Polydatin prevents fructose-induced liver inflammation and lipid deposition through increasing miR-200a to regulate Keap1/Nrf2 pathway.
Polydatin prevents fructose-induced liver inflammation and lipid deposition through increasing miR-200a to regulate Keap1/Nrf2 pathway.
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虎杖苷通过增加 miR-200a 调节 Keap1/Nrf2 通路来预防果糖诱导的肝脏炎症和脂质沉积
DOI：
10.1016/j.redox.2018.07.002
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发表时间：
2018-09
期刊：
影响因子：
11.4
通讯作者：
Kong LD
中科院分区：
文献类型：
--
作者：
Zhao XJ;Yu HW;Yang YZ;Wu WY;Chen TY;Jia KK;Kang LL;Jiao RQ;Kong LD
氧化应激是非酒精性脂肪肝发病机制中的一个关键因素。MicroRNA-200 a（miR-200 a）被报道靶向Kelch-like ECH相关蛋白1（Keap 1），其调节核因子红细胞2相关因子2（Nrf 2）抗氧化途径。虎杖苷（3，4 ′，5-trihydroxy-stilbene-3-β-D-glucoside）是虎杖根茎中的一种多酚类化合物，具有抗氧化、抗炎、降血脂等作用。然而，miR-200 a是否控制果糖诱导的肝脏炎症和脂质沉积中的Keap 1/Nrf 2通路以及虎杖苷的阻断作用仍不清楚。在此，我们检测了miR-200 a下调、Keap 1上调、Nrf 2抗氧化途径失活、ROS驱动的硫氧还蛋白相互作用蛋白（TXNIP）过表达、NOD样受体（NLR）家族、含pyrin结构域3（NLRP 3）的炎性小体激活以及过氧化物酶体增殖物激活受体-α（PPAR-α）、肉毒碱棕榈酰转移酶-1（CPT-1）、在高果糖诱导下，大鼠肝脏、BRL-3A和HepG 2细胞中的固醇调节元件结合蛋白1（SREBP-1）和硬脂酰辅酶A去饱和酶1（SCD-1）。此外，通过miR-200 a minic、Keap 1和TXNIP siRNA、Nrf 2激活剂和ROS抑制剂处理或转染的数据表明，果糖诱导的miR-200 a低表达增加Keap 1从而阻断Nrf 2抗氧化途径，然后增强ROS驱动的TXNIP从而激活NLRP 3炎性体并干扰脂质代谢相关蛋白，导致BRL-3A细胞中的炎症和脂质沉积。我们还发现虎杖苷上调miR-200 a以抑制Keap 1并激活Nrf 2抗氧化途径，从而在这些动物和细胞模型中减弱这些干扰。这些发现为果糖诱导的氧化还原状态失衡提供了一种新的病理机制，并表明虎杖苷增强miR-200 a控制Keap 1/Nrf 2通路是果糖相关肝脏炎症和脂质沉积的治疗策略。果糖降低miR-200 a表达以损害NAFLD中的Keap 1/Nrf 2通路。MiR-200 a驱动的氧化应激是果糖诱导的NAFLD的原因。虎杖苷上调miR-200 a对果糖诱导的NAFLD中Keap 1/Nrf 2通路的调节作用虎杖苷降低果糖引起的氧化应激，炎症和脂质沉积。通过虎杖苷增强miR-200 a表达是NAFLD的治疗策略。
Oxidative stress is a critical factor in nonalcoholic fatty liver disease pathogenesis. MicroRNA-200a (miR-200a) is reported to target Kelch-like ECH-associated protein 1 (Keap1), which regulates nuclear factor erythroid 2-related factor 2 (Nrf2) anti-oxidant pathway. Polydatin (3,4′,5-trihydroxy-stilbene-3-β-D-glucoside), a polyphenol found in the rhizome of Polygonum cuspidatum, have anti-oxidative, anti-inflammatory and anti-hyperlipidemic effects. However, whether miR-200a controls Keap1/Nrf2 pathway in fructose-induced liver inflammation and lipid deposition and the blockade of polydatin are still not clear. Here, we detected miR-200a down-regulation, Keap1 up-regulation, Nrf2 antioxidant pathway inactivation, ROS-driven thioredoxin-interacting protein (TXNIP) over-expression, NOD-like receptor (NLR) family, pyrin domain containing 3 (NLRP3) inflammasome activation and dysregulation of peroxisome proliferator activated receptor-α (PPAR-α), carnitine palmitoyl transferase-1 (CPT-1), sterol regulatory element binging protein 1 (SREBP-1) and stearoyl-CoA desaturase-1 (SCD-1) in rat livers, BRL-3A and HepG2 cells under high fructose induction. Furthermore, the data from the treatment or transfection of miR-200a minic, Keap1 and TXNIP siRNA, Nrf2 activator and ROS inhibitor demonstrated that fructose-induced miR-200a low-expression increased Keap1 to block Nrf2 antioxidant pathway, and then enhanced ROS-driven TXNIP to activate NLRP3 inflammasome and disturb lipid metabolism-related proteins, causing inflammation and lipid deposition in BRL-3A cells. We also found that polydatin up-regulated miR-200a to inhibit Keap1 and activate Nrf2 antioxidant pathway, resulting in attenuation of these disturbances in these animal and cell models. These findings provide a novel pathological mechanism of fructose-induced redox status imbalance and suggest that the enhancement of miR-200a to control Keap1/Nrf2 pathway by polydatin is a therapeutic strategy for fructose-associated liver inflammation and lipid deposition. Fructose decreases miR-200a expression to impair Keap1/Nrf2 pathway in NAFLD. MiR-200a-driven oxidative stress is a causer in fructose-induced NAFLD. Polydatin elevates miR-200a to regulate Keap1/Nrf2 pathway in fructose-induced NAFLD. Polydatin lowers fructose-caused oxidative stress, inflammation and lipid deposition. Enhancement of miR-200a expression by polydatin is a therapeutic strategy for NAFLD.
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