积和脂肪酸合成，提示AA激活FXR-LXR轴是缓解NAFLD的有效策略。
Acanthoic acid (AA) is a pimaradiene diterpene isolated from Acanthopanax koreanum Nakai (Araliaceae), with anti-inflammatory and hepatic-protective effects. The present study intended to reveal the effect and mechanism of AA on nonalcoholic fatty liver disease (NAFLD) associated with lipid accumulation by activating Farnesoid X receptor (FXR) and liver X receptors (LXRs) signaling. C57BL/6 mice were received a modified Lieber-DeCarli diet with 71% high-fat (L-D) and treated with AA (20 and 40 mg/kg) or equal volume of saline for 12 weeks. The regulation of AA on lipid accumulation was also detected in pro-steatotic stimulated AML12 cells with palmitic acid (PA). When L-D diet-fed mice were treated with AA, loss in body weight, liver index, and liver lipid droplet were observed along with reduced triglyceride (TG) and serum transaminase. Furthermore, AA decreased sterol regulatory element binding protein 1 (SREBP-1) and target genes expression, regulated PPAR alpha and PPAR gamma expressions, ameliorated hepatic fibrosis markers, enhanced hepatic FXR and LXR, and regulated AMPK-LKB1 and SIRT1 signaling pathway. Moreover, AA attenuated lipid accumulation via FXR and LXR activation in steatotic AML-12 cells, which was confirmed by guggulsterones (FXR antagonist) or GW3965 (LXR agonist). Activation of FXR and LXR signaling caused by AA might increase AMPK-SIRT1 signaling and then contribute to modulating lipid accumulation and fatty acid synthesis, which suggested that activated FXR-LXR axis by AA represented an effective strategy for relieving NAFLD.